| 1. |
- Avram, Vlad F., et al.
(author)
-
Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Statin Toxicity
- 2021
-
In: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:1
-
Journal article (peer-reviewed)abstract
- Statins are the cornerstone of lipid-lowering therapy. Although generally well tolerated, statin-associated muscle symptoms (SAMS) represent the main reason for treatment discontinuation. Mitochondrial dysfunction of complex I has been implicated in the pathophysiology of SAMS. The present study proposed to assess the concentration-dependent ex vivo effects of three statins on mito-chondrial respiration in viable human platelets and to investigate whether a cell-permeable prodrug of succinate (complex II substrate) can compensate for statin-induced mitochondrial dysfunction. Mitochondrial respiration was assessed by high-resolution respirometry in human platelets, acutely exposed to statins in the presence/absence of the prodrug NV118. Statins concentration-dependently inhibited mitochondrial respiration in both intact and permeabilized cells. Further, statins caused an increase in non-ATP generating oxygen consumption (uncoupling), severely limiting the OXPHOS coupling efficiency, a measure of the ATP generating capacity. Cerivastatin (commercially withdrawn due to muscle toxicity) displayed a similar inhibitory capacity compared with the widely prescribed and tolerable atorvastatin, but did not elicit direct complex I inhibition. NV118 increased succinate-supported mitochondrial oxygen consumption in atorvastatin/cerivastatin-exposed platelets leading to normalization of coupled (ATP generating) respiration. The results acquired in isolated human platelets were validated in a limited set of experiments using atorvastatin in HepG2 cells, reinforcing the generalizability of the findings.
|
|
| 2. |
- Avram, Vlad Florian, et al.
(author)
-
Improvement of platelet respiration by cell-permeable succinate in diabetic patients treated with statins
- 2021
-
In: Life. - : MDPI AG. - 0024-3019 .- 2075-1729. ; 11:4
-
Journal article (peer-reviewed)abstract
- Diabetes mellitus (DM) is the most severe metabolic disease that reached the level of a global pandemic and is associated with high cardiovascular morbidity. Statins are the first-line lipid- lowering therapy in diabetic patients with or without a history of atherosclerotic disease. Although well tolerated, chronic treatment may result in side effects that lead to treatment interruption. Mitochondrial dysfunction has emerged as a central pathomechanism in DM- and statin-induced side effects. Assessment of mitochondrial respiration in peripheral platelets has been increasingly used as a mirror of organ mitochondrial dysfunction. The present study aimed to assess the: (i) changes in mitochondrial respiration elicited by statins in patients with type 2 DM and (ii) the effects of cell-permeable succinate (NV118) on respiratory parameters in platelets harvested from these patients. No significant changes were found in global mitochondrial respiration of intact platelets isolated from diabetic patients treated with either atorvastatin or rosuvastatin. Similarly, no significant changes in mitochondrial respiration of permeabilized platelets were found between diabetic patients treated with atorvastatin and healthy controls. Acute ex vivo administration of NV118 significantly improved respiration in isolated platelets. These results prompt further research on the role of permeable succinate as a therapeutic alternative for improving mitochondrial function in metabolic pathologies and point to the role of peripheral platelets as a potential biomarker of treatment response.
|
|
| 3. |
- Bengzon, Johan, et al.
(author)
-
Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures
- 1997
-
In: Proceedings of the National Academy of Sciences. - 1091-6490. ; 94:19, s. 10432-10437
-
Journal article (peer-reviewed)abstract
- Neuronal apoptosis was observed in the rat dentate gyrus in two experimental models of human limbic epilepsy. Five hours after one hippocampal kindling stimulation, a marked increase of in situ terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) of fragmented DNA was observed in nuclei located within and on the hilar border of the granule cell layer and in the polymorphic region. Forty kindling stimulations with 5-min interval produced higher numbers of labeled nuclei compared with one stimulation. The increase of TUNEL-positive nuclei was prevented by the protein synthesis inhibitor cycloheximide but not affected by the N-methyl-D-aspartate receptor antagonist MK-801. Kainic acid-induced seizures lead to a pattern of labeling in the hippocampal formation identical to that evoked by kindling. A large proportion of cells displaying TUNEL-positive nuclei was double-labeled by the neuron-specific antigen NeuN, demonstrating the neuronal identity of apoptotic cells. Either 1 or 40 kindling stimulations also gave rise to a marked increase of the number of cells double-labeled with the mitotic marker bromodeoxyuridine and NeuN in the subgranular zone and on the hilar border of the dentate granule cell layer. The present data show that single and intermittent, brief seizures induce both apoptotic death and proliferation of dentate gyrus neurons. We hypothesize that these processes, occurring early during epileptogenesis, are primary events in the development of hippocampal pathology in animals and possibly also in patients suffering from temporal lobe epilepsy.
|
|
| 4. |
- Beţiu, Alina Maria, et al.
(author)
-
Dose-dependent effects of acetaminophen and ibuprofen on mitochondrial respiration of human platelets
-
In: Molecular and Cellular Biochemistry. - 0300-8177.
-
Journal article (peer-reviewed)abstract
- Acetaminophen and ibuprofen are widely used over-the-counter medications to reduce fever, pain, and inflammation. Although both drugs are safe in therapeutic concentrations, self-medication is practiced by millions of aged patients with comorbidities that decrease drug metabolism and/or excretion, thus raising the risk of overdosage. Mitochondrial dysfunction has emerged as an important pathomechanism underlying the organ toxicity of both drugs. Assessment of mitochondrial oxygen consumption in peripheral blood cells is a novel research field Cu several applications, including characterization of drug toxicity. The present study, conducted in human platelets isolated from blood donor-derived buffy coat, was aimed at assessing the acute, concentration-dependent effects of each drug on mitochondrial respiration. Using the high-resolution respirometry technique, a concentration-dependent decrease of oxygen consumption in both intact and permeabilized platelets was found for either drug, mainly by inhibiting complex I-supported active respiration. Moreover, ibuprofen significantly decreased the maximal capacity of the electron transport system already from the lowest concentration. In conclusion, platelets from healthy donors represents a population of cells easily available, which can be routinely used in studies assessing mitochondrial drug toxicity. Whether these results can be recapitulated in patients treated with these medications is worth further investigation as potential peripheral biomarker of drug overdose.
|
|
| 5. |
- Bețiu, Alina M., et al.
(author)
-
Cell‐permeable succinate rescues mitochondrial respiration in cellular models of amiodarone toxicity
- 2021
-
In: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:21
-
Journal article (peer-reviewed)abstract
- Amiodarone is a potent antiarrhythmic drug and displays substantial liver toxicity in hu-mans. It has previously been demonstrated that amiodarone and its metabolite (desethylamioda-rone, DEA) can inhibit mitochondrial function, particularly complexes I (CI) and II (CII) of the elec-tron transport system in various animal tissues and cell types. The present study, performed in human peripheral blood cells, and one liver‐derived human cell line, is primarily aimed at assessing the concentration‐dependent effects of these drugs on mitochondrial function (respiration and cellular ATP levels). Furthermore, we explore the efficacy of a novel cell‐permeable succinate prodrug in alleviating the drug‐induced acute mitochondrial dysfunction. Amiodarone and DEA elicit a con-centration‐dependent impairment of mitochondrial respiration in both intact and permeabilized platelets via the inhibition of both CI‐ and CII‐supported respiration. The inhibitory effect seen in human platelets is also confirmed in mononuclear cells (PBMCs) and HepG2 cells. Additionally, amiodarone elicits a severe concentration‐dependent ATP depletion in PBMCs, which cannot be explained solely by mitochondrial inhibition. The succinate prodrug NV118 alleviates the respiratory deficit in platelets and HepG2 cells acutely exposed to amiodarone. In conclusion, amiodarone severely inhibits metabolism in primary human mitochondria, which can be counteracted by in-creasing mitochondrial function using intracellular delivery of succinate.
|
|
| 6. |
- Bețiu, Alina M., et al.
(author)
-
Mitochondrial Effects of Common Cardiovascular Medications : The Good, the Bad and the Mixed
- 2022
-
In: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 23:21
-
Research review (peer-reviewed)abstract
- Mitochondria are central organelles in the homeostasis of the cardiovascular system via the integration of several physiological processes, such as ATP generation via oxidative phosphorylation, synthesis/exchange of metabolites, calcium sequestration, reactive oxygen species (ROS) production/buffering and control of cellular survival/death. Mitochondrial impairment has been widely recognized as a central pathomechanism of almost all cardiovascular diseases, rendering these organelles important therapeutic targets. Mitochondrial dysfunction has been reported to occur in the setting of drug-induced toxicity in several tissues and organs, including the heart. Members of the drug classes currently used in the therapeutics of cardiovascular pathologies have been reported to both support and undermine mitochondrial function. For the latter case, mitochondrial toxicity is the consequence of drug interference (direct or off-target effects) with mitochondrial respiration/energy conversion, DNA replication, ROS production and detoxification, cell death signaling and mitochondrial dynamics. The present narrative review aims to summarize the beneficial and deleterious mitochondrial effects of common cardiovascular medications as described in various experimental models and identify those for which evidence for both types of effects is available in the literature.
|
|
| 7. |
- Borlongan, C V, et al.
(author)
-
Cyclosporine-A enhances choline acetyltransferase immunoreactivity in the septal region of adult rats
- 2000
-
In: Neuroscience Letters. - 0304-3940. ; 279:2, s. 73-76
-
Journal article (peer-reviewed)abstract
- Cyclosporine-A (CsA) is the primary anti-rejection drug used for organ and neural transplantation therapy. In addition to its immunosuppressive action, CsA has been recently shown to exert neuroprotective and neurotrophic effects in the central nervous system when able to cross the blood-brain barrier. Postulated mechanisms for these CsA-induced beneficial effects include the drug's powerful inhibition of the calcium-dependent phosphatase calcineurin (CN) and blockade of the assembly of the mitochondrial permeability transition pore. We report here, for the first time, that adult Wistar rats treated with CsA (10 mg/kg per day, i.p. for 9 days) displayed significantly reduced septal CN expression in combination with enhanced levels of septal choline acetyltransferase (ChAT) immunoreactivity as compared to controls. The observed enhancement of septal ChAT immunoreactivity suggests potential therapeutic utility of CsA for brain disorders characterized by alterations of the cholinergic system.
|
|
| 8. |
- Burguillos Garcia, Miguel, et al.
(author)
-
Microchannel Acoustophoresis does not Impact Survival or Function of Microglia, Leukocytes or Tumor Cells.
- 2013
-
In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:5
-
Journal article (peer-reviewed)abstract
- The use of acoustic forces to manipulate particles or cells at the microfluidic scale (i.e. acoustophoresis), enables non-contact, label-free separation based on intrinsic cell properties such as size, density and compressibility. Acoustophoresis holds great promise as a cell separation technique in several research and clinical areas. However, it has been suggested that the force acting upon cells undergoing acoustophoresis may impact cell viability, proliferation or cell function via subtle phenotypic changes. If this were the case, it would suggest that the acoustophoresis method would be a less useful tool for many cell analysis applications as well as for cell therapy.
|
|
| 9. |
- Chumarina, Margarita, et al.
(author)
-
Cellular alterations identified in pluripotent stem cell-derived midbrain spheroids generated from a female patient with progressive external ophthalmoplegia and parkinsonism who carries a novel variation (p.Q811R) in the POLG1 gene
- 2019
-
In: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 7:1
-
Journal article (peer-reviewed)abstract
- Variations in the POLG1 gene encoding the catalytic subunit of the mitochondrial DNA polymerase gamma, have recently been associated with Parkinson's disease (PD), especially in patients diagnosed with progressive external ophthalmoplegia (PEO). However, the majority of the studies reporting this association mainly focused on the genetic identification of the variation in POLG1 in PD patient primary cells, and determination of mitochondrial DNA copy number, providing little information about the cellular alterations existing in patient brain cells, in particular dopaminergic neurons. Therefore, through the use of induced pluripotent stem cells (iPSCs), we assessed cellular alterations in novel p.Q811R POLG1 (POLG1Q811R) variant midbrain dopaminergic neuron-containing spheroids (MDNS) from a female patient who developed early-onset PD, and compared them to cultures derived from a healthy control of the same gender. Both POLG1 variant and control MDNS contained functional midbrain regionalized TH/FOXA2-positive dopaminergic neurons, capable of releasing dopamine. Western blot analysis identified the presence of high molecular weight oligomeric alpha-synuclein in POLG1Q811R MDNS compared to control cultures. In order to assess POLG1Q811R-related cellular alterations within the MDNS, we applied mass-spectrometry based quantitative proteomic analysis. In total, 6749 proteins were identified, with 61 significantly differentially expressed between POLG1Q811R and control samples. Pro-And anti-inflammatory signaling and pathways involved in energy metabolism were altered. Notably, increased glycolysis in POLG1Q811R MDNS was suggested by the increase in PFKM and LDHA levels and confirmed using functional analysis of glycolytic rate and oxygen consumption levels. Our results validate the use of iPSCs to assess cellular alterations in relation to PD pathogenesis, in a unique PD patient carrying a novel p.Q811R variation in POLG1, and identify several altered pathways that may be relevant to PD pathogenesis.
|
|
| 10. |
- Cung, T. -T., et al.
(author)
-
Cyclosporine before PCI in Patients with Acute Myocardial Infarction
- 2015
-
In: New England Journal of Medicine. - 0028-4793. ; 373:11, s. 1021-1031
-
Journal article (peer-reviewed)abstract
- BACKGROUND Experimental and clinical evidence suggests that cyclosporine may attenuate reperfusion injury and reduce myocardial infarct size. We aimed to test whether cyclosporine would improve clinical outcomes and prevent adverse left ventricular remodeling. METHODS In a multicenter, double-blind, randomized trial, we assigned 970 patients with an acute anterior ST-segment elevation myocardial infarction (STEMI) who were undergoing percutaneous coronary intervention (PCI) within 12 hours after symptom onset and who had complete occlusion of the culprit coronary artery to receive a bolus injection of cyclosporine (administered intravenously at a dose of 2.5 mg per kilogram of body weight) or matching placebo before coronary recanalization. The primary outcome was a composite of death from any cause, worsening of heart failure during the initial hospitalization, rehospitalization for heart failure, or adverse left ventricular remodeling at 1 year. Adverse left ventricular remodeling was defined as an increase of 15% or more in the left ventricular end-diastolic volume. RESULTS A total of 395 patients in the cyclosporine group and 396 in the placebo group received the assigned study drug and had data that could be evaluated for the primary outcome at 1 year. The rate of the primary outcome was 59.0% in the cyclosporine group and 58.1% in the control group (odds ratio, 1.04; 95% confidence interval, 0.78 to 1.39; P = 0.77). Cyclosporine did not reduce the incidence of the separate clinical components of the primary outcome or other events, including recurrent infarction, unstable angina, and stroke. No significant difference in the safety profile was observed between the two treatment groups. CONCLUSIONS In patients with anterior STEMI who had been referred for primary PCI, intravenous cyclosporine did not result in better clinical outcomes than those with placebo and did not prevent adverse left ventricular remodeling at 1 year. (Funded by the French Ministry of Health and NeuroVive Pharmaceutical; CIRCUS ClinicalTrials.gov number, NCT01502774; EudraCT number, 2009-013713-99.)
|
|
| 11. |
- Ederoth, Per, et al.
(author)
-
Ciclosporin to Protect Renal function In Cardiac Surgery (CiPRICS) : A study protocol for a double-blind, randomised, placebo-controlled, proof-of-concept study
- 2016
-
In: BMJ Open. - 2044-6055. ; 6:12
-
Journal article (peer-reviewed)abstract
- Introduction: Acute kidney injury (AKI) after cardiac surgery is common and results in increased morbidity and mortality. One possible mechanism for AKI is ischaemia-reperfusion injury caused by the extracorporeal circulation (ECC), resulting in an opening of the mitochondrial permeability transition pore (mPTP) in the kidneys, which can lead to cell injury or cell death. Ciclosporin may block the opening of mPTP if administered before the ischaemia- reperfusion injury. We hypothesised that ciclosporin given before the start of ECC in cardiac surgery can decrease the degree of AKI. Methods and analysis: Ciclosporin to Protect Renal function In Cardiac Surgery (CiPRICS) study is an investigator-initiated double-blind, randomised, placebo-controlled, parallel design, single-centre study performed at a tertiary university hospital. The primary objective is to assess the safety and efficacy of ciclosporin to limit the degree of AKI in patients undergoing coronary artery bypass grafting surgery. We aim to evaluate 150 patients with a preoperative estimated glomerular filtration rate of 15-90 mL/min/ 1.73 m2. Study patients are randomised in a 1:1 ratio to receive study drug 2.5 mg/kg ciclosporin or placebo as an intravenous injection after anaesthesia induction but before start of surgery. The primary end point consists of relative P-cystatin C changes from the preoperative day to postoperative day 3. The primary variable will be tested using an analysis of covariance method. Secondary end points include evaluation of P-creatinine and biomarkers of kidney, heart and brain injury. Ethics and dissemination: The trial is conducted in compliance with the current version of the Declaration of Helsinki and the International Council for Harmonisation (ICH) Good Clinical Practice guidelines E6 (R1) and was approved by the Regional Ethical Review Board, Lund and the Swedish Medical Products Agency (MPA). Written and oral informed consent is obtained before enrolment into the study.
|
|
| 12. |
|
|
| 13. |
- EHINGER, JOHANNES, et al.
(author)
-
Bioequivalence and Tolerability Assessment of a Novel Intravenous Ciclosporin Lipid Emulsion Compared to Branded Ciclosporin in Cremophor(®) EL.
- 2013
-
In: Clinical Drug Investigation. - : Springer Science and Business Media LLC. - 1179-1918 .- 1173-2563. ; 33:1, s. 25-34
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Ciclosporin is used as an immunosuppressant in current clinical practice but recent research implies novel indications for the drug, such as neuro- and cardioprotection. The intravenous formulation currently on the market, Sandimmune(®) Injection (Sandimmune(®)), uses Cremophor(®) EL as emulsifying excipient. Cremophor(®) EL is known to cause hypersensitivity reactions in some patients, ranging from skin reactions to potentially fatal anaphylactic shock. OBJECTIVES: The primary objective was to assess if CicloMulsion(®), a Cremophor(®) EL-free lipid emulsion of ciclosporin for intravenous administration, is bioequivalent to Sandimmune(®), and the secondary objective was to compare the tolerability profiles of the two preparations. METHODS: This was a single-centre, open-label, subject-blind, laboratory-blind, single-dose, randomized, two-treatment, two-period, two-sequence crossover study of the pharmacokinetics of two formulations of intravenous ciclosporin. Fifty-two healthy volunteer subjects were administered 5 mg/kg of each of the two formulations of ciclosporin as a 4-h intravenous infusion. The last blood sample was acquired 48 h after the end of the infusion. Bioequivalence assessments according to current guidelines were performed. RESULTS: The geometric mean ratios for CicloMulsion(®)/Sandimmune(®) (90 % confidence interval [CI]) were 0.90 (0.88, 0.92) for AUC(0-last) (area under the blood concentration-time curve from time zero to time of last measurable concentration) and 0.95 (0.92, 0.97) for C(max) (maximum blood concentration). For all additional variables analysed, the 90 % CIs were also within the accepted bioequivalence range of 0.80-1.25. One anaphylactoid and one anaphylactic reaction, both classified as serious adverse events, were reported after treatment with Sandimmune(®). No serious adverse events were recorded after treatment with CicloMulsion(®). CONCLUSION: We have assessed the pharmacokinetics and tolerability of a new Cremophor(®) EL-free lipid emulsion of ciclosporin, CicloMulsion(®), compared to Sandimmune(®). The proportion of adverse events was significantly higher for the Cremophor(®) EL-based product Sandimmune(®). We conclude that CicloMulsion(®) is bioequivalent to Sandimmune(®) and exhibits fewer adverse reactions.
|
|
| 14. |
- Ehinger, Johannes K., et al.
(author)
-
Cell-permeable succinate prodrugs bypass mitochondrial complex i deficiency
- 2016
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
Journal article (peer-reviewed)abstract
- Mitochondrial complex I (CI) deficiency is the most prevalent defect in the respiratory chain in paediatric mitochondrial disease. This heterogeneous group of diseases includes serious or fatal neurological presentations such as Leigh syndrome and there are very limited evidence-based treatment options available. Here we describe that cell membrane-permeable prodrugs of the complex II substrate succinate increase ATP-linked mitochondrial respiration in CI-deficient human blood cells, fibroblasts and heart fibres. Lactate accumulation in platelets due to rotenone-induced CI inhibition is reversed and rotenone-induced increase in lactate:pyruvate ratio in white blood cells is alleviated. Metabolomic analyses demonstrate delivery and metabolism of [ 13 C]succinate. In Leigh syndrome patient fibroblasts, with a recessive NDUFS2 mutation, respiration and spare respiratory capacity are increased by prodrug administration. We conclude that prodrug-delivered succinate bypasses CI and supports electron transport, membrane potential and ATP production. This strategy offers a potential future therapy for metabolic decompensation due to mitochondrial CI dysfunction.
|
|
| 15. |
- Ehinger, Johannes K., et al.
(author)
-
Mitochondrial function in peripheral blood cells across the human lifespan
- 2024
-
In: npj Aging. - 2731-6068. ; 10:1
-
Journal article (peer-reviewed)abstract
- Mitochondrial dysfunction is considered a hallmark of aging. Up to now, a gradual decline of mitochondrial respiration with advancing age has mainly been demonstrated in human muscle tissue. A handful of studies have examined age-related mitochondrial dysfunction in human blood cells, and only with small sample sizes and mainly in platelets. In this study, we analyzed mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) and platelets from 308 individuals across the human lifespan (0–86 years). In regression analyses, with adjustment for false discovery rate (FDR), we found age-related changes in respiratory measurements to be either small or absent. The main significant changes were an age-related relative decline in complex I-linked respiration and a corresponding rise of complex II-linked respiration in PBMCs. These results add to the understanding of mitochondrial dysfunction in aging and to its possible role in immune cell and platelet senescence.
|
|
| 16. |
- Ehinger, Johannes, et al.
(author)
-
Mitochondrial dysfunction in blood cells from amyotrophic lateral sclerosis patients.
- 2015
-
In: Journal of Neurology. - : Springer Science and Business Media LLC. - 1432-1459 .- 0340-5354. ; 262:6, s. 1493-1503
-
Journal article (peer-reviewed)abstract
- Mitochondrial dysfunction is implicated in amyotrophic lateral sclerosis, where the progressive degeneration of motor neurons results in muscle atrophy, paralysis and death. Abnormalities in both central nervous system and muscle mitochondria have previously been demonstrated in patient samples, indicating systemic disease. In this case-control study, venous blood samples were acquired from 24 amyotrophic lateral sclerosis patients and 21 age-matched controls. Platelets and peripheral blood mononuclear cells were isolated and mitochondrial oxygen consumption measured in intact and permeabilized cells with additions of mitochondrial substrates, inhibitors and titration of an uncoupler. Respiratory values were normalized to cell count and for two markers of cellular mitochondrial content, citrate synthase activity and mitochondrial DNA, respectively. Mitochondrial function was correlated with clinical staging of disease severity. Complex IV (cytochrome c-oxidase)-activity normalized to mitochondrial content was decreased in platelets from amyotrophic lateral sclerosis patients both when normalized to citrate synthase activity and mitochondrial DNA copy number. In mononuclear cells, complex IV-activity was decreased when normalized to citrate synthase activity. Mitochondrial content was increased in amyotrophic lateral sclerosis patient platelets. In mononuclear cells, complex I activity declined and mitochondrial content increased progressively with advancing disease stage. The findings are, however, based on small subsets of patients and need to be confirmed. We conclude that when normalized to mitochondria-specific content, complex IV-activity is reduced in blood cells from amyotrophic lateral sclerosis patients and that there is an apparent compensatory increase in cellular mitochondrial content. This supports systemic involvement in amyotrophic lateral sclerosis and suggests further study of mitochondrial function in blood cells as a future biomarker for the disease.
|
|
| 17. |
- EHINGER, JOHANNES, et al.
(author)
-
Mitochondrial Respiratory Function in Peripheral Blood Cells from Huntington's Disease Patients
- 2016
-
In: Movement Disorders Clinical Practice. - : Wiley. - 2330-1619. ; 3:5, s. 472-482
-
Journal article (peer-reviewed)abstract
- BackgroundPatients with Huntington's disease display symptoms from both the central nervous system and peripheral tissues. Mitochondrial dysfunction has been implicated as part of the pathogenesis of the disease and has been reported in brain tissue and extracerebral tissues, such as muscle and blood cells, but the results are inconsistent. Therefore, the authors performed a refined evaluation of mitochondrial function in 2 types of peripheral blood cells from 14 patients with Huntington's disease and 21 control subjects. Several hypotheses were predefined, including impaired mitochondrial complex II function (primary), complex I function (secondary), and maximum oxidative phosphorylation capacity (secondary) in patient cells.MethodsHigh-resolution respirometry was applied to viable platelets and mononuclear cells. Data were normalized to cell counts, citrate synthase activity, and mitochondrial DNA copy numbers.ResultsNormalized to citrate synthase activity, platelets from patients with Huntington's disease displayed respiratory dysfunction linked to complex I, complex II, and lower maximum oxidative phosphorylation capacity. No difference was seen in mononuclear cells or when platelet data were normalized to cell counts or mitochondrial DNA. The ratio of complex I respiration through maximum oxidative phosphorylation was significantly decreased in patients compared with controls. The corresponding ratio for complex II was unaffected.ConclusionsThe data indicate decreased function of mitochondrial complex I in peripheral blood cells from patients with Huntington's disease, although this could not be uniformly confirmed. The results do not confirm a systemic complex II dysfunction and do not currently support the use of mitochondrial function in blood cells as a biomarker for the disease.
|
|
| 18. |
- Ekdahl, Christine T, et al.
(author)
-
Caspase inhibitors increase short-term survival of progenitor-cell progeny in the adult rat dentate gyrus following status epilepticus
- 2001
-
In: European Journal of Neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 14:6, s. 937-945
-
Journal article (peer-reviewed)abstract
- The dentate gyrus (DG) is one of the few regions in the brain that continues to produce new neurons throughout adulthood. Seizures not only increase neurogenesis, but also lead to death of DG neurons. We investigated the relationship between cell death and neurogenesis following seizures in the DG of adult rats by blocking caspases, which are key components of apoptotic cell death. Multiple intracerebroventricular infusions of caspase inhibitors (pancaspase inhibitor zVADfmk, and caspase 3 and 9 inhibitor) prior to, just after, 1 day after, and 1 week following 2 h of lithium-pilocarpine-induced status epilepticus reduced the number of terminal deoxynucleotidyl transferase-mediated fluorescein-dUTP nick-end labelled (TUNEL) cells and increased the number of bromodeoxyuridine (BrdU) -stained proliferated cells in the subgranular zone at 1 week. The caspase inhibitor-treated group did not differ from control at 2 days or 5 weeks following the epileptic insult. Our findings suggest that caspases modulate seizure-induced neurogenesis in the DG, probably by regulating apoptosis of newly born neurons, and that this action can be suppressed transiently by caspase inhibitors. Furthermore, although previous studies have indicated that increased neuronal death can trigger neurogenesis, we show here that reduction in apoptotic death may be associated with increased neurogenesis.
|
|
| 19. |
- Elmer, Eskil, et al.
(author)
-
Delayed kindling development after rapidly recurring seizures: relation to mossy fiber sprouting and neurotrophin, GAP-43 and dynorphin gene expression
- 1996
-
In: Brain Research. - : Elsevier BV. - 1872-6240 .- 0006-8993. ; 712:1, s. 19-34
-
Journal article (peer-reviewed)abstract
- Development of kindling and mossy fiber sprouting, and changes of gene expression were studied after 40 seizures produced during about 3 h by electrical stimulation every 5 min in the ventral hippocampus. As assessed by 5 test stimulations, enhanced responsiveness was present already after 6-24 h but from 1 week post-seizure increased gradually up to 4 weeks without additional stimuli. Sprouting of mossy fibers in the dentate gyrus was demonstrated only at 4 weeks with Timm's staining. In situ hybridization showed a transient increase (maximum at 2 h) of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), TrkB and TrkC mRNA levels and reduction (maximum at 12-24 h) of neurotrophin-3 (NT-3) mRNA expression in dentate granule cells after the seizures. In addition, BDNF mRNA levels were elevated in CA1 and CA3 regions, amygdala and piriform cortex. Marked increases of mRNA for growth-associated protein (GAP-43), with maximum expression at 12-24 h, were observed in dentate granule cells and in amygdala-piriform cortex. Dynorphin mRNA levels showed biphasic changes in dentate granule cells with an increase at 2 h followed by a decrease at 24 h. No long-term alterations of gene expression were observed. These findings indicate that increased responsiveness develops rapidly after recurring seizures but that the kindled state is reached gradually in about 4 weeks. Mossy fiber sprouting occurs in parallel to epileptogenesis and may play a causative role. Short-term changes of neurotrophin and Trk, GAP-43 and dynorphin mRNA levels and the assumed alterations of the corresponding proteins could trigger structural rearrangements underlying kindling but might also contribute to the initial increase of seizure susceptibility.
|
|
| 20. |
- Elmer, Eskil, et al.
(author)
-
Dynamic changes of brain-derived neurotrophic factor protein levels in the rat forebrain after single and recurring kindling-induced seizures
- 1998
-
In: Neuroscience. - 1873-7544. ; 83:2, s. 351-362
-
Journal article (peer-reviewed)abstract
- Regional levels of brain-derived neurotrophic factor protein were measured in the rat brain using enzyme immunoassay following seizures evoked by hippocampal kindling stimulations. One stimulation, which induced a brief, single episode of epileptiform activity in hippocampus and piriform cortex but not in parietal cortex or striatum, gave rise to a transient increase of brain-derived neurotrophic factor levels in dentate gyrus and CA3 region and a decrease in piriform cortex. After 40 rapidly recurring seizures, with epileptiform activity also involving parietal cortex and striatum, increases were observed in dentate gyrus, CA3 and CA1 regions, piriform cortex and striatum. Maximum levels were reached at 2-24 h and brain-derived neurotrophic factor then returned to baseline except in dentate gyrus, where elevated protein content was sustained for four days. The differential regulation of brain-derived neurotrophic factor protein levels in various forebrain structures, which only partly correlates to messenger RNA changes, could indicate regional differences in protein release, antero- or retrograde transport, or brain-derived neurotrophic factor promotor activation. The dynamic changes of brain-derived neurotrophic factor levels in regions involved in the generation and spread of seizure activity may regulate excitability and trigger plastic responses in the post-seizure period.
|
|
| 21. |
- Elmer, Eskil, et al.
(author)
-
Epileptogenesis induced by rapidly recurring seizures in genetically fast- but not slow-kindling rats
- 1998
-
In: Brain Research. - 1872-6240. ; 789:1, s. 111-117
-
Journal article (peer-reviewed)abstract
- A brief period of rapidly recurring hippocampal seizures can lead to the progressive development of a permanent increase of seizure susceptibility over several weeks, so-called 'delayed kindling'. We have analyzed seizure parameters critical for the induction of delayed kindling in two strains of rats characterized by fast and slow rates of traditional kindling, respectively. Forty seizures were produced during about 3 h by electrical kindling stimulations every 5 min in the ventral hippocampus. The fast rats displayed several generalized convulsions and had long periods of epileptiform activity, whereas the slow animals only exhibited brief, focal seizures. Changes in excitability were determined after 4 weeks using five test stimulations, and 2 weeks later by subjecting all animals to traditional hippocampal kindling. The fast rats showed clearly enhanced responsiveness at these time points, whereas no evidence of permanently increased seizure susceptibility was obtained in the slow rats. Our data indicate that the long-lasting stimulus-evoked seizures are mainly responsible for inducing delayed kindling, whereas the number of seizure events or generalized convulsions, and the total duration of epileptiform activity are less important. We hypothesize that long seizure episodes may be necessary to trigger the cascade of gene changes regulating the development of epilepsy.
|
|
| 22. |
- Elmer, Eskil
(author)
-
Mechanisms of Hyperexcitability in the Kindling Model of Epilepsy
- 1997
-
Doctoral thesis (other academic/artistic)abstract
- Epilepsy is a syndrome characterized by recurring attacks of sudden, excessive and synchronous discharge in populations of cerebral neurons. Kindling is an animal model for complex partial epilepsy, and is particularly useful for studies on the development of the abnormal excitability underlying the generation and spread of epileptic seizures. Here we have used the kindling model to investigate mechanisms important for the development of hyperexcitability, with particular emphasis on the role of neurotrophic factors and hippocampal synaptic reorganization. We demonstrate for the first time that a brief period of stimulus-evoked recurring seizures can trigger a long-term increase of excitability, which develops in two phases: an acute, transient, and a late phase developing gradually over a 4 week period. This type of rapidly recurring seizures induced delayed epileptogenesis in a strain of genetically fast but not slow kindling rats. Comparisons between these two strains and normal rats suggest that long duration of individual focal seizures during the initial stimulation procedure plays a more important role than, e. g., seizure generalization and total seizure duration for the delayed increase in excitability. Results from the studies presented here in neurotrophin knockout mice, indicate a facilitatory role for the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 in kindling epileptogenesis. Using a recently developed enzyme immonoassay, prominent alterations in BDNF protein levels were detected following single and recurring kindling-induced seizures in various forebrain regions important for seizure generation and spread. Granule cell mossy fiber sprouting to the inner molecular layer of the dentate gyrus developed in parallel to increased excitability following both traditional kindling and recurring seizures. Kindling epileptogenesis could be evoked without sprouting in genetically slow and fast kindlers, suggesting that mossy fiber sprouting does not play a crucial facilitatory role in epileptogenesis. Directly supporting an inhibitory action of mossy fiber reorganization in epileptogenesis was the finding that non-stimulated genetically slow animals had a more dense projection of mossy fibers to the inner molecular layer as compared to fast animals. The results of the present thesis suggest that attenuation of neurotrophin responses after seizures and other brain insults, such as traumatic injury, might have an antiepileptogenic action. In addition, the findings of delayed epileptogenesis after recurring seizures might initiate future pharmacological intervention for the prevention of chronic epilepsy following head trauma or status epilepticus in patients.
|
|
| 23. |
- Elmer, Eskil, et al.
(author)
-
Mossy fibre sprouting: evidence against a facilitatory role in epileptogenesis
- 1997
-
In: NeuroReport. - 1473-558X. ; 8:5, s. 1193-1196
-
Journal article (peer-reviewed)abstract
- Sprouting of mossy fibres from dentate granule cells occurs in several animal models of epilepsy and in epileptic humans. Mossy fibre sprouting might contribute to epileptogenesis but also could be a compensatory, inhibitory response. We analysed mossy fibre sprouting in the supragranular zone of the dentate gyrus using Timm's histochemical method in genetically fast and slow kindling rats. Before the start of amygdala kindling, the slow rats showed higher Timm's staining scores than did the fast kindlers. No increase of mossy fibre density was observed when the animals were stimulated until either the fast or the slow rats had reached the fully kindled state. Our data argue against the hypothesis that mossy fibre sprouting facilitates epileptogenesis.
|
|
| 24. |
- Elmer, Eskil, et al.
(author)
-
Regulation of neuronal nitric oxide synthase mRNA levels in rat brain by seizure activity
- 1996
-
In: NeuroReport. - 1473-558X. ; 7:7, s. 1335-1335
-
Journal article (peer-reviewed)abstract
- The regulation of neuronal nitric oxide synthase (NOS) mRNA levels during kindling epileptogenesis in the rat brain was investigated using in situ hybridization. Following 40 rapidly recurring seizures evoked by hippocampal stimulations, NOS mRNA expression decreased by 56% in the dentate granule cell layer (maximum at 2 h) and increased by 420,105 and 1260% in the CA1 and CA3 pyramidal layers and piriform cortex, respectively (maximum at 12-24 h). Gene expression had returned to control levels after one week. The presumed alterations of nitric oxide production, following the changes in NOS mRNA shown here, may modulate synaptic function during kindling development, and could influence neuronal vulnerability after epileptic insults.
|
|
| 25. |
- Elmer, Eskil, et al.
(author)
-
Suppressed kindling epileptogenesis and perturbed BDNF and TrkB gene regulation in NT-3 mutant mice
- 1997
-
In: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 145:1, s. 93-103
-
Journal article (peer-reviewed)abstract
- In the kindling model of epilepsy, repeated electrical stimulations lead to progressive and permanent intensification of seizure activity. We find that the development of amygdala kindling is markedly retarded in mice heterozygous for a deletion of the neurotrophin-3 (NT-3) gene (NT-3+/- mice). These mice did not reach the fully kindled state (3rd grade 5 seizure) until after 28 +/- 4 days of stimulation compared to 17 +/- 2 days in the wild-type animals. The deficit in the NT-3+/- mice reflected dampening of the progression from focal to generalized seizures. The number of stimulations required to evoke focal (grade 1 and 2) seizures did not differ between the groups, but the NT-3 mutants spent a considerably longer period of time (13 +/- 3 days) than wild-type mice (2 +/- 1 days) in grade 2 seizures. As assessed by test stimulation 4-12 weeks after the 10th grade 5 seizure, kindling was maintained in the NT-3 mutants. In situ hybridization showed 30% reduction of basal NT-3 mRNA levels and lack of upregulation of TrkC mRNA expression at 2 h after a generalized seizure in dentate granule cells of the NT-3+/- mice, whereas the seizure-evoked increase in brain-derived neurotrophic factor (BDNF) and TrkB mRNA levels was enhanced. These results indicate that endogenous NT-3 levels can influence the rate of epileptogenesis, and suggest a link between NT-3 and BDNF gene regulation in dentate granule cells.
|
|
