| 1. |
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| 2. |
- Gustafsson Brywe, Katarina, 1965, et al.
(författare)
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Growth hormone-releasing peptide hexarelin reduces neonatal brain injury and alters Akt/glycogen synthase kinase-3beta phosphorylation
- 2005
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 146:11, s. 4665-72
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Tidskriftsartikel (refereegranskat)abstract
- Hexarelin (HEX) is a peptide GH secretagogue with a potent ability to stimulate GH secretion and recently reported cardioprotective actions. However, its effects in the brain are largely unknown, and the aim of the present study was to examine the potential protective effect of HEX on the central nervous system after injury, as well as on caspase-3, Akt, and extracellular signal-regulated protein kinase (ERK) signaling cascades in a rat model of neonatal hypoxia-ischemia. Hypoxic-ischemic insult was induced by unilateral carotid ligation and hypoxic exposure (7.7% oxygen), and HEX treatment was administered intracerebroventricularly, directly after the insult. Brain damage was quantified at four coronal levels and by regional neuropathological scoring. Brain damage was reduced by 39% in the treatment group, compared with vehicle group, and injury was significantly reduced in the cerebral cortex, hippocampus, and thalamus but not in the striatum. The cerebroprotective effect was accompanied by a significant reduction of caspase-3 activity and an increased phosphorylation of Akt and glycogen synthase kinase-3beta, whereas ERK was unaffected. In conclusion, we demonstrate for the first time that HEX is neuroprotective in the neonatal setting in vivo and that increased Akt signaling is associated with downstream attenuation of glycogen synthase kinase-3beta activity and caspase-dependent cell death.
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| 3. |
- Gustafsson Brywe, Katarina, 1965, et al.
(författare)
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IGF-I neuroprotection in the immature brain after hypoxia-ischemia, involvement of Akt and GSK3beta?
- 2005
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Ingår i: Eur J Neurosci. - : Wiley. - 0953-816X. ; 21:6, s. 1489-502
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-like growth factor I (IGF-I) is a neurotrophic factor that promotes neuronal growth, differentiation and survival. Neuroprotective effects of IGF-I have previously been shown in adult and juvenile rat models of brain injury. We wanted to investigate the neuroprotective effect of IGF-I after hypoxia-ischemia (HI) in 7-day-old neonatal rats and the mechanisms of IGF-I actions in vivo. We also wanted to study effects of HI and/or IGF-I on the serine/threonine kinases Akt and glycogen synthase kinase 3beta (GSK3beta) in the phophatidylinositol-3 kinase (PI3K) pathway. Immediately after HI, phosphorylated Akt (pAkt) and phosphorylated GSK3beta (pGSK3beta) immunoreactivity was lost in the ipsilateral and reduced in the contralateral hemisphere. After 45 min, pAkt levels were restored to control values, whereas pGSK3beta remained low 4 h after HI. Administration of IGF-I (50 microg i.c.v.) after HI resulted in a 40% reduction in brain damage (loss of microtubule-associated protein) compared with vehicle-treated animals. IGF-I treatment without HI was shown to increase pAkt whereas pGSK3beta decreased in the cytosol, but increased in the nuclear fraction. IGF-I treatment after HI increased pAkt in the cytosol and pGSK3beta in both the cytosol and the nuclear fraction in the ipsilateral hemisphere compared with vehicle-treated rats, concomitant with a reduced caspase-3- and caspase-9-like activity. In conclusion, IGF-I induces activation of Akt during recovery after HI which, in combination with inactivation of GSK3beta, may explain the attenuated activation of caspases and reduction of injury in the immature brain.
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| 4. |
- Gustavsson, Malin, 1975, et al.
(författare)
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Global gene expression in the developing rat brain after hypoxic preconditioning: involvement of apoptotic mechanisms?
- 2007
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Ingår i: Pediatr Res. ; 61:4, s. 444-50
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Tidskriftsartikel (refereegranskat)abstract
- Exposure to hypoxia before hypoxia-ischemia (HI) confers substantial protection referred to as preconditioning (PC). We hypothesized that PC induces critical changes of genes related to apoptotic cell death to render the brain more resistant. PC hypoxia (8% O2, 36 degrees C, 3 h) was induced in rats on postnatal day (PND) 6, and the rats were killed at 0, 2, 8, and 24 h. Total RNA was extracted from cerebral cortex and analyzed using Affymetrix rat genome 230 2.0 array. PC induced significant changes in 906 genes at 0 h, 927 at 2 h, 389 at 8 h, and 114 at 24 h. Ontology analysis revealed significant alterations in genes involved in cell communication, signal transduction, transcription, phosphorylation, and transport. Genes involved in cell death/apoptosis as well as those related to brain development (cell differentiation, neurogenesis, organogenesis, blood vessel development) were overrepresented. A detailed analysis demonstrated that 77 significantly regulated genes were involved in apoptosis, specifically related to the Bcl-2 family, JNK pathway, trophic factor pathways, inositol triphosphate (PI3) kinase/Akt pathway, extrinsic or intrinsic pathway, or the p53 pathway. The study supports that the epidermal growth factor receptor family, mitogen-activated protein kinase phosphatases, and Bcl-2-related proteins and the PI3 kinase/Akt pathway may have roles in providing resistance in the developing central nervous system (CNS).
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| 5. |
- Gustavsson, Malin, 1975, et al.
(författare)
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Hypoxic preconditioning confers long-term reduction of brain injury and improvement of neurological ability in immature rats
- 2005
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Ingår i: Pediatr Res. ; 57:2, s. 305-9
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Tidskriftsartikel (refereegranskat)abstract
- Exposure to preconditioning (PC) hypoxia 24 h before a severe hypoxic-ischemic (HI) insult reduces development of injury in the immature brain. Several protective regimens have proved effective in the short-term but not in the long-term perspective. The aim of the present study, therefore, was to evaluate the PC effect on long-term morphologic and neurologic outcome in the developing brain. Six-day-old rats were subjected to hypoxia (36 degrees C, 8.0% O2; PC/HI group) and sham controls to normoxia (36 degrees C; HI group) for 3 h. Twenty-four hours later, all rats were exposed to cerebral HI produced by unilateral carotid artery occlusion combined with 1 h, 15 min of hypoxia (36 degrees C, 7.7% O2). A cylinder test was used to evaluate forelimb asymmetry to determine sensorimotor function at 4, 6, and 8 wk of age. Spatial/cognitive ability was assessed by Morris water maze trials at 7 wk of recovery. Neuropathologic analysis was performed 8 wk after insult. Brain damage was reduced (p<0.0001) in PC/HI (45.0+/-11.1 mm3) in comparison with HI (159.3+/-12.2 mm3) rats. A bias for using the ipsilateral forelimb in wall movements was observed in the cylinder test in HI compared with PC/HI rats at 4 (p<0.001), 6 (p<0.01), and 8 (p<0.0001) wk of age. Results of the Morris water maze test revealed differences (p<0.0001) in average path length between groups on the third and fourth day of trials. Hypoxic PC before HI reduced brain injury by 72% at 8 wk after the insult and provided long-term improvement of sensorimotor and spatial/cognitive functions.
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| 6. |
- Gustavsson, Malin, 1975, et al.
(författare)
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Vascular response to hypoxic preconditioning in the immature brain
- 2007
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Ingår i: J Cereb Blood Flow Metab. ; 27:5, s. 928-38
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Tidskriftsartikel (refereegranskat)abstract
- We hypothesized that hypoxic preconditioning (PC) modifies the microvasculature in the immature brain and thereby affects the cerebral blood flow (CBF) during a subsequent hypoxic-ischemic (HI) insult. On postnatal day 6 rats were exposed to hypoxia (36 degrees C, 8.0% O2) or normoxia for 3 h. Unilateral HI (unilateral carotid ligation and 8% hypoxia) was induced 24 h later. Cortical CBF was measured with the 14C-iodoantipyrine technique (at the end of HI) or with laser Doppler flowmetry (Perimed PF5001) before and during HI. At 0, 2, 8, and 24 h cerebral cortex was sampled and analyzed with gene arrays (Affymetrix 230 2.0). L-nitroarginine or vehicle was administrated before hypoxic PC or 30 mins before HI followed by CBF measurement (laser Doppler) during subsequent HI. Twenty-four hours after PC animals were perfusion-fixed and brains immunolabeled for von Willebrand factor and vascular density was determined by stereological quantification. The decrease in CBF during HI was attenuated significantly in PC versus control animals (P<0.01), as detected by both techniques. Several vascular genes (Angpt2, Adm, Apln, Vegf, Flt1, Kdr, Pdgfra, Agtrap, Adora2a, Ednra, serpine1, caveolin, Id1, Prrx1, Ero1l, Acvrl1, Egfl7, Nudt6, Angptl4, Anxa2, and NOS3) were upregulated and a few (Csrp2, Adora2b) were downregulated after PC. A significant increase in vascular density (P<0.05) was seen after PC. Nitric oxide synthase inhibition did not affect CBF during HI after PC. In conclusion, hypoxic PC upregulates vascular genes, increases vascular density and attenuates the decrease of CBF during a subsequent HI, which could contribute to tolerance.
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| 7. |
- Hagberg Gustavsson, Malin
(författare)
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Forskning för djurens skull - katt, hund & häst 2018
- 2019
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Rapporten som du nu har i din hand presenterar ett axplock av de resultat som kom ut av Sveriges lantbruksuniversitets (SLU) forskning om katter, hundar och hästar under förra året. Djurhälsa och djurvälfärd är centrala områden vid SLU och här pågår studier av friska och sjuka djur, deras behov och beteenden. SLU är också det enda universitet i Sverige som utbildar veterinärer, djursjukskötare och husdjursagronomer. Att leva nära djur har positiva effekter på människors välbefinnande och livskvalitet. Många människor finner till exempel en meningsfull fritid i hund-, katt- och hästägande. Inte minst hälsoaspekten av att röra på sig tillsammans med sitt djur får stor betydelse i ett samhälle där de negativa konsekvenserna av ett stillasittande liv uppmärksammas allt mer. Samvaron med sport- och sällskapsdjur är dessutom hälsobringande eftersom den bland annat sänker puls och blodtryck. Vi håller djuren för vår egen skull och på våra villkor vilket gör oss ansvariga för deras hälsa och välmående. Forskning om sport- och sällskapsdjur är viktig i en samhällsutveckling för välmående människor och djur. Utvecklingen i samhället visar att vi behöver öka kunskapen om modern, etisk, hållbar djurhållning, inkluderat hur djuren används för arbete, sport och sällskap. Forskning om djurs spontant uppkomna sjukdomar är grunden för utveckling av förebyggande djurhälsoinsatser och behandling av sjuka djur, men ger också ökad kunskap om de sjukdomar som drabbar både människor och djur. Våra forskare arbetar med alla dessa aspekter av djurhälsa och djurvälfärd.
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| 8. |
- Hagberg, Henrik, 1955, et al.
(författare)
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PARP-1 gene disruption in mice preferentially protects males from perinatal brain injury
- 2004
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Ingår i: J Neurochem. ; 90:5, s. 1068-75
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Tidskriftsartikel (refereegranskat)abstract
- Poly(ADP-ribose) polymerase-1 is over-activated in the adult brain in response to ischemia and contributes to neuronal death, but its role in perinatal brain injury remains uncertain. To address this issue, 7-day-old wild-type (wt) and PARP-1 gene deficient (parp+/- and parp-/-) Sv129/CD-1 hybrid mice were subjected to unilateral hypoxia-ischemia and histologic damage was assessed 10 days later by two evaluators. Poly(ADP-ribose) polymerase-1 knockout produced moderate but significant (p < 0.05) protection in the total group of animals, but analysis by sex revealed that males were strongly protected (p < 0.05) in contrast to females in which there was no significant effect. Separate experiments demonstrated that PARP-1 was activated over 1-24 h in both females and males after the insult in neonatal wt mice and rats using immnocytochemistry and western blotting for poly(ADP-ribose). Brain levels of NAD+ were also significantly reduced, but the decrease of NAD+ during the early post-hypoxia-ischemia (HI) phase was only seen in males. The results indicate that hypoxia-ischemia activates Poly(ADP-ribose) polymerase-1 in the neonatal brain and that the sex of the animal strongly influences its role in the pathogenesis of brain injury.
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| 9. |
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| 10. |
- Hoffmann, Ruben, et al.
(författare)
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Economic Perspective on the Value of Cats and Dogs
- 2019
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Ingår i: Society and Animals. - : Brill. - 1063-1119 .- 1568-5306. ; 27, s. 595-613
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Tidskriftsartikel (refereegranskat)abstract
- Although various benefits of cats and dogs have been extensively studied, their fundamental economic value is poorly understood. Economic values are, in contrast to monetary values, determined subjectively and guide individuals in their decisions. This study presents a conceptual economic model of the value of cats and dogs which provides a basis for future research. Benefits of cats and dogs identified in the literature are categorized in relation to the model. The multidimensional value of these nonhuman animals includes different use and non-use values, for caretakers and other humans. Data from an online survey on the salience (importance of attributes in memory) of cats and dogs in Sweden provide support for the proposed model. It is argued that the subjective well-being approach developed in psychology provides a good starting point for estimating many of the economic values of these animals, but that different types of values may require different approaches.
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| 11. |
- Holmgren, Sofia, et al.
(författare)
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Cytokine mRNA expression in bronchoalveolar lavage cells during Dictyocaulus viviparus infection in calves
- 2014
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Ingår i: Parasite Immunology. - : Wiley. - 0141-9838 .- 1365-3024. ; 36, s. 78-86
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this study was to monitor local cytokine responses to Dictyocaulus viviparus in calves during primary infection and re-infection. Bronchoalveolar lavage fluid (BALF) was collected weekly from experimentally infected calves and interleukin-2 (IL-2), IL-4, IL-5, IL-10 and IFN- mRNA expression was quantified in BALF cells. The major finding was a prominent transient increase in IL-4 mRNA expression, compared with that of uninfected calves, observed in BALF cells collected 2-3weeks post-primary D.viviparus infection. At 2weeks post-infection, macroscopic worms were also first observed in BALF. Calves re-infected after 10weeks were partially immune which was evident at slaughter 5weeks post-infection as a lower worm burden than in previously naive calves infected at the same time. IL-4 mRNA expression in BALF cells 2weeks post-re-infection was increased compared with that of uninfected animals but not as high as that of primarily infected calves. BALF cell expression of the other cytokines tested for was not as clearly effected by the D.viviparus infection. It seems likely that the strong IL-4 response observed during primary infection reflects an innate response to the worms that may initiate an ensuing Th2 response, which confers protective immunity.
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| 12. |
- Johansson Wensman, Jonas, et al.
(författare)
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Expression of interferon gamma in the brain of cats with natural Borna disease virus infection
- 2011
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Ingår i: Veterinary Immunology and Immunopathology. - : Elsevier BV. - 0165-2427 .- 1873-2534. ; 141, s. 162-167
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Tidskriftsartikel (refereegranskat)abstract
- Borna disease virus (BDV) is a neurotropic, negative-stranded RNA virus, which causes a non-suppurative meningoencephalomyelitis in a wide range of animals. In cats, BDV infection leads to staggering disease. In spite of a vigorous immune response the virus persists in the central nervous system (CNS) in both experimentally and naturally infected animals. Since the CNS is vulnerable to cytotoxic effects mediated via NK-cells and cytotoxic T-cells, other non-cytolytic mechanisms such as the interferon (IFN) system is favourable for viral clearance. In this study, IFN-gamma expression in the brain of cats with clinical signs of staggering disease (N = 12) was compared to the expression in cats with no signs of this disease (N = 7) by quantitative RT-PCR. The IFN-gamma expression was normalised against the expression of three reference genes (HPRT, RPS7, YWHAZ). Cats with staggering disease had significantly higher expression of IFN-gamma compared to the control cats (p-value <= 0.001). There was no significant difference of the IFN-gamma expression in BDV-positive (N = 7) and negative (N = 5) cats having clinical signs of staggering disease. However, as BDV-RNA still could be detected, despite an intense IFN-gamma expression, BDV needs to have mechanisms to evade this antiviral immune response of the host, to be able to persist. (C) 2011 Elsevier B.V. All rights reserved.
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| 13. |
- Johansson Wensman, Jonas, et al.
(författare)
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Markers of Borna disease virus infection in cats with staggering disease
- 2012
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Ingår i: Journal of Feline Medicine and Surgery. - 1098-612X .- 1532-2750. ; 14, s. 573-582
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Tidskriftsartikel (refereegranskat)abstract
- Borna disease virus (BDV) is a RNA-virus causing neurological disorders in a wide range of mammals. In cats, BDV infection may cause staggering disease. Presently, staggering disease is a tentative clinical diagnosis, only confirmed at necropsy. In this study, cats with staggering disease were investigated to study markers of BDV infection aiming for improvement of current diagnostics. Nineteen cats fulfilled the inclusion criteria based on neurological signs and pathological findings. In 17/19 cats, BDV infection markers (BDV-specific antibodies and/or BDV-RNA) were found, and antibodies in serum (13/16, 81%) were the most common marker. BDV-RNA was found in 11/19 cats (58%). In a reference population without neurological signs, 4/25 cats were seropositive (16%). The clinical history and neurological signs in combination with presence of BDV infection markers, where serology and rRT-PCR on blood can be helpful tools, improve the diagnostic accuracy in the living cat.
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| 14. |
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| 15. |
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| 16. |
- Ström Holst, Bodil, et al.
(författare)
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Canine Herpesvirus During Pregnancy and Non-Pregnant Luteal Phase
- 2012
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Ingår i: Reproduction in Domestic Animals. - : Wiley. - 0936-6768 .- 1439-0531. ; 47, s. 362-365
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Tidskriftsartikel (refereegranskat)abstract
- Canine herpesvirus (CHV) is a widespread infection among dogs that typically get latently infected after exposure and can reactivate the infection after stress. The aim of the present study was to study the effects of latent CHV infection during pregnancy on pregnancy outcome, and to study if there are signs of genital viral reactivation during pregnancy or during non-pregnant luteal phase. Twelve mated bitches and eight control bitches were followed and sampled regularly during pregnancy or non-pregnant luteal phase. Blood samples were taken for antibody analysis and vaginal swabs for real-time PCR analysis. Three of the pregnant bitches were vaccinated against CHV during pregnancy. All bitches had antibodies to CHV. Two pregnant bitches that were not vaccinated had a twofold or larger increase in CHV titre, with no negative effects detected on pregnancy. Higher titres were not associated with smaller litters or with vaccination. There was no consistent variation in antibody titres due to pregnancy or non-pregnant luteal phase. Vaginal excretion of CHV was not detected from any of the bitches.
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| 17. |
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| 18. |
- Ström Holst, Bodil, et al.
(författare)
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Expression of four canine leukocyte adhesion factors in fresh and stored whole blood samples evaluated using a no-lyse, no-wash method
- 2011
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Ingår i: Veterinary Immunology and Immunopathology. - : Elsevier BV. - 0165-2427 .- 1873-2534. ; 139, s. 271-276
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Tidskriftsartikel (refereegranskat)abstract
- Expression of four leukocyte adhesion factors on canine leukocytes was studied by flow cytometry using a no-lyse, no-wash method. The effect of fixation and storage for up to 14 days in 1% paraformaldehyde on labelled samples and within assay variation was evaluated. Monoclonal antibodies directed to monocyte marker CD14, and to adhesion molecules CD11 a, CD18,CD32 and CD49d were used. Cell surface marker, cell population, time, and the interactions between time and cell marker significantly affected expression of cell adhesion factors. For CD18, there was a significant difference in mean fluorescence intensity (MFI) between fresh and stored samples (P<0.001), but no significant difference between stored samples. The MFIs of CD11a and CD49d were not significantly affected by fixation and storage. The CVs differed significantly depending on cell marker (P<0.001) and cell population (P=0.005). Fixation and storage did not significantly affect the CV. In conclusion, a no-lyse, no-wash method can be applied to canine leukocytes. The effect of fixation and storage on the resulting MFI differs between monoclonal antibodies, and should be evaluated for each antibody before use. The coefficient of variation was generally acceptable, and high CVs were related to a low MFIs or low numbers of analysed cells. (C) 2010 Elsevier B.V. All rights reserved.
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| 19. |
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| 20. |
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| 21. |
- Ström Holst, Bodil, et al.
(författare)
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Inflammatory changes during canine pregnancy
- 2019
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Ingår i: Theriogenology. - : Elsevier BV. - 0093-691X .- 1879-3231. ; 125, s. 285-292
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Tidskriftsartikel (refereegranskat)abstract
- Pregnancy is considered a pro-inflammatory state that requires physiologic adaptation of the immune system of the mother. The aim of the present study was to study inflammatory and hormonal changes during canine pregnancy. Studies included analyses of peripheral concentrations of the acute phase proteins fibrinogen and C-reactive protein (CRP), the hormones progesterone and insulin-like growth factor I (IGF-I), hemoglobin, and analyses of the total leukocyte numbers and expression of cell surface antigens. Twenty bitches were included in the present study; 12 pregnant bitches and eight nonpregnant control bitches that were followed during the corresponding phase of the oestrous cycle. Blood samples were collected at the day of optimal mating (day 0) and then on days 7, 14, 21, 28 and 42. Progesterone, IGF-I and CRP were analysed in serum and fibrinogen in EDTA plasma. Haematology and leukocyte expression of a panel of inflammation-associated adhesion molecules (CD 11a, CD 18 and CD 49d) were evaluated from EDTA blood. The data were analyzed as repeated-measures data, using a mixed model approach. Progesterone varied with time in both pregnant and control bitches, and IGF-I varied with time in pregnant bitches. Both fibrinogen and CRP increased significantly with time for the pregnant bitches, but no significant change was detected for the control bitches. Increases were seen from day 21. The hemoglobin concentration decreased significantly with time in both pregnant and non-pregnant bitches. The neutrophil and monocyte numbers increased significantly in pregnant but not in control bitches. Pregnancy induced increased granulocyte expression of cell surface marker CD 18, increased monocyte expression of CD 18 and CD 49d, and increased lymphocyte expression of CD 49d. In conclusion, we describe inflammatory changes during canine pregnancy that are manifested as increases in concentrations of CRP and fibrinogen, an increase in neutrophils and monocytes, and in activation of granulocytes, monocytes and lymphocytes. The changes should be taken into account when evaluating concentrations of APPS and WBC in bitches during pregnancy. A variation in IGF-I concentrations was detected during pregnancy.
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| 22. |
- Ström Holst, Bodil, et al.
(författare)
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Leucocyte phagocytosis during the luteal phase in bitches
- 2013
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Ingår i: Veterinary Immunology and Immunopathology. - : Elsevier BV. - 0165-2427 .- 1873-2534. ; 153, s. 77-82
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Tidskriftsartikel (refereegranskat)abstract
- Pyometra is a disease that affects a large proportion of intact bitches, and typically is seen during the latter half of dioestrus. Several factors contribute to the development of pyometra, including genetic factors, an infectious component (most often Escherichia coli), and hormonal factors. Hormones may act directly on the endometrium, and also affect the immune system. In dogs, the phagocytic ability has been shocvn to decrease with age, and ovarian hormones have also been shown to affect immune resistance. The aim of the present study was to examine whether phagocytosis by canine leucocytes varies significantly during the luteal phase. Eight bitches were followed by repeated blood sampling. Samples were taken at the calculated optimal day for mating (Day 1), and thereafter on days 8, 15 and 22 (early luteal phase) and 29, 43, 57 and 71 (late luteal phase). Blood was collected from the cephalic vein into EDTA tubes for leucocyte counts and heparinised tubes for testing of phagocytosis and oxidative burst using commercial kits and flow cytometry. The cell activity of the phagocyting leucocytes, expressed as mean fluorescence activity, ME, was significantly lower during late luteal phase than during early luteal phase. The proportion of leucocytes that was induced to phagocyte did not differ significantly. The percentage of cells stimulated by E. coli to oxidative burst was significantly lower during late luteal phase. Their activity did not differ between the two periods. The number of cells stimulated to oxidative burst by a low stimulus was too low to evaluate, and leucocytes stimulated with the high stimulus did not vary in oxidative burst between the two periods. The changes in phagocytic activity and in the number of leucocytes that showed oxidative burst were not associated with any change in the proportion of different leucocytes. The decreased phagocytic capacity possibly contributes to the higher incidence of diseases such as pyometra during the latter part of the luteal phase. (C) 2013 Elsevier B.V. All rights reserved.
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| 23. |
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| 24. |
- Svedin, Pernilla, 1979, et al.
(författare)
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Delayed peripheral administration of a GPE analogue induces astrogliosis and angiogenesis and reduces inflammation and brain injury following hypoxia-ischemia in the neonatal rat.
- 2007
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Ingår i: Developmental neuroscience. - : S. Karger AG. - 1421-9859 .- 0378-5866. ; 29:4-5, s. 393-402
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Tidskriftsartikel (refereegranskat)abstract
- Glycine 2-methyl proline glutamate (G-2mPE) is a proline-modified analogue to the naturally existing N-terminal tripeptide glycine-proline-glutamate that is a cleaved product from insulin-like growth factor-1. G-2mPE is designed to be more enzymatically resistant than glycine-proline-glutamate and to increase its bioavailability. The current study has investigated the protective effects of G-2mPE following hypoxic-ischemic brain injury in the neonatal brain. On postnatal day 7, Wistar rats were exposed to hypoxia-ischemia (HI). HI was induced by unilateral ligation of the left carotid artery followed by hypoxia (7.7% O2, 36 degrees C) for 60 min. The drug treatment started 2 h after the insult, and the pups were given either 1.2 mg/kg (bolus), 1.2 mg/ml once a day for 7 days, or vehicle. The degree of brain damage was determined histochemically by thionin/acid fuchsin staining. G-2mPE's anti-inflammatory properties were investigated by IL-1beta, IL-6, and IL-18 ELISA, and effects on apoptosis by caspase 3 activity. Vascularization was determined immunohistochemically by the total length of isolectin-positive blood vessels. Effect on astrocytosis was also determined in the hippocampus. Animals treated with multiple doses of G-2mPE demonstrated reduced overall brain injury 7 days after HI, particularly in the hippocampus and thalamus compared to vehicle-treated rats. The expression of IL-6 was decreased in G-2mPE-treated animals compared to vehicle-treated pups, and both the capillary length and astrogliosis were increased in the drug-treated animals. There was no effect on caspase 3 activity. This study indicates that peripheral administration of G-2mPE, starting 2 h after a hypoxic-ischemic insult, reduces the degree of brain injury in the immature rat brain. The normalization of IL-6 levels and the promotion of both neovascularization and reactive astrocytosis may be potential mechanisms that underlie its protective effects.
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| 25. |
- Wang, Xiaoyang, 1965, et al.
(författare)
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N-acetylcysteine reduces lipopolysaccharide-sensitized hypoxic-ischemic brain injury.
- 2007
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Ingår i: Annals of neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 61:3, s. 263-71
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Maternal inflammation/infection alone or in combination with birth asphyxia increases the risk for perinatal brain injury. Free radicals are implicated as major mediators of inflammation and hypoxia-ischemia (HI)-induced perinatal brain injury. This study evaluated the neuroprotective efficacy of a scavenging agent, N-acetylcysteine (NAC), in a clinically relevant model. METHODS: Lipopolysaccharide (LPS)-sensitized HI brain injury was induced in 8-day-old neonatal rats. NAC was administered in multiple doses, and brain injury was evaluated at 7 days after HI. RESULTS: NAC (200mg/kg) provided marked neuroprotection with up to 78% reduction of brain injury in the pre+post-HI treatment group and 41% in the early (0 hour) post-HI treatment group, which was much more pronounced protection than another free radical scavenger, melatonin. Protection by NAC was associated with the following factors: (1) reduced isoprostane activation and nitrotyrosine formation; (2) increased levels of the antioxidants glutathione, thioredoxin-2, and (3) inhibition of caspase-3, calpain, and caspase-1 activation. INTERPRETATION: NAC provides substantial neuroprotection against brain injury in a model that combines infection/inflammation and HI. Protection by NAC was associated with improvement of the redox state and inhibition of apoptosis, suggesting that these events play critical roles in the development of lipopolysaccharide-sensitized HI brain injury.
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