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1.	Sharma, Hari S., et al. (författare) Cerebrolysin Attenuates Heat Shock Protein (HSP 72 KD) Expression in the Rat Spinal Cord Following Morphine Dependence and Withdrawal : Possible New Therapy for Pain Management 2011 Ingår i: Current Neuropharmacology. - 1570-159X .- 1875-6190. ; 9:1, s. 223-235 Tidskriftsartikel (refereegranskat)abstract The possibility that pain perception and processing in the CNS results in cellular stress and may influence heat shock protein (HSP) expression was examined in a rat model of morphine dependence and withdrawal. Since activation of pain pathways result in exhaustion of growth factors, we examined the influence of cerebrolysin, a mixture of potent growth factors (BDNF, GDNF, NGF, CNTF etc,) on morphine induced HSP expression. Rats were administered morphine (10 mg/kg, s.c. /day) for 12 days and the spontaneous withdrawal symptoms were developed by cessation of the drug administration on day 13(th) that were prominent on day 14(th) and continued up to day 15(th) (24 to 72 h periods). In a separate group of rats, cerebrolysin was infused intravenously (5 ml/kg) once daily from day one until day 15(th). In these animals, morphine dependence and withdrawal along with HSP immunoreactivity was examined using standard protocol. In untreated group mild HSP immunoreaction was observed during morphine tolerance, whereas massive upregulation of HSP was seen in CNS during withdrawal phase that correlated well with the withdrawal symptoms and neuronal damage. Pretreatment with cerebrolysin did not affect morphine tolerance but reduced the HSP expression during this phase. Furthermore, cerebrolysin reduced the withdrawal symptoms on day 14(th) to 15(th). Taken together these observations suggest that cellular stress plays an important role in morphine induced pain pathology and exogenous supplement of growth factors, i.e. cerebrolysin attenuates HSP expression in the CNS and induce neuroprotection. This indicates a new therapeutic role of cerebrolysin in the pathophysiology of drugs of abuse, not reported earlier.
2.	Huang, Hongyun, et al. (författare) Beijing declaration of International Association of Neurorestoratology (2023 Xi'an version) 2023 Ingår i: Journal of Neurorestoratology. - : Elsevier. - 2324-2426. ; 11:2 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
3.	Huang, Hongyun, et al. (författare) Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017) 2018 Ingår i: Cell Transplantation. - : SAGE Publications. - 0963-6897 .- 1555-3892. ; 27:2, s. 310-324 Forskningsöversikt (refereegranskat)abstract Cell therapy has been shown to be a key clinical therapeutic option for central nervous system diseases or damage. Standardization of clinical cell therapy procedures is an important task for professional associations devoted to cell therapy. The Chinese Branch of the International Association of Neurorestoratology (IANR) completed the first set of guidelines governing the clinical application of neurorestoration in 2011. The IANR and the Chinese Association of Neurorestoratology (CANR) collaborated to propose the current version "Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017)". The IANR council board members and CANR committee members approved this proposal on September 1, 2016, and recommend it to clinical practitioners of cellular therapy. These guidelines include items of cell type nomenclature, cell quality control, minimal suggested cell doses, patient-informed consent, indications for undergoing cell therapy, contraindications for undergoing cell therapy, documentation of procedure and therapy, safety evaluation, efficacy evaluation, policy of repeated treatments, do not charge patients for unproven therapies, basic principles of cell therapy, and publishing responsibility.
4.	Huang, Hongyun, et al. (författare) Review of clinical neurorestorative strategies for spinal cord injury : Exploring history and latest progresses 2018 Ingår i: JOURNAL OF NEURORESTORATOLOGY. - : TSINGHUA UNIV PRESS. - 2324-2426. ; 6, s. 171-178 Forskningsöversikt (refereegranskat)abstract Clinical neurorestorative therapies recently made great progress for patients with spinal cord injury (SCI). This paper systemically reviews historical perspectives, recent advancements and achievements in SCI through key neurorestorative strategies. In this study, a search was performed in the PubMed, Scopus, and Scholar Google search engines using the keywords "neurorestorative strategies", "spinal cord injury", "cell therapy", "neuromodulation", and "nerve bridges". Clinical studies published in the English language were included. It is paramount for academic community involved in this field to take the initiative of a multicenter randomized, double-blind, and placebo-control clinical study with high level of evidence-based treatments for most SCI neurorestorative strategies in patient management. It is of utmost need to establish standard therapeutic methods for patients with SCI as early as possible.
5.	Menon, Preeti K., et al. (författare) Intravenous Administration of Functionalized Magnetic Iron Oxide Nanoparticles Does Not Induce CNS Injury in the Rat : Influence of Spinal Cord Trauma and Cerebrolysin Treatment 2017 Ingår i: Nanomedicine In Central Nervous System Injury And Repair. - : Elsevier. - 9780128123812 ; , s. 47-63 Bokkapitel (refereegranskat)abstract Influence of iron oxide magnetic nanoparticles (IOMNPs, 10nm in diameter, 0.25 or 0.50mg/mL in 100 mu L, i.v.) on the blood-brain barrier (BBB) permeability, edema formation, and neuronal or glial changes within 4-24h after administration was examined in normal rats and after a focal spinal cord injury (SCI). Furthermore, effect of cerebrolysin, a balanced composition of several neurotrophic factors, and active peptide fragments was also evaluated on IOMNP-induced changes in central nervous system (CNS) pathology. The SCI was inflicted in rats by making a longitudinal incision into the right dorsal horn of the T10-11 segments and allowed to survive 4 or 24h after trauma. Cerebrolysin (2.5 mL/kg, i.v.) was given either 30min before IOMNP injection in the 4-h SCI group or 4h after injury in the 24-h survival groups. Control group received cerebrolysin in identical situation following IOMNP administration. In all groups, leakage of serum albumin in the CNS as a marker of BBB breakdown and activation of astrocytes using glial fibrillary acidic protein was evaluated by immunohistochemistry. The neuronal injury was examined by Nissl staining. The IOMNPs alone in either low or high doses did not induce CNS pathology either following 4 or 24h after administration. However, administration of IOMNPs in SCI group slightly enhanced the pathological changes in the CNS after 24h but not 4h after trauma. Cerebrolysin treatment markedly attenuated IOMNP-induced aggravation of SCI-induced cord pathology and induced significant neuroprotection. These observations are the first to show that IOMNPs are safe for the CNS and cerebrolysin treatment prevented CNS pathology following a combination of trauma and IOMNP injection. This indicated that cerebrolysin might be used as adjunct therapy during IOMNP administration in disease conditions, not reported earlier.
6.	Muresanu, Dafin F., et al. (författare) Cerebrolysin restores amino acid neurotransmitters balance in the brain following traumatic head injury : an experimental study in the rat 2013 Ingår i: Amino Acids. - 0939-4451 .- 1438-2199. ; 45:3, s. 565-565 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
7.	Muresanu, Dafin F, et al. (författare) Chronic hypertension aggravates heat stress induced cognitive dysfunction and brain pathology : an experimental study in the rat, using growth hormone therapy for possible neuroprotection 2007 Ingår i: Neuroprotective agents. - : Wiley. ; , s. 1-22 Konferensbidrag (refereegranskat)abstract Hyperthermia following heat stress results in profound brain edema formation and damage to the central nervous system (CNS). However, whether acute or chronic diseases such as cardiovascular, endocrine, or metabolic ailments further influence the vulnerability of human populations to heat-related deaths is still unclear. In this investigation, we examined the effect of hyperthermia on chronic hypertensive rats. The influence of growth hormone (GH) as a therapy to attenuate brain dysfunction was also evaluated. Subjecting rats to 4 h of heat stress at 38°C in a biological oxygen demand (BOD) incubator resulted in profound impairment of motor and cognitive functions, breakdown of the blood-brain barrier (BBB), reduction in regional cerebral blood flow (CBF), edema formation, and brain damage. These effects were further aggravated when chronic hypertensive rats (two-kidney, one-clip model for 4 weeks) were subjected to similar hyperthermic conditions (38°C for 4 h). Interestingly, the behavioral alterations and impairment of motor and cognitive functions in hypertensive rats were much worse than those in the normotensive animals subjected to heat stress. Pretreatment with GH (50 μg/kg/min i.v. for 60 min, before heat stress) significantly attenuated behavioral and cognitive deficits in normotensive rats and reduced the BBB dysfunction and brain pathology. On the other hand, similar treatment with GH in hypertensive animals only mildly reduced brain damage or cognitive dysfunction after heat stress. These novel observations indicate that patients suffering from various chronic diseases respond differently to various health hazards such as hyperthermia and to other neuroprotective agents.
8.	Muresanu, Dafin F., et al. (författare) Diabetes aggravates heat stress-induced blood-brain barrier breakdown, reduction in cerebral blood flow, edema formation, and brain pathology : Possible neuroprotection with growth hormone 2010 Ingår i: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923 .- 1749-6632. ; 1199, s. 15-26 Tidskriftsartikel (refereegranskat)abstract The possibility that diabetes influences the outcome of heat stress-induced brain pathology was examined in our experimental rat model. Because growth hormone (GH) deficiency is an important factor in diabetes, the possible neuroprotective role of GH supplements was also examined in diabetic rats following heat stress. Rats receiving streptozotocine once daily for three days (50 mg/kg, i.p.) and allowed to survive four weeks resulted in diabetes (blood glucose level 18 and 20 mMol/L) compared to controls (blood glucose 4-6 mMol/L). Control or diabetic rats when subjected to four hours' heat stress at 38 degrees C in a biological oxygen demand incubator (BOD) showed profound disruption of the blood-brain barrier (BBB), reduction in cerebral blood flow (CBF), brain edema formation, and cell injury. These effects were most pronounced in diabetic rats. Pretreatment with GH (50 mu g/kg/min for 10 min before heat stress) significantly attenuated brain pathology in normal animals subjected to hyperthermia. On the other hand, almost a double dose of the growth hormone (80 to 120 mu g/g/min for 10 min) is needed in diabetic rats to induce considerable neuroprotection following heat stress. These observations are the first to suggest that diabetic rats are more vulnerable to heat stress-induced brain pathology and further show that the efficacy of neuroprotective drugs is also severely reduced in diabetic rats. Taken together, our results demonstrate that the dosage of neuroprotective drugs requires adjustment to enhance neuroprotection depending on the patient's endocrine or metabolic status, for example, diabetes mellitus, a finding not reported earlier.
9.	Muresanu, Dafin F., et al. (författare) Diabetes exacerbates brain pathology following a focal blast brain injury : New role of a multimodal drug cerebrolysin and nanomedicine 2020 Ingår i: Neuropharmacology of Neuroprotection. - : ELSEVIER. - 9780128208137 ; 258, s. 285-367 Bokkapitel (refereegranskat)abstract Blast brain injury (bBI) is a combination of several forces of pressure, rotation, penetration of sharp objects and chemical exposure causing laceration, perforation and tissue losses in the brain. The bBI is quite prevalent in military personnel during combat operations. However, no suitable therapeutic strategies are available so far to minimize bBI pathology. Combat stress induces profound cardiovascular and endocrine dysfunction leading to psychosomatic disorders including diabetes mellitus (DM). This is still unclear whether brain pathology in bBI could exacerbate in DM. In present review influence of DM on pathophysiology of bBI is discussed based on our own investigations. In addition, treatment with cerebrolysin (a multimodal drug comprising neurotrophic factors and active peptide fragments) or H-290/51 (a chain-breaking antioxidant) using nanowired delivery of for superior neuroprotection on brain pathology in bBI in DM is explored. Our observations are the first to show that pathophysiology of bBI is exacerbated in DM and TiO2-nanowired delivery of cerebrolysin induces profound neuroprotection in bBI in DM, not reported earlier. The clinical significance of our findings with regard to military medicine is discussed.
10.	Muresanu, Dafin F., et al. (författare) Nanodelivery of cerebrolysin induces profound neuroprotection in heat stroke following chronic hypertension in combination with carbon nanoparticles induced exacerbation of brain damage 2016 Ingår i: Brain Injury. - 0269-9052 .- 1362-301X. ; 30:5-6, s. 506-507 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
11.	Muresanu, Dafin F., et al. (författare) Nanowired Delivery of Growth Hormone Attenuates Pathophysiology of Spinal Cord Injury and Enhances Insulin-Like Growth Factor-1 Concentration in the Plasma and the Spinal Cord 2015 Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 52:2, s. 837-845 Tidskriftsartikel (refereegranskat)abstract Previous studies from our laboratory showed that topical application of growth hormone (GH) induced neuroprotection 5 h after spinal cord injury (SCI) in a rat model. Since nanodelivery of drugs exerts superior neuroprotective effects, a possibility exists that nanodelivery of GH will induce long-term neuroprotection after a focal SCI. SCI induces GH deficiency that is coupled with insulin-like growth factor-1 (IGF-1) reduction in the plasma. Thus, an exogenous supplement of GH in SCI may enhance the IGF-1 levels in the cord and induce neuroprotection. In the present investigation, we delivered TiO2-nanowired growth hormone (NWGH) after a longitudinal incision of the right dorsal horn at the T10-11 segments in anesthetized rats and compared the results with normal GH therapy on IGF-1 and GH contents in the plasma and in the cord in relation to blood-spinal cord barrier (BSCB) disruption, edema formation, and neuronal injuries. Our results showed a progressive decline in IGF-1 and GH contents in the plasma and the T9 and T12 segments of the cord 12 and 24 h after SCI. Marked increase in the BSCB breakdown, as revealed by extravasation of Evans blue and radioiodine, was seen at these time points after SCI in association with edema and neuronal injuries. Administration of NWGH markedly enhanced the IGF-1 levels and GH contents in plasma and cord after SCI, whereas normal GH was unable to enhance IGF-1 or GH levels 12 or 24 h after SCI. Interestingly, NWGH was also able to reduce BSCB disruption, edema formation, and neuronal injuries after trauma. On the other hand, normal GH was ineffective on these parameters at all time points examined. Taken together, our results are the first to demonstrate that NWGH is quite effective in enhancing IGF-1 and GH levels in the cord and plasma that may be crucial in reducing pathophysiology of SCI.
12.	Muresanu, Dafin F., et al. (författare) Nanowired Drug Delivery of Antioxidant Compound H-290/51 Enhances Neuroprotection in Hyperthermia-Induced Neurotoxicity 2012 Ingår i: CNS & Neurological Disorders. - : Bentham Science Publishers Ltd.. - 1871-5273 .- 1996-3181. ; 11:1, s. 50-64 Forskningsöversikt (refereegranskat)abstract Nanoparticles from the environment or through industrial sources can induce profound alterations in human health, often leading to brain dysfunction. However, it is still unclear whether nanoparticle intoxication could also alter the physiological or pathological responses of additional brain injury, stress response or disease processes. Military personals engaged in combat or peacekeeping operations are often exposed to nanoparticles from various environmental sources, e.g., Ag, Cu, Si, C, Al. In addition, these military personals are often exposed to high environmental heat, or gun and missle explosion injury leading to head or spinal trauma. Thus it is likely that additional CNS injury or stress-induced pathophysiological processes are influenced by nanoparticle intoxication. In this situation, when a combination of nanoparticles and central nervous system (CNS) injury or stress exist together, drug therapy needed to correct these anomalies may not work as effectively as in normal situation. Previous studies from our laboratory show that nanoparticle-intoxicated animals when subjected to hyperthermia resulted in exacerbation of brain pathology. In these animals, antioxidant compounds, e.g., H-290/51 that inhibits free radical formation and induces marked neuroprotection in normal rats after heat stress, failed to protect brain damage when a combination of nanoparticles and heat exposure was used. However, nanowired H-290/51 resulted in better neuroprotection in nanoparticles intoxicated animals after heat stress. Interestingly, high doses of the normal compound induced some neuroprotection in these nanoparticle-treated, heat-stressed rats. These observations suggest that a combination of nanoparticles and heat stress is dangerous and in such situations modification of drug dosage is needed to achieve comparable neuroprotection. In this review possible mechanisms of nanoparticle-induced exacerbation of heat induced neurotoxicity and brain protection achieved by nanowired drug delivery is discussed that is largely based on our own investigations.
13.	Niu, Feng, et al. (författare) Co-administration of TiO2-nanowired DL-3-n-butylphthalide (DL-NBP) and mesenchymal stem cells enhanced neuroprotection in Parkinson's disease exacerbated by concussive head injury 2020 Ingår i: Neuropharmacology of Neuroprotection. - : ELSEVIER. - 9780128208137 ; , s. 101-155 Bokkapitel (refereegranskat)abstract DL-3-n-butylphthalide (DL-NBP) is a powerful antioxidant compound with profound neuroprotective effects in stroke and brain injury. However, its role in Parkinson's disease (PD) is not well known. Traumatic brain injury (TBI) is one of the key factors in precipitating PD like symptoms in civilians and particularly in military personnel. Thus, it would be interesting to explore the possible neuroprotective effects of NBP in PD following concussive head injury (CHI). In this chapter effect of nanowired delivery of NBP together with mesenchymal stem cells (MSCs) in PD with CHI is discussed based on our own investigations. It appears that CHI exacerbates PD pathophysiology in terms of p-tau, alpha-synuclein (ASNC) levels in the cerebrospinal fluid (CSF) and the loss of TH immunoreactivity in substantia niagra pars compacta (SNpc) and striatum (STr) along with dopamine (DA), dopamine decarboxylase (DOPAC). And homovanillic acid (HVA). Our observations are the first to show that a combination of NBP with MSCs when delivered using nanowired technology induces superior neuroprotective effects in PD brain pathology exacerbated by CHI, not reported earlier.
14.	Niu, Feng, et al. (författare) Nanodelivery of oxiracetam enhances memory, functional recovery and induces neuroprotection following concussive head injury 2021 Ingår i: Progress in Brain Research. - Amsterdam : Elsevier. - 0079-6123 .- 1875-7855. ; 265, s. 139-230, s. 139-230 Tidskriftsartikel (refereegranskat)abstract Military personnel are the most susceptible to concussive head injury (CHI) caused by explosion, blast or missile or blunt head trauma. Mild to moderate CHI could induce lifetime functional and cognitive disturbances causing significant decrease in quality of life. Severe CHI leads to instant death and lifetime paralysis. Thus, further exploration of novel therapeutic agents or new features of known pharmacological agents are needed to enhance quality of life of CHI victims.Previous reports from our laboratory showed that mild CHI induced by weight drop technique causing an impact of 0.224 N results in profound progressive functional deficit, memory impairment and brain pathology from 5 h after trauma that continued over several weeks of injury.In this investigation we report that TiO2 nanowired delivery of oxiracetam (50 mg/kg, i.p.) daily for 5 days after CHI resulted in significant improvement of functional deficit on the 8th day. This was observed using Rota Rod treadmill, memory improvement assessed by the time spent in finding hidden platform under water. The motor function improvement is seen in oxiracetam treated CHI group by placing forepaw on an inclined mesh walking and foot print analysis for stride length and distance between hind feet. TiO2-nanowired oxiracetam also induced marked improvements in the cerebral blood flow, reduction in the BBB breakdown and edema formation as well as neuroprotection of neuronal, glial and myelin damages caused by CHI at light and electron microscopy on the 7th day after 5 days TiO2 oxiracetam treatment. Adverse biochemical events such as upregulation of CSF nitrite and nitrate, IL-6, TNF-a and p-Tau are also reduced significantly in oxiracetam treated CHI group. On the other hand post treatment of 100 mg/kg dose of normal oxiracetam in identical conditions after CHI is needed to show slight but significant neuroprotection together with mild recovery of memory function and functional deficits on the 8th day. These observations are the first to point out that nanowired delivery of oxiracetam has superior neuroprotective ability in CHI. These results indicate a promising clinical future of TiO2 oxiracetam in treating CHI patients for better quality of life and neurorehabilitation, not reported earlier.
15.	Niu, Feng, et al. (författare) Nanowired delivery of DL-3-n-butylphthalide induces superior neuroprotection in concussive head injury 2019 Ingår i: NANONEUROPROTECTION AND NANONEUROTOXICOLOGY. - : ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD. - 9780444642080 ; , s. 89-118 Bokkapitel (refereegranskat)abstract Concussive head injury (CHI) is quite prevalent in military personnel leading to lifetime disability in more than 85% of cases. Other reasons of CHI include motor vehicle accident, fall or blunt trauma under various conditions. In United States of America (USA) alone more than 150k cases of head injury are added every year for which no suitable therapeutic strategies are still available. Thus, there is a need to expand our knowledge in treating CHI cases with novel therapeutic measures to enhance the quality of life of head injury victims. With recent advancements in nanodelivery of drugs for superior neuroprotective effects in neurological diseases, our laboratory is engaged in understanding the role of nanowired delivery of suitable drugs in treating CHI and other neurodegenerative diseases. DL-3-n-butylphthalide (NBP) is an extract of Chinese celery and is able to induce profound neuroprotection following ischemic stroke and other related neurological dysfunction. Thus, it is quite likely that synthetic NBP could have pronounced neuroprotective effects in CHI as well. We believe that nanodelivery of NBP have superior neuroprotection in CHI. In this review neuroprotective effects of nanowired delivery of NBP in CHI induced brain pathology is described. Our experimental observations show that nanowired delivery of NBP results in superior neuroprotection than the regular NBP in CHI. The probable mechanisms and functional significance of our finding in relation to military medicine is discussed based on our own investigations.
16.	Ozkizilcik, Asya, et al. (författare) Nanodelivery of cerebrolysin reduces pathophysiology of Parkinson's disease 2019 Ingår i: NANONEUROPROTECTION AND NANONEUROTOXICOLOGY. - : ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD. - 9780444642080 ; , s. 201-246 Bokkapitel (refereegranskat)abstract Parkinson's disease (PD) is affecting >10 million people worldwide for which no suitable cure has been developed so far. Roughly, about two people per thousand populations are affected with PD like symptoms especially over the age of 50. About 1% of the populations above 60 years suffer from PD-like disease. The prevalence of the disease is increasing over the years, and future projections by 2020 could be 12-14 millions people affected by the disease. Thus, exploration of suitable therapeutic measures is the need of the hour to enhance quality of the life of PD patients. PD induced brain pathology includes loss of dopaminergic neurons in the substantia niagra that could later extends to other cortical regions causing loss of voluntary motor control. Deposition of alpha-synuclein in the brain further leads to neurodegeneration. However, the exact cause of PD is still unknown. It appears that breakdown of the blood-brain barrier (BBB) and leakage of serum component into the brain could lead to neurodegeneration in PD. Thus, novel treatment strategies that are able to restore BBB breakdown and enhance neuronal plasticity and neuroregeneration in PD could be effective in future therapy. With the advancement of nanotechnology, it is worthwhile to understand the role of nanodelivery of selected agents in PD to enhance neuroprotection. In this review new role of BBB, brain edema, and neuropathology in PD is discussed. In addition, superior neuroprotection induced by nanowired delivery of a multimodal drug cerebrolysin in PD is summarized based on our own investigations.
17.	Ozkizilcik, Asya, et al. (författare) Timed Release of Cerebrolysin Using Drug-Loaded Titanate Nanospheres Reduces Brain Pathology and Improves Behavioral Functions in Parkinson's Disease 2018 Ingår i: Molecular Neurobiology. - : HUMANA PRESS INC. - 0893-7648 .- 1559-1182. ; 55:1, s. 359-369 Tidskriftsartikel (refereegranskat)abstract Previous studies from our laboratory show that intraperitoneal injections of 1-metyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP, 20 mg/kg) daily within 2-h intervals for 5 days in mice induce Parkinson's disease (PD)-like symptoms on the 8th day. A significant decrease in dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) along with a marked decrease in the number of tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta (SNpc) and striatum (STr) confirms the validity of this model for studying PD. Since cerebrolysin (CBL) is a well-balanced composition of several neurotrophic factors and active peptide fragments, in the present investigation we examined the timed release of CBL using titanate nanospheres (TiNS) in treating PD in our mouse model. Our observations show that TiNS-CBL (in a dose of 3 ml/kg, i.v.) given after 2 days of MPTP administration for 5 days resulted in a marked increase in TH-positive cells in the SNpc and STr as compared to normal CBL. Also, TiNS-CBL resulted in significantly higher levels of DA, DOPAC, and HVA in SNpc and STr on the 8th day as compared to normal CBL therapy. TiNS-CBL also thwarted increased alpha-synuclein levels in the brain and in the cerebrospinal fluid (CSF) as well as neuronal nitric oxide synthase (nNOS) in the in PD brain as compared to untreated group. Behavioral function was also significantly improved in MPTP-treated animals that received TiNS-CBL. These observations are the first to demonstrate that timed release of TiNS-CBL has far more superior neuroprotective effects in PD than normal CBL.
18.	Pandey, Anand Kumar, et al. (författare) Quercetin in hypoxia-induced oxidative stress : novel target for neuroprotection 2012 Ingår i: New Perspectives of Central Nervous System Injury and Neuroprotection. - : Elsevier. - 9780123869869 ; , s. 107-146 Bokkapitel (refereegranskat)abstract Oxidative stress in the central nervous system is one of the key players for neurodegeneration. Thus, antioxidants could play important roles in treating several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and aging-related brain disorders. This review is focused on the new developments in oxidative stress-induced neurodegeneration. Further, based on our own investigations, new roles of quercetin, an antioxidant compound in hypoxia and ischemia induced neuroprotection in relation to suppression of oxidative stress, improvement in behavioral function, reduction in infarct volume, brain swelling, and cellular injury in both in vivo and in vitro models are discussed. Our new findings clearly suggest that antioxidant compounds have potential role in therapeutic strategies to treat neurodegenerative diseases in clinical settings.
19.	Patnaik, Ranjana, et al. (författare) Histamine H3 Inverse Agonist BF 2649 or Antagonist with Partial H4 Agonist Activity Clobenpropit Reduces Amyloid Beta Peptide-Induced Brain Pathology in Alzheimer's Disease 2018 Ingår i: Molecular Neurobiology. - : Humana Press. - 0893-7648 .- 1559-1182. ; 55:1, s. 312-321 Tidskriftsartikel (refereegranskat)abstract Alzheimer's disease (AD) is one of the leading causes for disability and death affecting millions of people worldwide. Thus, novel therapeutic strategies are needed to reduce brain pathology associated with AD. In view of increasing awareness regarding involvement of histaminergic pathways in AD, we explored the role of one H3 receptor inverse agonist BF 2649 and one selective H3 receptor antagonist with partial H4 agonist activity in amyloid beta peptide (A beta P) infusion-induced brain pathology in a rat model. AD-like pathology was produced by administering A beta P (1-40) intracerebroventricular (i.c.v.) in the left lateral ventricle (250 ng/10 mu l, once daily) for 4 weeks. Control rats received saline. In separate group of rats, either BF 2649 (1 mg/kg, i.p.) or clobenpropit (1 mg/kg, i.p.) was administered once daily for 1 week after 3weeks of A beta P administration. After 30 days, blood-brain barrier (BBB) breakdown, edema formation, neuronal, glial injuries, and A beta P deposits were examined in the brain. A significant reduction in A beta P deposits along with marked reduction in neuronal or glial reactions was seen in the drug-treated group. The BBB breakdown to Evans blue albumin and radioiodine in the cortex, hippocampus, hypothalamus, and cerebellum was also significantly reduced in these drug-treated groups. Clobenpropit showed superior effects than the BF2649 in reducing brain pathology in AD. Taken together, our observations are the first to show that blockade of H3 and stimulation of H4 receptors are beneficial for the treatment of AD pathology, not reported earlier.
20.	Ruozi, Barbara, et al. (författare) PLGA Nanoparticles Loaded Cerebrolysin : Studies on Their Preparation and Investigation of the Effect of Storage and Serum Stability with Reference to Traumatic Brain Injury 2015 Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 52:2, s. 899-912 Tidskriftsartikel (refereegranskat)abstract Cerebrolysin is a peptide mixture able to ameliorate symptomatology and delay progression of neurological disorders such as Alzheimer's disease and dementia. The administration of this drug in humans presents several criticisms due to its short half-life, poor stability, and high doses needed to achieve the effect. This paper investigates the potential of polylactic-co-glycolide (PLGA) nanoparticles (NPs) as sustained release systems for iv administration of cerebrolysin in normal and brain injured rats. NPs were prepared by water-in-oil-in-water (w/o/w) double emulsion technique and characterized by light scattering for mean size and zeta potential and by scanning electron microscopy (SEM) for surface morphology. The NPs produced by double sonication under cooling at 60 W for 45 s, 12 mL of 1 % w:v of PVA, and 1:0.6 w:w drug/PLGA ratio (C-NPs4) displayed an adequate loading of drug (24 +/- 1 mg/100 mg of NPs), zeta potential value (-13 mV), and average diameters (ranged from 250 to 330 nm) suitable to iv administration. SEM images suggested that cerebrolysin was molecularly dispersed into matricial systems and partially adhered to the NP surface. A biphasic release with an initial burst effect followed by sustained release over 24 h was observed. Long-term stability both at room and at low temperature of freeze-dried NPs was investigated. To gain deeper insight into NP stability after in vivo administration, the stability of the best NP formulation was also tested in serum. These PLGA NPs loaded with cerebrolysin were able to reduce brain pathology following traumatic brain injury. However, the size, the polydispersivity, and the surface properties of sample were significantly affected by the incubation time and the serum concentration.
21.	Sahib, Seaab, et al. (författare) Cerebrolysin enhances spinal cord conduction and reduces blood-spinal cord barrier breakdown, edema formation, immediate early gene expression and cord pathology after injury 2020. - 1 Ingår i: Neuropharmacology of Neuroprotection. - Amsterdam : Elsevier. - 9780128208137 - 9780128208144 ; , s. 397-438 Bokkapitel (refereegranskat)abstract Spinal cord evoked potentials (SCEP) are good indicators of spinal cord function in health and disease. Disturbances in SCEP amplitudes and latencies during spinal cord monitoring predict spinal cord pathology following trauma. Treatment with neuroprotective agents preserves SCEP and reduces cord pathology after injury. The possibility that cerebrolysin, a balanced composition of neurotrophic factors improves spinal cord conduction, attenuates blood-spinal cord barrier (BSCB) disruption, edema formation, and cord pathology was examined in spinal cord injury (SCI). SCEP is recorded from epidural space over rat spinal cord T9 and T12 segments after peripheral nerves stimulation. SCEP consists of a small positive peak (MPP), followed by a prominent negative peak (MNP) that is stable before SCI. A longitudinal incision (2mm deep and 5mm long) into the right dorsal horn (T10 and T11 segments) resulted in an immediate long-lasting depression of the rostral MNP with an increase in the latencies. Pretreatment with either cerebrolysin (CBL 5mL/kg, i.v. 30min before) alone or TiO2 nanowired delivery of cerebrolysin (NWCBL 2.5mL/kg, i.v.) prevented the loss of MNP amplitude and even enhanced further from the pre-injury level after SCI without affecting latencies. At 5h, SCI induced edema, BSCB breakdown, and cell injuries were significantly reduced by CBL and NWCBL pretreatment. Interestingly this effect on SCEP and cord pathology was still prominent when the NWCBL was delivered 2min after SCI. Moreover, expressions of c-fos and c-jun genes that are prominent at 5h in untreated SCI are also considerably reduced by CBL and NWCBL treatment. These results are the first to show that CBL and NWCBL enhanced SCEP activity and thwarted the development of cord pathology after SCI. Furthermore, NWCBL in low doses has superior neuroprotective effects on SCEP and cord pathology, not reported earlier. The functional significance and future clinical potential of CBL and NWCBL in SCI are discussed.
22.	Sahib, Seaab, et al. (författare) Nanodelivery of traditional Chinese Gingko Biloba extract EGb-761 and bilobalide BN-52021 induces superior neuroprotective effects on pathophysiology of heat stroke 2021 Ingår i: Progress in Brain Research. - : Elsevier. - 0079-6123 .- 1875-7855. ; 265, s. 249-315, s. 249-315 Tidskriftsartikel (refereegranskat)abstract Military personnel often exposed to high summer heat are vulnerable to heat stroke (HS) resulting in abnormal brain function and mental anomalies. There are reasons to believe that leakage of the blood-brain barrier (BBB) due to hyperthermia and development of brain edema could result in brain pathology. Thus, exploration of suitable therapeutic strategies is needed to induce neuroprotection in HS. Extracts of Gingko Biloba (EGb-761) is traditionally used in a variety of mental disorders in Chinese traditional medicine since ages. In this chapter, effects of TiO2 nanowired EGb-761 and BN-52021 delivery to treat brain pathologies in HS is discussed based on our own investigations. We observed that TiO2 nanowired delivery of EGb-761 or TiO2 BN-52021 is able to attenuate more that 80% reduction in the brain pathology in HS as compared to conventional drug delivery. The functional outcome after HS is also significantly improved by nanowired delivery of EGb-761 and BN-52021. These observations are the first to suggest that nanowired delivery of EGb-761 and BN-52021 has superior therapeutic effects in HS not reported earlier. The clinical significance in relation to the military medicine is discussed.
23.	Sharma, Aruna, et al. (författare) Cold Environment Exacerbates Brain Pathology and Oxidative Stress Following Traumatic Brain Injuries : Potential Therapeutic Effects of Nanowired Antioxidant Compound H-290/51 2018 Ingår i: Molecular Neurobiology. - : Humana Press. - 0893-7648 .- 1559-1182. ; 55:1, s. 276-285 Tidskriftsartikel (refereegranskat)abstract The possibility that traumatic brain injury (TBI) occurring in a cold environment exacerbates brain pathology and oxidative stress was examined in our rat model. TBI was inflicted by making a longitudinal incision into the right parietal cerebral cortex (2 mm deep and 4 mm long) in cold-acclimatized rats (5 degrees C for 3 h daily for 5 weeks) or animals at room temperature under Equithesin anesthesia. TBI in cold-exposed rats exhibited pronounced increase in brain lucigenin (LCG), luminol (LUM), and malondialdehyde (MDA) and marked pronounced decrease in glutathione (GTH) as compared to identical TBI at room temperature. The magnitude and intensity of BBB breakdown to radioiodine and Evans blue albumin, edema formation, and neuronal injuries were also exacerbated in cold-exposed rats after injury as compared to room temperature. Nanowired delivery of H-290/51 (50 mg/kg) 6 and 8 h after injury in cold-exposed group significantly thwarted brain pathology and oxidative stress whereas normal delivery of H-290/51 was neuroprotective after TBI at room temperature only. These observations are the first to demonstrate that (i) cold aggravates the pathophysiology of TBI possibly due to an enhanced production of oxidative stress, (ii) and in such conditions, nanodelivery of antioxidant compound has superior neuroprotective effects, not reported earlier.
24.	Sharma, Aruna, et al. (författare) Concussive head injury exacerbates neuropathology of sleep deprivation : Superior neuroprotection by co-administration of TiO2-nanowired cerebrolysin, alpha-melanocyte-stimulating hormone, and mesenchymal stem cells 2020 Ingår i: Neuropharmacology of Neuroprotection. - : ELSEVIER. - 9780128208137 ; , s. 1-77 Bokkapitel (refereegranskat)abstract Sleep deprivation (SD) is common in military personnel engaged in combat operations leading to brain dysfunction. Military personnel during acute or chronic SD often prone to traumatic brain injury (TBI) indicating the possibility of further exacerbating brain pathology. Several lines of evidence suggest that in both TBI and SD alpha-melanocyte-stimulating hormone (alpha-MSH) and brain-derived neurotrophic factor (BDNF) levels decreases in plasma and brain. Thus, a possibility exists that exogenous supplement of alpha-MSH and/or BDNF induces neuroprotection in SD compounded with TBI. In addition, mesenchymal stem cells (MSCs) are very portent in inducing neuroprotection in TBI. We examined the effects of concussive head injury (CHI) in SD on brain pathology. Furthermore, possible neuroprotective effects of alpha-MSH, MSCs and neurotrophic factors treatment were explored in a rat model of SD and CHI. Rats subjected to 48h SD with CHI exhibited higher leakage of BBB to Evans blue and radioiodine compared to identical SD or CHI alone. Brain pathology was also exacerbated in SD with CHI group as compared to SD or CHI alone together with a significant reduction in alpha-MSH and BDNF levels in plasma and brain and enhanced level of tumor necrosis factor-alpha (TNF-alpha). Exogenous administration of alpha-MSH (250 mu g/kg) together with MSCs (1 x 10(6)) and cerebrolysin (a balanced composition of several neurotrophic factors and active peptide fragments) (5mL/kg) significantly induced neuroprotection in SD with CHI. Interestingly, TiO2 nanowired delivery of alpha-MSH (100 mu g), MSCs, and cerebrolysin (2.5mL/kg) induced enhanced neuroprotection with higher levels of alpha-MSH and BDNF and decreased the TNF-alpha in SD with CHI. These observations are the first to show that TiO2 nanowired administration of alpha-MSH, MSCs and cerebrolysin induces superior neuroprotection following SD in CHI, not reported earlier. The clinical significance of our findings in light of the current literature is discussed.
25.	Sharma, Aruna, et al. (författare) Histamine H3 and H4 receptors modulate Parkinson's disease induced brain pathology : Neuroprotective effects of nanowired BF-2649 and clobenpropit with anti-histamine-antibody therapy 2021 Ingår i: Brain protection strategies and nanomedicine. - : Elsevier BV. - 9780323989275 ; 266, s. 1-73 Bokkapitel (refereegranskat)abstract Military personnel deployed in combat operations are highly prone to develop Parkinson's disease (PD) in later lives. PD largely involves dopaminergic pathways with hallmarks of increased alpha synuclein (ASNC), and phosphorylated tau (p-tau) in the cerebrospinal fluid (CSF) precipitating brain pathology. However, increased histaminergic nerve fibers in substantia nigra pars Compacta (SNpc), striatum (STr) and caudate putamen (CP) associated with upregulation of Histamine H3 receptors and downregulation of H4 receptors in human cases of PD is observed in postmortem cases. These findings indicate that modulation of histamine H3 and H4 receptors and/or histaminergic transmission may induce neuroprotection in PD induced brain pathology. In this review effects of a potent histaminergic H3 receptor inverse agonist BF-2549 or clobenpropit (CLBPT) partial histamine H4 agonist with H3 receptor antagonist, in association with monoclonal anti-histamine antibodies (AHmAb) in PD brain pathology is discussed based on our own observations. Our investigation shows that chronic administration of conventional or TiO2 nanowired BF 2649 (1 mg/kg, i.p.) or CLBPT (1 mg/kg, i.p.) once daily for 1 week together with nanowired delivery of HAmAb (25 mu L) significantly thwarted ASNC and p-tau levels in the SNpC and STr and reduced PD induced brain pathology. These observations are the first to show the involvement of histamine receptors in PD and opens new avenues for the development of novel drug strategies in clinical strategies for PD, not reported earlier.
26.	Sharma, Aruna, et al. (författare) Mild traumatic brain injury exacerbates Parkinson's disease induced hemeoxygenase-2 expression and brain pathology : Neuroprotective effects of co-administration of TiO2 nanowired mesenchymal stem cells and cerebrolysin 2020 Ingår i: Neuropharmacology of Neuroprotection. - : ELSEVIER. - 9780128208137 ; , s. 157-231 Bokkapitel (refereegranskat)abstract Mild traumatic brain injury (mTBI) is one of the leading predisposing factors in the development of Parkinson's disease (PD). Mild or moderate TBI induces rapid production of tau protein and alpha synuclein (ASNC) in the cerebrospinal fluid (CSF) and in several brain areas. Enhanced tau-phosphorylation and ASNC alters the molecular machinery of the brain leading to PD pathology. Recent evidences show upregulation of constitutive isoform of hemeoxygenase (HO-2) in PD patients that correlates well with the brain pathology. mTBI alone induces profound upregulation of HO-2 immunoreactivity. Thus, it would be interesting to explore whether mTBI exacerbates PD pathology in relation to tau, ASNC and HO-2 expression. In addition, whether neurotrophic factors and stem cells known to reduce brain pathology in TBI could induce neuroprotection in PD following mTBI. In this review role of mesenchymal stem cells (MSCs) and cerebrolysin (CBL), a well-balanced composition of several neurotrophic factors and active peptide fragments using nanowired delivery in PD following mTBI is discussed based on our own investigation. Our results show that mTBI induces concussion exacerbates PD pathology and nanowired delivery of MSCs and CBL induces superior neuroprotection. This could be due to reduction in tau, ASNC and HO-2 expression in PD following mTBI, not reported earlier. The functional significance of our findings in relation to clinical strategies is discussed.
27.	Sharma, Aruna, et al. (författare) Nanowired Drug Delivery Across the Blood-Brain Barrier in Central Nervous System Injury and Repair 2016 Ingår i: CNS & Neurological Disorders. - : Bentham Science Publishers Ltd.. - 1871-5273 .- 1996-3181. ; 15:9, s. 1092-1117 Forskningsöversikt (refereegranskat)abstract The blood-brain barrier (BBB) is a physiological regulator of transport of essential items from blood to brain for the maintenance of homeostasis of the central nervous system (CNS) within narrow limits. The BBB is also responsible for export of harmful or metabolic products from brain to blood to keep the CNS fluid microenvironment healthy. However, noxious insults to the brain caused by trauma, ischemia or environmental/chemical toxins alter the BBB function to small as well as large molecules e.g., proteins. When proteins enter the CNS fluid microenvironment, development of brain edema occurs due to altered osmotic balance between blood and brain. On the other hand, almost all neurodegenerative diseases and traumatic insults to the CNS and subsequent BBB dysfunction lead to edema formation and cell injury. To treat these brain disorders suitable drug therapy reaching their brain targets is needed. However, due to edema formation or only a focal disruption of the BBB e.g., around brain tumors, many drugs are unable to reach their CNS targets in sufficient quantity. This results in poor therapeutic outcome. Thus, new technology such as nanodelivery is needed for drugs to reach their CNS targets and be effective. In this review, use of nanowires as a possible novel tool to enhance drug delivery into the CNS in various disease models is discussed based on our investigations. These data show that nanowired delivery of drugs may have superior neuroprotective ability to treat several CNS diseases effectively indicating their role in future therapeutic strategies.
28.	Sharma, Aruna, et al. (författare) Novel Treatment Strategies Using TiO2-Nanowired Delivery of Histaminergic Drugs and Antibodies to Tau With Cerebrolysin for Superior Neuroprotection in the Pathophysiology of Alzheimer's Disease 2017 Ingår i: Nanomedicine In Central Nervous System Injury And Repair. - : Elsevier. - 9780128123812 ; , s. 123-165 Bokkapitel (refereegranskat)abstract More than 5.5 million Americans of all ages are suffering from Alzheimer's disease (AD) till today for which no suitable therapy has been developed so far. Thus, there is an urgent need to explore novel therapeutic measures to contain brain pathology in AD. The hallmark of AD includes amyloid-beta peptide (A beta P) deposition and phosphorylation of tau in AD brain. Recent evidences also suggest a marked decrease in neurotrophic factors in AD. Thus, exogenous supplement of neurotrophic factors could be one of the possible ways for AD therapy. Human postmortem brain in AD shows alterations in histamine receptors as well, indicating an involvement of the amine in AD-induced brain pathology. In this review, we focused on role of histamine 3 and 4 receptor-modulating drugs in the pathophysiology of AD. Moreover, antibodies to histamine and tau appear to be also beneficial in reducing brain pathology, blood-brain barrier breakdown, and edema formation in AD. Interestingly, TiO2-nanowired delivery of cerebrolysin-a balanced composition of several neurotrophic factors attenuated A beta P deposition and reduced tau phosphorylation in AD brain leading to neuroprotection. Coadministration of cerebrolysin with histamine antibodies or tau antibodies has further enhanced neuroprotection in AD. These novel observations strongly suggest a role of nanomedicine in AD that requires further investigation.
29.	Sharma, Aruna, et al. (författare) Size- and Age-Dependent Neurotoxicity of Engineered Metal Nanoparticles in Rats 2013 Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 48:2, s. 386-396 Tidskriftsartikel (refereegranskat)abstract Earlier we showed that chronic administration of engineered nanoparticles (NPs) from metals, e.g., Cu, Ag, or Al (50-60 nm, 50 mg/kg, i.p. daily for 1 week) alter blood-brain barrier (BBB) disruption and induce brain pathology in adult rats (age 18 to 22 weeks). However, effects of size-dependent neurotoxicity of NPs in vivo are still largely unknown. In present investigation, we examined the effects of different size ranges of the above-engineered NPs on brain pathology in rats. Furthermore, the fact that age is also an important factor in brain pathology was also investigated in our rat model. Our results showed that small-sized NPs induced the most pronounced BBB breakdown (EBA +480 to 680 %; radioiodine +850 to 1025 %), brain edema formation (+4 to 6 %) and neuronal injuries (+30 to 40 %), glial fibrillary acidic protein upregulation (+40 to 56 % increase), and myelin vesiculation (+30 to 35 % damage) in young animals as compared to controls. Interestingly, the oldest animals (30 to 35 weeks of age) also showed massive brain pathology as compared to young adults (18 to 20 weeks old). The Ag and Cu exhibited greater brain damage compared with Al NPs in all age groups regardless of their size. This suggests that apart from the size, the composition of NPs is also important in neurotoxicity. The very young and elderly age groups exhibited greater neurotoxicity to NPs suggests that children and elderly are more vulnerable to NPs-induced brain damage. The NPs-induced brain damage correlated well with the upregulation of neuronal nitric oxide synthase activity in the brain indicating that NPs-induced neurotoxicity may be mediated via increased production of nitric oxide, not reported earlier.
30.	Sharma, Aruna, et al. (författare) Sleep deprivation exacerbates concussive head injury induced brain pathology : Neuroprotective effects of nanowired delivery of cerebrolysin with alpha-melanocyte-stimulating hormone 2019 Ingår i: NANONEUROPROTECTION AND NANONEUROTOXICOLOGY. - : ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD. - 9780444642080 ; , s. 1-55 Bokkapitel (refereegranskat)abstract Sleep deprivation (SD) is very common in military personnel resulting in mental anomalies and interfering with decision-making capabilities. Moreover during combat operation, these sleep-deprived soldiers often receive blunt head trauma casing concussive head injury (CHI). Recent observations clearly suggest that SD alone induces brain pathology and additional CHI further exacerbates brain damage. Thus, the need of the hour is to explore possible effective therapeutic measures to induce neuroprotection to enhance quality of life of these military personnel. This review deals with novel aspects of treatment using nanotechnology to induce superior neuroprotection following CHI in SD based on our own investigation in the light of recent literature in the field.
31.	Sharma, Aruna, et al. (författare) Sleep Deprivation-Induced Blood-Brain Barrier Breakdown and Brain Dysfunction are Exacerbated by Size-Related Exposure to Ag and Cu Nanoparticles. Neuroprotective Effects of a 5-HT3 Receptor Antagonist Ondansetron 2015 Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 52:2, s. 867-881 Tidskriftsartikel (refereegranskat)abstract Military personnel are often subjected to sleep deprivation (SD) during combat operations. Since SD is a severe stress and alters neurochemical metabolism in the brain, a possibility exists that acute or long-term SD will influence blood-brain barrier (BBB) function and brain pathology. This hypothesis was examined in young adult rats (age 12 to 14 weeks) using an inverted flowerpot model. Rats were placed over an inverted flowerpot platform (6.5 cm diameter) in a water pool where the water levels are just 3 cm below the surface. In this model, animals can go to sleep for brief periods but cannot achieve deep sleep as they would fall into water and thus experience sleep interruption. These animals showed leakage of Evans blue in the cerebellum, hippocampus, caudate nucleus, parietal, temporal, occipital, cingulate cerebral cortices, and brain stem. The ventricular walls of the lateral and fourth ventricles were also stained blue, indicating disruption of the BBB and the blood-cerebrospinal fluid barrier (BCSFB). Breakdown of the BBB or the BCSFB fluid barrier was progressive in nature from 12 to 48 h but no apparent differences in BBB leakage were seen between 48 and 72 h of SD. Interestingly, rats treated with metal nanoparticles, e.g., Cu or Ag, showed profound exacerbation of BBB disruption by 1.5- to 4-fold, depending on the duration of SD. Measurement of plasma and brain serotonin showed a close correlation between BBB disruption and the amine level. Repeated treatment with the serotonin 5-HT3 receptor antagonist ondansetron (1 mg/kg, s.c.) 4 and 8 h after SD markedly reduced BBB disruption and brain pathology after 12 to 24 h SD but not following 48 or 72 h after SD. However, TiO2-nanowired ondansetron (1 mg/kg, s.c) in an identical manner induced neuroprotection in rats following 48 or 72 h SD. However, plasma and serotonin levels were not affected by ondansetron treatment. Taken together, our observations are the first to show that (i) SD could induce BBB disruption and brain pathology, (ii) nanoparticles exacerbate SD-induced brain damage, and (iii) serotonin 5-HT3 receptor antagonist ondansetron is neuroprotective in SD that is further potentiated byTiO2-nanowired delivery, not reported earlier.
32.	Sharma, Aruna, et al. (författare) Topical application of CNTF, GDNF and BDNF in combination attenuates blood-spinal cord barrier permeability, edema formation, hemeoxygenase-2 upregulation, and cord pathology 2021 Ingår i: Brain protection strategies and nanomedicine. - : Elsevier BV. - 9780323989275 ; 266, s. 357-376 Bokkapitel (refereegranskat)abstract Spinal cord injury (SCI) is one of the leading causes of disability in Military personnel for which no suitable therapeutic strategies are available till today. Thus, exploration of novel therapeutic measures is highly needed to enhance the quality of life of SCI victims. Previously, topical application of BDNF and GDNF in combination over the injured spinal cord after 90min induced marked neuroprotection. In present investigation, we added CNTF in combination with BDNF and/or GDNF treatment to examine weather the triple combination applied over the traumatic cord after 90 or 120min could thwart cord pathology. Since neurotrophins attenuate nitric oxide (NO) production in SCI, the role of carbon monoxide (CO) production that is similar to NO in inducing cell injury was explored using immunohistochemistry of the constitutive isoform of enzyme hemeoxygenase-2 (HO-2). SCI inflicted over the right dorsal horn of the T10-11 segments by making an incision of 2mm deep and 5mm long upregulated the HO-2 immunostaining in the T9 and T12 segments after 5h injury. These perifocal segments are associated with breakdown of the blood-spinal cord barrier (BSCB), edema development and cell injuries. Topical application of CNTF with BDNF and GDNF in combination (10ng each) after 90 and 120min over the injured spinal cord significantly attenuated the BSCB breakdown, edema formation, cell injury and overexpression of HO-2. These observations are the first to show that CNTF with BDNF and GDNF induced superior neuroprotection in SCI probably by downregulation of CO production, not reported earlier.
33.	Sharma, Hari S., et al. (författare) Alzheimer's disease : cerebrolysin and nanotechnology as a therapeutic strategy 2016 Ingår i: Neurodegenerative Disease Management. - : Future Medicine Ltd. - 1758-2024 .- 1758-2032. ; 6:6, s. 453-456 Tidskriftsartikel (refereegranskat)
34.	Sharma, Hari Shanker, et al. (författare) Alzheimer's disease neuropathology is exacerbated following traumatic brain injury. Neuroprotection by co-administration of nanowired mesenchymal stem cells and cerebrolysin with monoclonal antibodies to amyloid beta peptide 2021 Ingår i: Progress in Brain Research. - : Elsevier. - 0079-6123 .- 1875-7855. ; 265, s. 1-97, s. 1-97 Tidskriftsartikel (refereegranskat)abstract Military personnel are prone to traumatic brain injury (TBI) that is one of the risk factors in developing Alzheimer's disease (AD) at a later stage. TBI induces breakdown of the blood-brain barrier (BBB) to serum proteins into the brain and leads to extravasation of plasma amyloid beta peptide (ΑβP) into the brain fluid compartments causing AD brain pathology. Thus, there is a need to expand our knowledge on the role of TBI in AD. In addition, exploration of the novel roles of nanomedicine in AD and TBI for neuroprotection is the need of the hour. Since stem cells and neurotrophic factors play important roles in TBI and in AD, it is likely that nanodelivery of these agents exert superior neuroprotection in TBI induced exacerbation of AD brain pathology. In this review, these aspects are examined in details based on our own investigations in the light of current scientific literature in the field. Our observations show that TBI exacerbates AD brain pathology and TiO2 nanowired delivery of mesenchymal stem cells together with cerebrolysin—a balanced composition of several neurotrophic factors and active peptide fragments, and monoclonal antibodies to amyloid beta protein thwarted the development of neuropathology following TBI in AD, not reported earlier.
35.	Sharma, Hari Shanker, et al. (författare) Cerebrolysin Attenuates Exacerbation of Neuropathic Pain, Blood-spinal Cord Barrier Breakdown and Cord Pathology Following Chronic Intoxication of Engineered Ag, Cu or Al (50-60 nm) Nanoparticles 2023 Ingår i: Neurochemical Research. - : Springer Nature. - 0364-3190 .- 1573-6903. ; 48, s. 1864-1888 Tidskriftsartikel (refereegranskat)abstract Neuropathic pain is associated with abnormal sensations and/or pain induced by non-painful stimuli, i.e., allodynia causing burning or cold sensation, pinching of pins and needles like feeling, numbness, aching or itching. However, no suitable therapy exists to treat these pain syndromes. Our laboratory explored novel potential therapeutic strategies using a suitable composition of neurotrophic factors and active peptide fragments-Cerebrolysin (Ever Neuro Pharma, Austria) in alleviating neuropathic pain induced spinal cord pathology in a rat model. Neuropathic pain was produced by constrictions of L-5 spinal sensory nerves for 2-10 weeks period. In one group of rats cerebrolysin (2.5 or 5 ml/kg, i.v.) was administered once daily after 2 weeks until sacrifice (4, 8 and 10 weeks). Ag, Cu and Al NPs (50 mg/kg, i.p.) were delivered once daily for 1 week. Pain assessment using mechanical (Von Frey) or thermal (Hot-Plate) nociceptive showed hyperalgesia from 2 weeks until 10 weeks progressively that was exacerbated following Ag, Cu and Al NPs intoxication in nerve lesioned groups. Leakage of Evans blue and radioiodine across the blood-spinal cord barrier (BSCB) is seen from 4 to 10 weeks in the rostral and caudal cord segments associated with edema formation and cell injury. Immunohistochemistry of albumin and GFAP exhibited a close parallelism with BSCB leakage that was aggravated by NPs following nerve lesion. Light microscopy using Nissl stain exhibited profound neuronal damages in the cord. Transmission electron microcopy (TEM) show myelin vesiculation and synaptic damages in the cord that were exacerbated following NPs intoxication. Using ELISA spinal tissue exhibited increased albumin, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP) and heat shock protein (HSP 72kD) upregulation together with cytokines TNF-alpha, IL-4, IL-6, IL-10 levels in nerve lesion that was exacerbated following NPs intoxication. Cerebrolysin treatment significantly reduced hyperalgesia and attenuated BSCB disruption, edema formation and cellular changes in nerve lesioned group. The levels of cytokines were also restored near normal levels with cerebrolysin treatment. Albumin, GFAP, MABP and HSP were also reduced in cerebrolysin treated group and thwarted neuronal damages, myelin vesiculation and cell injuries. These neuroprotective effects of cerebrolysin with higher doses were also effective in nerve lesioned rats with NPs intoxication. These observations suggest that cerebrolysin actively protects spinal cord pathology and hyperalgesia following nerve lesion and its exacerbation with metal NPs, not reported earlier.
36.	Sharma, Hari Shanker, et al. (författare) Cerebrolysin restores balance between excitatory and inhibitory amino acids in brain following concussive head injury : Superior neuroprotective effects of TiO2 nanowired drug delivery 2021 Ingår i: Brain protection strategies and nanomedicine. - : Elsevier BV. - 9780323989275 ; , s. 211-267 Bokkapitel (refereegranskat)abstract Concussive head injury (CHI) often associated with military personnel, soccer players and related sports personnel leads to serious clinical situation causing lifetime disabilities. About 3-4 k head injury per 100 k populations are recorded in the United States since 2000-2014. The annual incidence of concussion has now reached to 1.2% of population in recent years. Thus, CHI inflicts a huge financial burden on the society for rehabilitation. Thus, new efforts are needed to explore novel therapeutic strategies to treat CHI cases to enhance quality of life of the victims. CHI is well known to alter endogenous balance of excitatory and inhibitory amino acid neurotransmitters in the central nervous system (CNS) leading to brain pathology. Thus, a possibility exists that restoring the balance of amino acids in the CNS following CHI using therapeutic measures may benefit the victims in improving their quality of life. In this investigation, we used a multimodal drug Cerebrolysin (Ever NeuroPharma, Austria) that is a well-balanced composition of several neurotrophic factors and active peptide fragments in exploring its effects on CHI induced alterations in key excitatory (Glutamate, Aspartate) and inhibitory (GABA, Glycine) amino acids in the CNS in relation brain pathology in dose and time-dependent manner. CHI was produced in anesthetized rats by dropping a weight of 114.6 g over the right exposed parietal skull from a distance of 20 cm height (0.224 N impact) and blood-brain barrier (BBB), brain edema, neuronal injuries and behavioral dysfunctions were measured 8, 24, 48 and 72 h after injury. Cerebrolysin (CBL) was administered (2.5, 5 or 10 mL/kg, i.v.) after 4-72 h following injury. Our observations show that repeated CBL induced a dose-dependent neuroprotection in CHI (5-10 mL/kg) and also improved behavioral functions. Interestingly when CBL is delivered through TiO2 nanowires superior neuroprotective effects were observed in CHI even at a lower doses (2.5-5 mL/kg). These observations are the first to demonstrate that CBL is effectively capable to attenuate CHI induced brain pathology and behavioral disturbances in a dose dependent manner, not reported earlier.
37.	Sharma, Hari Shanker, et al. (författare) Conference Report : 13th International Congress on Amino Acids, Peptides and Proteins (ICAPP); Neurobiology Symposium, October 5-7, 2013; Galveston TX, USA 2014 Ingår i: CNS & Neurological Disorders. - : Bentham Science Publishers Ltd.. - 1871-5273 .- 1996-3181. ; 13:1, s. 2-3 Tidskriftsartikel (refereegranskat)
38.	Sharma, Hari Shanker, et al. (författare) Development of in vivo drug-induced neurotoxicity models 2014 Ingår i: Expert Opinion on Drug Metabolism & Toxicology. - : Informa Healthcare. - 1742-5255 .- 1744-7607. ; 10:12, s. 1637-1661 Forskningsöversikt (refereegranskat)abstract Introduction: Neurotoxicity caused by diverse psychostimulant drugs, for example, methamphetamine, 3,4-methylenedioxy-methamphetamine, cocaine or morphine is a cause of concern to human populations especially the young generation across the world. These recreational drugs affect brain function severely leading to addiction and brain pathology. Use of psychostimulants may induce breakdown of the blood-brain barrier to serum proteins resulting in adverse brain microenvironment, edema cell injury or eventually neuronal death. Thus, there is an urgent need to find out detailed mechanisms of psychostimulants-induced neurotoxicity in vivo models for suitable therapeutic strategies to induce neuroprotection and also to help de-addiction in clinical situations. Areas covered: In this review, psychostimulants drugs-induced neurotoxicity is discussed in view of recent literature and the financial burden it may pose on our society due to rehabilitation and de-addiction. Furthermore, experimental evidences of drug-induced neuroprotection are also discussed. Expert opinion: Use of in vivo models of neurotoxicity caused by psychostimulants is discussed based on author's own research and to find suitable drugs that could induce neuroprotection including nanodelivery. Furthermore, novel therapeutic agents for de-addiction and reducing neurotoxicity following psychostimulants administration are presented.
39.	Sharma, Hari S., et al. (författare) Exacerbation of Brain Pathology After Partial Restraint in Hypertensive Rats Following SiO2 Nanoparticles Exposure at High Ambient Temperature 2013 Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 48:2, s. 368-379 Forskningsöversikt (refereegranskat)abstract This investigation examines the possibility that exposure to silica dust of hypertensive individuals may exacerbate brain pathology and sensory motor dysfunction at high environmental temperature. Hypertension was produced in rats (200-250 g) by two-kidney one clip (2K1C) method, and in these animals, SiO2 nanoparticles (NPs; 50 to 60 nm) were administered at 50 mg/kg, i.p. daily for 1 week. On the 8th day, these rats were subjected to partial restraint in a Perspex box for 4 h either at room temperature (21 A degrees C) or at 33 A degrees C in a biological oxygen demand incubator (wind velocity, 2.6 cm/s; relative humidity, 65 to 67 %). In these animals, behavioral functions, blood-brain barrier (BBB) permeability to Evans blue albumin (EBA) and radioiodine (([131]-)Iodine), brain water content and neuronal injuries were determined. Hypertensive rats subjected to 4 h restraint at room temperature did not exhibit BBB dysfunction, brain edema, neural injury, or alterations in rotarod or inclined plane angle performances. However, when these hypertensive rats were subjected to restraint at 33 A degrees C, breakdown of the cortical BBB (EBA, +38 %; radioiodine, +56 %), brain water (+0.88 %), neuronal damages (+18 %), and behavioral impairment were exacerbated. Interestingly, SiO2 exposure to these rats further exacerbated BBB breakdown (EBA, 280 %; radioiodine, 350 %), brain edema (4 %), and neural injury (30 %) after identical restraint depending on the ambient temperature. SiO2 treatment also induced brain pathology and alteration in behavioral functions in normotensive rats after restraint at high temperature. These observations clearly show that hypertension significantly enhances restraint-induced brain pathology, and behavioral anomalies particularly at high ambient temperature and SiO2 intoxication further exacerbated these brain pathologies and cognitive dysfunctions.
40.	Sharma, Hari Shanker, et al. (författare) Exacerbation of Methamphetamine Neurotoxicity in Cold and Hot Environments : Neuroprotective Effects of an Antioxidant Compound H-290/51 2015 Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 52:2, s. 1023-1033 Tidskriftsartikel (refereegranskat)abstract In this study, we examined the influence of cold and hot environments on methamphetamine (METH) neurotoxicity in both drug-naive rats and animals previously exposed to different types of nanoparticles (NPs). Since METH induces oxidative stress, we also examined how a potential chain-breaking antioxidant H-290/51 (Astra-Zeneca, Molndal, Sweden) affects METH-induced neurotoxicity. Exposure of drug-naive rats to METH (9 mg/kg, s.c.) at 4, 21, or 34 A degrees C for 3 h resulted in breakdown of the blood-brain barrier (BBB), brain edema, and neuronal injuries, which all differed in severity depending upon ambient temperatures. The changes were moderate at 21 A degrees C, 120-180 % larger at 34 A degrees C, and almost absent at 4 A degrees C. In rats chronically treated with NPs (SiO2, Cu, or Ag; 50-60 nm, 50 mg/kg, i.p. for 7 days), METH-induced brain alterations showed a two- to fourfold increase at 21 A degrees C, a four- to sixfold increase at 34 A degrees C, and three- to fourfold increase at 4 A degrees C. SiO2 exposure showed the most pronounced METH-induced brain pathology at all temperatures followed by Ag and Cu NPs. Pretreatment with a potent antioxidant compound H-290/51 (50 mg/kg, p.o., 30 min before METH) significantly reduced brain pathology in naive animals exposed to METH at 21 and 34 A degrees C. In NPs-treated animals, however, attenuation of METH-induced brain pathology occurred only after repeated exposure of H-290/51 (-30 min, 0 min, and +30 min). These observations are the first to show that NPs exacerbate METH-induced brain pathology in both cold and hot environments and demonstrate that timely intervention with antioxidant H-290/51 could have neuroprotective effects.
41.	Sharma, Hari Shanker, et al. (författare) Histaminergic Receptors Modulate Spinal Cord Injury-Induced Neuronal Nitric Oxide Synthase Upregulation and Cord Pathology : New Roles of Nanowired Drug Delivery for Neuroprotection 2017 Ingår i: Nanomedicine In Central Nervous System Injury And Repair. - : Elsevier. - 9780128123812 ; , s. 65-98 Bokkapitel (refereegranskat)abstract The possibility that histamine influences the spinal cord pathophysiology following trauma through specific receptor-mediated upregulation of neuronal nitric oxide synthase (nNOS) was examined in a ratmodel. A focal spinal cord injury (SCI) was inflicted by a longitudinal incision into the right dorsal horn of the T10-11 segments. The animals were allowed to survive 5h. The SCI significantly induced breakdown of the blood-spinal cord barrier to protein tracers, reduced the spinal cord blood flowat 5h, and increased the edema formation and massive upregulation of nNOS expression. Pretreatment with histamine H1 receptor antagonist mepyramine (1mg, 5mg, and 10mg/kg, i.p., 30min before injury) failed to attenuate nNOS expression and spinal cord pathology following SCI. On the other hand, blockade of histamine H2 receptors with cimetidine or ranitidine (1mg, 5mg, or 10mg/kg) significantly reduced these early pathophysiological events and attenuated nNOS expression in a dose-dependent manner. Interestingly, TiO2-naowire delivery of cimetidine or ranitidine (5mg doses) exerted superior neuroprotective effects on SCIinduced nNOS expression and cord pathology. It appears that effects of ranitidine were far superior than cimetidine at identical doses in SCI. On the other hand, pretreatment with histamine H3 receptor agonist a-methylhistamine (1mg, 2mg, or 5mg/kg, i.p.) that inhibits histamine synthesis and release in the central nervous systemthwarted the spinal cord pathophysiology and nNOS expression when used in lower doses. Interestingly, histamine H3 receptor antagonist thioperamide (1mg, 2mg, or 5mg/kg, i.p.) exacerbated nNOS expression and cord pathology after SCI. These novel observations suggest that blockade of histamine H2 receptors or stimulation of histamine H3 receptors attenuates nNOS expression and induces neuroprotection in SCI. Taken together, our results are the first to demonstrate that histamine-induced pathophysiology of SCI is mediated via nNOS expression involving specific histamine receptors.
42.	Sharma, Hari Shanker, et al. (författare) Methamphetamine exacerbates pathophysiology of traumatic brain injury at high altitude. Neuroprotective effects of nanodelivery of a potent antioxidant compound H-290/51 2021 Ingår i: Brain protection strategies and nanomedicine. - : Elsevier BV. - 9780323989275 ; 266, s. 123-193 Bokkapitel (refereegranskat)abstract Military personnel are often exposed to high altitude (HA, ca. 4500-5000 m) for combat operations associated with neurological dysfunctions. HA is a severe stressful situation and people frequently use methamphetamine (METH) or other psychostimulants to cope stress. Since military personnel are prone to different kinds of traumatic brain injury (TBI), in this review we discuss possible effects of METH on concussive head injury (CHI) at HA based on our own observations. METH exposure at HA exacerbates pathophysiology of CHI as compared to normobaric laboratory environment comparable to sea level. Increased blood-brain barrier (BBB) breakdown, edema formation and reductions in the cerebral blood flow (CBF) following CHI were exacerbated by METH intoxication at HA. Damage to cerebral microvasculature and expression of beta catenin was also exacerbated following CHI in METH treated group at HA. TiO2-nanowired delivery of H-290/51 (150 mg/kg, i.p.), a potent chain-breaking antioxidant significantly enhanced CBF and reduced BBB breakdown, edema formation, beta catenin expression and brain pathology in METH exposed rats after CHI at HA. These observations are the first to point out that METH exposure in CHI exacerbated brain pathology at HA and this appears to be related with greater production of oxidative stress induced brain pathology, not reported earlier.
43.	Sharma, Hari Shanker, et al. (författare) Nanoparticles Exacerbate Both Ubiquitin and Heat Shock Protein Expressions in Spinal Cord Injury : Neuroprotective Effects of the Proteasome Inhibitor Carfilzomib and the Antioxidant Compound H-290/51 2015 Ingår i: Molecular Neurobiology. - : Springer Science and Business Media LLC. - 0893-7648 .- 1559-1182. ; 52:2, s. 882-898 Tidskriftsartikel (refereegranskat)abstract Increased levels of ubiquitin and heat shock protein (HSP) 72 kD are often seen in spinal cord injury (SCI). However, their roles in cell injury or survival are not well known. Thus, we have investigated the possible relationship between ubiquitin and HSP expressions in relation to cell injury in healthy animals, or following nanoparticle (NP) intoxication in SCI animals. A focal SCI was inflicted on the T10-11 segments over the right dorsal horn; animals were allowed to survive from 5 to 8 h after trauma. Separate groups of rats were exposed to SiO2, Ag, or Cu NPs for 7 days and subjected to SCI on the eighth day. A marked increase in ubiquitin or HSP immunoreactive cells occurred in the T9 to T12 segments 5 h after the injury, which further extended to the T4 and L5 after 8 h of survival. At this time, a marked increase in blood-spinal cord barrier (BSCB) permeability to Evans blue and radioiodine, accompanied by an intense edema formation, was observed. Changes were further exacerbated in NP-treated traumatized rats. The most marked expressions of ubiquitin and HSP in SCI were seen in rats treated with SiO2, followed by Ag, and Cu NPs. Treatment with H-290/51 (50 mg/kg p.o., 30 to 60 min after injury) or carfilzomib (1 mg/kg, i.v., 30 to 60 min after trauma) significantly reduced the ubiquitin or HSP expressions, as well as the BSCB breakdown, the edema formation, and the cell injury in the cord both 5 and 8 h after the injury, in normal animals. However, a double dose of H-290/51 (100 mg/kg) or carfilzomib (2 mg/kg) is needed to reduce cord pathology or ubiquitin and HSP expressions in traumatized animals treated with NPs. H-290/51 showed superior beneficial effects in reducing cord pathology in SCI than carfilzomib. These observations are the first to demonstrate that (i) NP-treated traumatized animals induce a widespread BSCB leakage, edema formation, and cord pathology as well as an overexpression of ubiquitin and HSP, (ii) high doses of antioxidant compounds or proteasome inhibitors are required for neuroprotection in the NP-exposed traumatized group, and (iii) ubiquitin and HSP expressions play a key role in neuronal injury in SCI, not reported earlier.
44.	Sharma, Hari Shanker, et al. (författare) Nanoparticles influence pathophysiology of spinal cord injury and repair 2009 Ingår i: Progress in Brain Research. - Amsterdam : Elsevier. - 0079-6123 .- 1875-7855. - 9780444534316 ; 180, s. 155-180 Forskningsöversikt (refereegranskat)abstract Spinal cord injury (SCI) is a serious clinical problem for which no suitable therapeutic strategies have been worked out so far. Recent studies suggest that the SCI and its pathophysiological responses could be altered by systemic exposure to nanoparticles. Thus, SCI when made in animals intoxicated with engineered nanoparticles from metals or silica dust worsened the outcome. On the other hand, drugs tagged with titanium (TiO2) nanoparticles or encapsulated in liposomes could enhance their neuroprotective efficacy following SCI. Thus, to expand our knowledge on nanoparticle-induced alterations in the spinal cord pathophysiology further research is needed. These investigations will help to develop new strategies to achieve neuroprotection in SCI, for example, using nanodrug delivery. New results from our laboratory showed that nanoparticle-induced exacerbation of cord pathology following trauma can be reduced when the suitable drugs tagged with TiO2 nanowires were administered into the spinal cord as compared to those drugs given alone. This indicates that nanoparticles depending on the exposure and its usage could induce both neurotoxicity and neuroprotection. This review discusses the potential adverse or therapeutic utilities of nanoparticles in SCI largely based on our own investigations. In addition, possible mechanisms of nanoparticle-induced exacerbation of cord pathology or enhanced neuroprotection following nanodrug delivery is described in light of recently available data in this rapidly emerging field of nanoneurosciences.
45.	Sharma, Hari Shanker, et al. (författare) Nanowired delivery of cerebrolysin with neprilysin and p-Tau antibodies induces superior neuroprotection in Alzheimer's disease 2019 Ingår i: NANONEUROPROTECTION AND NANONEUROTOXICOLOGY. - : ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD. - 9780444642080 ; , s. 145-200 Bokkapitel (refereegranskat)abstract Alzheimer's disease (AD) is estimated to be afflicting over 55 millions of individual worldwide in 2018-19 for which no suitable clinical therapeutic measures have been developed so far. Thus, there is an urgent need to explore novel therapeutic strategies using nanodelivery of drugs and agents either alone or in combination for superior neuroprotection in AD and enhanced quality of life of the affected individuals. There are reports that AD is often associated with diminished neurotrophic factors and neprilysin together with enhancement of phosphorylated Tau (p-Tau) within the brain and in the cerebrospinal fluid (CSF). Thus, studies aiming to enhance neurotrophic factors and neprilysin together with neutralizing p-Tau within the central nervous system (CNS) may alleviate brain pathology in AD. In this review these strategies are discussed using nanotechnological approaches largely based on our own investigations in relation to current literature in the field.
46.	Sharma, Hari Shanker, et al. (författare) Neuroprotective effects of insulin like growth factor-1 on engineered metal nanoparticles Ag, Cu and Al induced blood-brain barrier breakdown, edema formation, oxidative stress, upregulation of neuronal nitric oxide synthase and brain pathology 2021 Ingår i: Progress in Brain Research. - : Elsevier. - 0079-6123 .- 1875-7855. ; 266, s. 97-121, s. 97-121 Tidskriftsartikel (refereegranskat)abstract Military personnel are vulnerable to environmental or industrial exposure of engineered nanoparticles (NPs) from metals. Long-term exposure of NPs from various sources affect sensory-motor or cognitive brain functions. Thus, a possibility exists that chronic exposure of NPs affect blood-brain barrier (BBB) breakdown and brain pathology by inducing oxidative stress and/or nitric oxide production. This hypothesis was examined in the rat intoxicated with Ag, Cu or Al (50–60 nm) nanoparticles (50 mg/kg, i.p. once daily) for 7 days. In these NPs treated rats the BBB permeability, brain edema, neuronal nitric oxide synthase (nNOS) immunoreactivity and brain oxidants levels, e.g., myeloperoxidase (MP), malondialdehyde (MD) and glutathione (GT) was examined on the 8th day. Cu and Ag but not Al nanoparticles increased the MP and MD levels by twofold in the brain although, GT showed 50% decline. At this time increase in brain water content and BBB breakdown to protein tracers were seen in areas exhibiting nNOS positive neurons and cell injuries. Pretreatment with insulin like growth factor-1 (IGF-1) in high doses (1 μg/kg, i.v. but not 0.5 μg/kg daily for 7 days) together with NPs significantly reduced the oxidative stress, nNOS upregulation, BBB breakdown, edema formation and cell injuries. These novel observations demonstrate that (i) NPs depending on their metal constituent (Cu, Ag but not Al) induce oxidative stress and nNOS expression leading to BBB disruption, brain edema and cell damage, and (ii) IGF-1 depending on doses exerts powerful neuroprotection against nanoneurotoxicity, not reported earlier.
47.	Sharma, Hari Shanker, et al. (författare) Neurotoxicity of single walled carbon nanotubes (SWCNT, 2-10 nm) and neuroprotection by TiO2 nanowired delivery of cerebrolysin 2013 Ingår i: Amino Acids. - 0939-4451 .- 1438-2199. ; 45:3, s. 565-565 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
48.	Sharma, Hari Shanker, et al. (författare) Novel therapeutic strategies using nanodrug delivery, stem cells and combination therapy for CNS trauma and neurodegenerative disorders 2013 Ingår i: Expert Review of Neurotherapeutics. - : Informa UK Limited. - 1473-7175 .- 1744-8360. ; 13:10, s. 1085-1088 Forskningsöversikt (refereegranskat)abstract The 10th Global College of Neuroproetction and Neuroregeneration Annual Conference together with the International Association of Neurorestoratology VI was held in Bucharest under the auspicious of the Society for the Study of Neuroprotection and Neuroplasticity during 4-7 April 2013. The focus of these unified societies meeting was on neurorestoration, neuroprotection and neuroregeneration in various clinical neurodegenerative diseases; for example, Alzheimer's, Parkinson's, Huntington's disease, stroke and brain or spinal cord injuries. The main aim to enhance healthcare was suggested by the use of stem cells, nanodrug delivery of drugs and stem cells, use of multimodal drugs as well as a combination of different approaches. The meeting was attended by more than 500 delegates including researches, policy makers and healthcare professionals along with several representatives from drug industries from Europe and USA. It appears that future of neuroprotection could be achieved by the use of stem cells and nanodrug delivery in chronic neurological disorders.
49.	Sharma, Hari Shanker, et al. (författare) Pathophysiology of Blood-Brain Barrier in Brain Injury in Cold and Hot Environments : Novel Drug Targets for Neuroprotection 2016 Ingår i: CNS & Neurological Disorders. - : Bentham Science Publishers Ltd.. - 1871-5273 .- 1996-3181. ; 15:9, s. 1045-1071 Forskningsöversikt (refereegranskat)abstract The blood-brain barrier (BBB) plays a pivotal role in the maintenance of central nervous system function in health and disease. Thus, in almost all neurodegenerative, traumatic or metabolic insults BBB breakdown occurs, allowing entry of serum proteins into the brain fluid microenvironment with subsequent edema formation and cellular injury. Accordingly, pharmacological restoration of BBB function will lead to neurorepair. However, brain injury which occurs following blast, bullet wounds, or knife injury appears to initiate different sets of pathophysiological responses. Moreover, other local factors at the time of injury such as cold or elevated ambient temperatures could also impact the final outcome. Obviously, drug therapy applied to different kinds of brain trauma occurring at either cold or hot environments may respond differently. This is largely due to the fact that internal defense mechanisms of the brain, gene expression, release of neurochemicals and binding of drugs to specific receptors are affected by external ambient temperature changes. These factors may also affect BBB function and development of edema formation after brain injury. In this review, the effects of seasonal exposure to heat and cold on traumatic brain injury using different models i.e., concussive brain injury and cerebral cortical lesion, on BBB dysfunction in relation to drug therapy are discussed. Our observations clearly suggest that closed head injury and open brain injury are two different entities and the external hot or cold environments affect both of them remarkably. Thus, effective pharmacological therapeutic strategies should be designed with these views in mind, as military personnel often experience blunt or penetrating head injuries in either cold or hot environments.
50.	Sharma, Hari Shanker, et al. (författare) Pathophysiology of blood-brain barrier in brain tumor. : Novel therapeutic advances using nanomedicine 2020 Ingår i: Novel Therapeutic Advances In Glioblastoma. - LONDON ENGLAND : Elsevier. - 9780128211144 ; , s. 1-66 Bokkapitel (refereegranskat)abstract Glioblastoma Multiforme (GBM) is one the most common intracranial tumors discovered by Burns (1800) and Abernethy (1804) based on gross morphology of the autopsied material and referred to as "medullary sarcoma" and later "fungus medullare" (Abernethy, 1804; Burns, 1800). Virchow in 1863 was the first German pathologist using histomorphological techniques discovered that GBM is a tumor of glial origin. Virchow (1863/65) also then used the term Glioma for the first time and classified as low-grade glioma and high-grade glioma very similar to that of today according to World health organization (WHO) classification (Jellinger, 1978; Virchow, 1863/65). After almost >50 years of this discovery, Baily and Cushing (1926) based on modern neuropathological tools provide the classification of gliomas that is still valid today (Baily & Cushing, 1926). Although, our knowledge about development of gliomas has advanced through development of modern cellular and molecular biological tools (Gately, McLachlan, Dowling, & Philip, 2017; Omuro & DeAngelis, 2013), therapeutic advancement of GBM still requires lot of efforts for the benefit of patients. This review summarizes new developments on pathophysiological aspects of GBM and novel therapeutic strategies to enhance quality of life of patients. These novel therapeutic approaches rely on enhanced penetration of drug therapy into the tumor tissues by use of nanomedicine for both the diagnostic and therapeutic purposes, referred to as "theranostic nanomedicine" (Alphandery, 2020; Zhao, van Straten, Broekman, Preat, & Schiffelers, 2020). Although, the blood-brain barrier (BBB) is fenestrated around the periphery of the tumor tissues, the BBB is still tight within the deeper tissues of the tumor. Thus, drug delivery is a challenge for gliomas and requires new therapeutic advances (Zhao et al., 2020). Associated edema development around tumor tissues is another factor hindering therapeutic effects (Liu, Mei, & Lin, 2013). These factors are discussed in details using novel therapeutic advances in gliomas.

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