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Neuroprotective Role (neuroprotective + role)
Selected AbstractsNeuroprotective role of bradykinin because of the attenuation of pro-inflammatory cytokine release from activated microgliaJOURNAL OF NEUROCHEMISTRY, Issue 2 2007Mami Noda Abstract Bradykinin (BK) has been reported to be a mediator of brain damage in acute insults. Receptors for BK have been identified on microglia, the pathologic sensors of the brain. Here, we report that BK attenuated lipopolysaccharide (LPS)-induced release of tumor necrosis factor-alpha (TNF-,) and interleukin-1, from microglial cells, thus acting as an anti-inflammatory mediator in the brain. This effect was mimicked by raising intracellular cAMP or stimulating the prostanoid receptors EP2 and EP4, while it was abolished by a cAMP antagonist, a prostanoid receptor antagonist, or by an inhibitor of the inducible cyclooxygenase (cyclooxygenase-2). BK also enhanced formation of prostaglandin E2 and expression of microsomal prostaglandin E synthase. Expression of BK receptors and EP2/EP4 receptors were also enhanced. Using physiological techniques, we identified functional BK receptors not only in culture, but also in microglia from acute brain slices. BK reduced LPS-induced neuronal death in neuron,microglia co-cultures. This was probably mediated via microglia as it did not affect TNF-,-induced neuronal death in pure neuronal cultures. Our data imply that BK has anti-inflammatory and neuroprotective effects in the central nervous system by modulating microglial function. [source] Growth hormone-releasing peptide 6 protection of hypothalamic neurons from glutamate excitotoxicity is caspase independent and not mediated by insulin-like growth factor IEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2009A. Delgado-Rubín Abstract Treatment of the fetal hypothalamic neuronal cell line RCA-6 with growth hormone-releasing peptide 6, an agonist of the ghrelin receptor, or insulin-like growth factor I activates intracellular signalling cascades associated with anti-apoptotic actions. Abnormally high concentrations of glutamate provoke over-excitation of neurons leading to cell damage and apoptosis. Thus, the aim of this study was to investigate whether the administration of growth hormone-releasing peptide 6 and insulin-like growth factor I attenuates monosodium glutamate-induced apoptosis in RCA-6 neurons and the mechanisms involved. Two different mechanisms are involved in glutamate-induced cell death, one by means of caspase activation and the second through activation of a caspase-independent pathway of apoptosis mediated by the translocation of apoptosis-inducing factor. Growth hormone-releasing peptide 6 partially reversed glutamate-induced cell death but not the activation of caspases, suggesting blockage of the caspase-independent cell death pathway, which included interference with the translocation of apoptosis-inducing factor to the nucleus associated with the induction of Bcl-2. In contrast, the addition of insulin-like growth factor I to RCA-6 neurons abolished glutamate-induced caspase activation and cell death. These data demonstrate for the first time a neuroprotective role for growth hormone secretagogues in the caspase-independent cell death pathway and indicate that these peptides have neuroprotective effects independent of its induction of insulin-like growth factor I. [source] Hippocampal vulnerability following traumatic brain injury: a potential role for neurotrophin-4/5 in pyramidal cell neuroprotectionEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2006N. C. Royo Abstract Traumatic brain injury (TBI) causes selective hippocampal cell death, which is believed to be associated with cognitive impairment observed both in clinical and experimental settings. Although neurotrophin administration has been tested as a strategy to prevent cell death following TBI, the potential neuroprotective role of neurotrophin-4/5 (NT-4/5) in TBI remains unknown. We hypothesized that NT-4/5 would offer neuroprotection for selectively vulnerable hippocampal neurons following TBI. Measurements of NT-4/5 in rats subjected to lateral fluid percussion (LFP) TBI revealed two,threefold increases in the injured cortex and hippocampus in the acute period (1,3 days) following brain injury. Subsequently, the response of NT-4/5 knockout (NT-4/5,/,) mice to controlled-cortical impact TBI was investigated. NT-4/5,/, mice were more susceptible to selective pyramidal cell loss in Ahmon's corn (CA) subfields of the hippocampus following TBI, and showed impaired motor recovery when compared with their brain-injured wild-type controls (NT-4/5wt). Additionally, we show that acute, prolonged administration of recombinant NT-4/5 (5 µg/kg/day) prevented up to 50% of the hippocampal CA pyramidal cell death following LFP TBI in rats. These results suggest that post-traumatic increases in endogenous NT-4/5 may be part of an adaptive neuroprotective response in the injured brain, and that administration of this neurotrophic factor may be useful as a therapeutic strategy following TBI. [source] Overexpression of spermidine/spermine N1 -acetyltransferase in transgenic mice protects the animals from kainate-induced toxicityEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2000Kyllikki Kaasinen Abstract We recently generated a transgenic mouse line with activated polyamine catabolism through overexpression of spermidine/spermine N1 -acetyltransferase (SSAT). A detailed analysis of brain polyamine concentrations indicated that all brain regions of these animals showed distinct signs of activated polyamine catabolism, e.g. overaccumulation of putrescine (three- to 17-fold), appearance of N1 -acetylspermidine and decreases in spermidine concentrations. In situ hybridization analyses revealed a marked overexpression of SSAT-specific mRNA all over the brain tissue of the transgenic animals. The transgenic animals appeared to tolerate subcutaneous injections of high-dose kainate substantially better as their overall mortality was less than 50% of that of their syngenic littermates. We used the expression of glial fibrillary acidic protein (GFAP) as a marker of brain injury in response to kainate. In situ hybridization analysis with GFAP oligonucleotide up to 7 days after the administration of sublethal kainate doses showed reduced GFAP expression in transgenic animals in comparison with their non-transgenic littermates. This difference was especially striking in the cerebral cortex of the transgenic mice where the exposure to kainate hardly induced GFAP expression. The treatment with kainate likewise resulted in loss of the hippocampal (CA3) neurons in non-transgenic but not transgenic animals. These results support our earlier findings indicating that elevated concentrations of brain putrescine, irrespective whether derived from an overexpression of ornithine decarboxylase, or as shown here, from an overexpression of SSAT, play in all likelihood a neuroprotective role in brain injury. [source] Enhanced Connexin 43 immunoreactivity in penumbral areas in the human brain following ischemiaGLIA, Issue 5 2006Taizen Nakase Abstract Astrocytes support neurons not only physically but also chemically by secreting neurotrophic factors and energy substrates. Moreover, astrocytes establish a glial network and communicate through gap junctions in the brain. Connexin 43 (Cx43) is one of major component proteins in astrocytic gap junctions. Heterozygote Cx43 KO mice and astrocyte specific Cx43 KO mice exhibited amplified brain damage after ischemic insults, suggesting a neuroprotective role for astrocytic gap junctions. However, some reports mentioned unfavorable effects of gap junctions in neuronal support. Therefore, the role of astrocytic gap junctions under ischemic condition remains controversial. Since these studies have been performed using animal models, we investigated the Cx43 expression in human brain after stroke. Brain slice sections were prepared from pathological samples in our hospital. Embolic stroke brains sectioned because of the stroke were considered as acute ischemic models. Multiple infarction brains sectioned because of pneumonia or cancer were considered as chronic models. We observed the levels of Cx43 in both lesioned and intact areas, and compared them with acute and chronic models. As the results, astrocytes were strongly activated in penumbral lesions both of acute and chronic ischemic models. The Cx43 immunoreactivity was significantly amplified in the penumbra of chronic model compared to that of the acute model. Neurons were well preserved in chronic model compared to acute model. These findings suggested that the brain may generate neuronal protection by increasing the levels of Cx43 and amplifying the astrocytic gap junctional intercellular communication under hypoxic condition. © 2006 Wiley-Liss, Inc. [source] Complement component C1q inhibits ,-amyloid- and serum amyloid P-induced neurotoxicity via caspase- and calpain-independent mechanismsJOURNAL OF NEUROCHEMISTRY, Issue 3 2008Karntipa Pisalyaput Abstract Alzheimer's disease is a neurodegenerative disorder characterized by neuronal loss, ,-amyloid (A,) plaques, and neurofibrillary tangles. Complement protein C1q has been found associated with fibrillar A, deposits, however the exact contributions of C1q to Alzheimer's disease is still unknown. There is evidence that C1q, as an initiator of the inflammatory complement cascade, may accelerate disease progression. However, neuronal C1q synthesis is induced after injury/infection suggesting that it may be a beneficial response to injury. In this study, we report that C1q enhances the viability of neurons in culture and protects neurons against A,- and serum amyloid P (SAP)-induced neurotoxicity. Investigation of potential signaling pathways indicates that caspase and calpain are activated by A,, but C1q had no effect on either of these pathways. Interestingly, SAP did not induce caspase and calpain activation, suggesting that C1q neuroprotection is in distinct from caspase and calpain pathways. In contrast to A,- and SAP-induced neurotoxicity, neurotoxicity induced by etoposide or FCCP was unaffected by the addition of C1q, indicating pathway selectivity for C1q neuroprotection. These data support a neuroprotective role for C1q which should be further investigated to uncover mechanisms which may be therapeutically targeted to slow neurodegeneration via direct inhibition of neuronal loss. [source] NO-induced neuroprotection in ischemic preconditioning stimulates mitochondrial Mn-SOD activity and expression via RAS/ERK1/2 pathwayJOURNAL OF NEUROCHEMISTRY, Issue 4 2007A. Scorziello Abstract To identify the transductional mechanisms responsible for the neuroprotective effect of nitric oxide (NO) during ischemic preconditioning (IPC), we investigated the effects of this gaseous mediator on mitochondrial Mn-superoxide dismutase (Mn-SOD) expression and activity. In addition, the possible involvement of Ras/extracellular-regulated kinase (ERK) ERK1/2 pathway in preserving cortical neurons exposed to oxygen and glucose deprivation (OGD) followed by reoxygenation was also examined. Ischemic preconditioning was obtained by exposing neurons to a 30-min sublethal OGD (95% N2 and 5% CO2). Then, after a 24-h interval, neurons were exposed to 3 h of OGD followed by 24 h of reoxygenation (OGD/Rx). Our results revealed that IPC reduced cytochrome c (cyt c) release into the cytosol, improved mitochondrial function, and decreased free radical production. Moreover, it induced an increase in nNOS expression and NO production and promoted ERK1/2 activation. These effects were paralleled by an increase in Mn-SOD expression and activity that persisted throughout the following OGD phase. When the neurons were treated with L-NAME, a well known NOS inhibitor, the increase in Mn-SOD expression occurring during IPC was reduced and, as a result, IPC-induced neuroprotection was prevented. Similarly, when ERK1/2 was inhibited by its selective inhibitor PD98059, the increase in Mn-SOD expression observed during IPC was almost completely abolished. As a result, its neuroprotective effect on cellular survival was thwarted. The present findings indicate that during IPC the increase in Mn-SOD expression and activity are paralleled by NO production. This suggests that NO neuroprotective role occurs through the stimulation of Mn-SOD expression and activity. In particular, NO via Ras activation stimulates downstream ERK1/2 cascade. This pathway, in turn, post-transcriptionally activates Mn-SOD expression and activity, thus promoting neuroprotection during preconditioning. [source] Novel targets for valproic acid: up-regulation of melatonin receptors and neurotrophic factors in C6 glioma cellsJOURNAL OF NEUROCHEMISTRY, Issue 5 2005Lyda M. Rincón Castro Abstract Valproic acid (VPA) is a potent anti-epileptic and effective mood stabilizer. It is known that VPA enhances central GABAergic activity and activates the mitogen-activated protein kinase,extracellular signal-regulated kinase (MAPK,ERK) pathway. It can also inhibit various isoforms of the enzyme, histone deacetylase (HDAC), which is associated with modulation of gene transcription. Recent in vivo studies indicate a neuroprotective role for VPA, which has been found to up-regulate the expression of brain-derived neurotrophic factor (BDNF) in the rat brain. Given the interaction between the pineal hormone, melatonin, and GABAergic systems in the central nervous system, the effects of VPA on the expression of the mammalian melatonin receptor subtypes, MT1 and MT2, were examined in rat C6 glioma cells. The effects of VPA on the expression of glial cell line-derived neurotrophic factor (GDNF) and BDNF were also examined. RT-PCR studies revealed a significant induction of melatonin MT1 receptor mRNA in C6 cells following treatment with 3 or 5 mm VPA for 24 h or 5 mm VPA for 48 h. Western analysis and immunocytochemical detection confirmed that the VPA-induced increase in MT1 mRNA results in up-regulation of MT1 protein expression. Blockade of the MAPK,ERK pathway by PD98059 enhanced the effect of VPA on MT1 expression, suggesting a negative role for this pathway in MT1 receptor regulation. In addition, significant increases in BDNF, GDNF and HDAC mRNA expression were observed after treatment with VPA for 24 or 48 h. Taken together, the present findings suggest that the neuroprotective properties of VPA involve modulation of neurotrophic factors and receptors for melatonin, which is also thought to play a role in neuroprotection. Moreover, the foregoing suggests that combinations of VPA and melatonin could provide novel therapeutic strategies in neurological and psychiatric disorders. [source] Neuroprotection by stem cell factor in rat cortical neurons involves AKT and NF,BJOURNAL OF NEUROCHEMISTRY, Issue 1 2005Krishnan M. Dhandapani Abstract Stem cell factor (SCF) is a highly expressed cytokine in the central nervous system. In the present study, we demonstrate a neuroprotective role for SCF and its tyrosine kinase receptor, c-kit, against camptothecin-induced apoptosis and glutamate excitotoxicity in rat cortical neurons. This protection was blocked by pharmacological or molecular inhibition of either the MEK/ERK or PI3K/Akt signaling pathways. The importance of these pathways was further confirmed by the activation of both ERK, in a MEK-dependent manner, and Akt, via PI3K. Activation of Akt increased the binding of the p50 and p65 subunits of NF,B, which was also important for neuroprotection. Akt inhibition prevented NF,B binding, suggesting a role for Akt in SCF-induced NF,B. Pharmacological inhibition of NF,B or dominant negative I,B also prevented neuroprotection by SCF. SCF up-regulated the anti-apoptotic genes, bcl-2 and bcl-xL in an NF,B-dependent manner. Together, these findings demonstrate a neuroprotective role for SCF in cortical neurons, an effect that was mediated by Akt and ERK, as well as NF,B-mediated gene transcription. SCF represents a novel therapeutic target in the treatment of neurodegenerative disease. [source] Tryptophan metabolism and oxidative stress in patients with Huntington's diseaseJOURNAL OF NEUROCHEMISTRY, Issue 3 2005N. Stoy Abstract Abnormalities in the kynurenine pathway may play a role in Huntington's disease (HD). In this study, tryptophan depletion and loading were used to investigate changes in blood kynurenine pathway metabolites, as well as markers of inflammation and oxidative stress in HD patients and healthy controls. Results showed that the kynurenine : tryptophan ratio was greater in HD than controls in the baseline state and after tryptophan depletion, indicating increased indoleamine dioxygenase activity in HD. Evidence for persistent inflammation in HD was provided by elevated baseline levels of C-reactive protein, neopterin and lipid peroxidation products compared with controls. The kynurenate : kynurenine ratio suggested lower kynurenine aminotransferase activity in patients and the higher levels of kynurenine in patients at baseline, after depletion and loading, do not result in any differences in kynurenic acid levels, providing no supportive evidence for a compensatory neuroprotective role for kynurenic acid. Quinolinic acid showed wide variations in blood levels. The lipid peroxidation data indicate a high level of oxidative stress in HD patients many years after disease onset. Levels of the free radical generators 3-hydroxykynurenine and 3-hydroxyanthranilic acid were decreased in HD patients, and hence did not appear to contribute to the oxidative stress. It is concluded that patients with HD exhibit abnormal handling of tryptophan metabolism and increased oxidative stress, and that these factors could contribute to ongoing brain dysfunction. [source] Poster Sessions CP10: Blood,Brain BarrierJOURNAL OF NEUROCHEMISTRY, Issue 2002M. A. García Kinetic analysis of vitamin C uptake has demonstrated that specialized cells take up ascorbic acid (AA), the reduced form of vitamin C, through sodium-AA cotransporters. Recently, two different isoforms of sodium-vitamin C cotransporters (SVCT 1, 2) that mediate high affinity Na+ -dependent l -ascorbic acid have been cloned. SVCT2 was detected mainly in choroid plexus cells and neurons, however, there are no evidences of SVCT2 expression in glial cells. High concentrations of vitamin C has been demonstrated in brain hypothalamic area. The hypothalamic glial cells, known as alpha and beta tanycytes, are specialized ependymal cells that bridge the cerebrospinal fluid and the portal blood of the median eminence. Our hypothesis postulates that tanycytes take up reduced vitamin C from the portal blood and cerebrospinal fluid generating an high concentration of this vitamin in brain hypothalamic area. In situ immunohistochemical analyses demonstrated that SVCT2 transporter is selectively expressed in apical region of tanycytes. A newly developed primary culture of mouse hypothalamic tanycytes was used to confirm the expression and function of SVCT2 isoform in these cells. Reduced vitamin C uptake was temperature and sodium dependent. Kinetic analysis showed an apparent Km of 20 ,m and a Vmax of 45 pmol/min per million cells for the transport of ascorbic acid. The expression of SVCT2 was confirmed by immunoblots and RT,PCR. Tanycytes may perform a neuroprotective role concentrating the vitamin C in the hypothalamic area. Acknowledgements:, Supported by Grands FONDECYT 1010843 and DIUC-GIA 201.034.006-1.4 from Concepción University. [source] Endogenous and Exogenous Fibroblast Growth Factor 2 Support Survival of Chick Retinal Neurons by Control of Neuronal Neuronal bcl-xL and bcl-2 Expression Through a Fibroblast Berowth Factor Receptor 1- and Erk-Dependent PathwayJOURNAL OF NEUROCHEMISTRY, Issue 1 2000Laurent Désiré Abstract : Fibroblast growth factor (FGF) 2 is a survival factor for various cell types, including retinal neurons. However, little is understood about the molecular bases of the neuroprotective role of FGF2 in the retina. In this report, FGF2 survival activity was studied in chick retinal neurons subjected to apoptosis by serum deprivation. Exogenous FGF2 supported neuronal survival after serum deprivation and increased neuronal bcl-xL and bcl-2 expression, through binding to its receptor R1 (FGF-R1), and subsequent extracellular signal-regulated kinase (ERK) activation. Endogenous FGF2 was transiently overexpressed after serum deprivation. Its down-regulation by antisense oligonucleotides and blockade of its signaling pathway (binding to FGF-R1, tyrosine phosphorylation, and ERK inhibition) decreased bcl-xL and bcl-2 levels and and enhanced apoptosis, suggesting that endogenous FGF2 supported neuronal survival through a pathway similar to that of exogenous FGF2. This pathway may serve to up-regulate, or maintain, bcl-xL and bcl-2 levels that normally decrease during the onset of apoptosis. Indeed, long-term ERK activation and high bcl-xL levels are necessary for the survival activity of both exogenous and endogenous FGF2. Because FGF2 is upregulated following retinal injury in vivo, we suggest that an injury-stimulated autocrine/paracrine FGF2 loop may serve to maintain high levels of survival proteins, such as Bcl-xL, through ERK activation in retinal neurons. [source] Molecular and cellular mechanisms of neuroprotection by vascular endothelial growth factorJOURNAL OF NEUROSCIENCE RESEARCH, Issue 1-2 2005Feng-Yan Sun Abstract The present view of the neuroprotective functions and mechanisms of action of vascular endothelial growth factor (VEGF) is based on studies of neuronal ischemic/hypoxic models in vivo and in vitro. Endogenous neuronal VEGF increases in the ischemic brain and plays a neuroprotective role in the pathophysiologic processes that follow stroke. Exogenous VEGF, directly administered or overexpressed by gene delivery into rat brains, reduces ischemic brain infarct and decreases hypoxic neuronal death. The main neuroprotective mechanisms of VEGF include: (1) modulation of the phosphatidylinositol 3,-kinase (PI3K)/Akt/nuclear factor-,B signaling pathway, inhibition of caspase-3 activity, and reduction of ischemic neuronal apoptosis; (2) inhibition of outward delayed rectifier potassium channel currents and increase of ischemia-induced tyrosine phosphorylation of Kv1.2 potassium channel proteins via activation of the PI3K pathway; and (3) enhancement of proliferation and migration of neural progenitors in the subventricular zone and improvement of striatal neurogenesis and maturation of newborn neurons in adult rat brains after stroke. © 2004 Wiley-Liss, Inc. [source] Role of vascular endothelial growth factor in neuronal DNA damage and repair in rat brain following a transient cerebral ischemiaJOURNAL OF NEUROSCIENCE RESEARCH, Issue 2 2002Zeng-Jin Yang Abstract The antisense knockdown technique and confocal laser scanning microscopic analysis were used to elucidate vascular endothelial growth factor (VEGF) induction and its effect on DNA damage and repair in rat brain following a transient middle cerebral artery occlusion. Immunohistochemical study and in situ hybridization showed that the expression of VEGF and its mRNA was enhanced in the ischemic core and penumbra of ischemic brain. Western blot analysis further illustrated that VEGF induction was time-dependently changed in these areas. Double-staining analysis indicated that VEGF-positive staining existed in the neuron, but not in the glia, and it colocalized with excision repair cross-complementing group 6 (ERCC6) mRNA, a DNA repair factor. VEGF antisense oligodeoxynucleotide infusion reduced VEGF induction and resulted in an enlargement of infarct volume of the brain caused by ischemia. Moreover, it also increased the number of DNA damaged cells and lessened the induction of ERCC6 mRNA in ischemic brains. These results suggest that the induction of endogenous VEGF in ischemic neurons plays a neuroprotective role probably associated with the expression of ERCC6 mRNA. © 2002 Wiley-Liss, Inc. [source] MRI monitoring of focal cerebral ischemia in peroxisome proliferator-activated receptor (PPAR)-deficient miceNMR IN BIOMEDICINE, Issue 3 2007Jean-Baptiste Pialat Abstract Peroxisome proliferator-activated receptors (PPARs) are a potential target for neuroprotection in focal ischemic stroke. These nuclear receptors have major effects in lipid metabolism, but they are also involved in inflammatory processes. Three PPAR isotypes have been identified: ,, , (or ,) and ,. The development of PPAR transgenic mice offers a promising tool for prospective therapeutic studies. This study used MRI to assess the role of PPAR, and PPAR, in the development of stroke. Permanent middle cerebral artery occlusion induced focal ischemia in wild-type, PPAR, -null mice and PPAR, -null mice. T2 -weighted MRI was performed with a 7 T MRI scan on day 0, 1, 3, 7 and 14 to monitor lesion growth in the various genotypes. General Linear Model statistical analysis found a significant difference in lesion volume between wild-type and PPAR-null mice for both , and , isotypes. These data validate high-resolution MRI for monitoring cerebral ischemic lesions, and confirm the neuroprotective role of PPAR, and PPAR, in the brain. Copyright © 2007 John Wiley & Sons, Ltd. [source] L-type calcium channel blockers and Parkinson disease in DenmarkANNALS OF NEUROLOGY, Issue 5 2010Beate Ritz MD Objective This study was undertaken to investigate L-type calcium channel blockers of the dihydropyridine class for association with Parkinson disease (PD), because some of these drugs traverse the blood,brain barrier, are potentially neuroprotective, and have previously been evaluated for impact on PD risk. Methods We identified 1,931 patients with a first-time diagnosis for PD between 2001 and 2006 as reported in the Danish national hospital/outpatient database and density matched them by birth year and sex to 9,651 controls from the population register. The index date for cases and their corresponding controls was advanced to the date of first recorded prescription for anti-Parkinson drugs, if prior to first PD diagnosis in the hospital records. Prescriptions were determined from the national pharmacy database. In our primary analyses, we excluded all calcium channel blocker prescriptions 2 years before index date/PD diagnosis. Results Employing logistic regression analysis adjusting for age, sex, diagnosis of chronic pulmonary obstructive disorder, and Charlson comorbidity score, we found that subjects prescribed dihydropyridines (excludes amlodipine) between 1995 and 2 years prior to the index date were less likely to develop PD (odds ratio, 0.73; 95% confidence interval, 0.54,0.97); this 27% risk reduction did not differ with length or intensity of use. Risk estimates were close to null for the peripherally acting drug amlodipine and for other antihypertensive medications. Interpretation Our data suggest a potential neuroprotective role for centrally acting L-type calcium channel blockers of the dihydropyridine class in PD that should be further investigated in studies that can distinguish between types of L-type channel blockers. ANN NEUROL 2010;67:600,606 [source] Alteration of NF-,B activity leads to mitochondrial apoptosis after infection with pathological prion proteinCELLULAR MICROBIOLOGY, Issue 9 2007Soizic Bourteele Summary Nuclear factor kappa B (NF-,B) is a key regulator of the immune response, but in almost the same manner it is involved in induction of inflammation, proliferation and regulation of apoptosis. In the central nervous system activated NF-,B plays a neuroprotective role. While in some neurodegenerative disorders the role of NF-,B is well characterized, there is poor knowledge on the role of NF-,B in prion disease. We found binding but no transcriptional activity of the transcription factor in vitro. Characterizing the mechanism of cell death after infection with pathological prion protein increased caspase-9 and caspase-3 activity was detected and the lack of NF-,B activity resulted in the inability to activate target genes that usually play an important role in neuroprotection. Additionally, we investigated the role of NF-,B after prion infection of Nfkb1,/,, Nfkb2,/, and Bcl3,/, mice and central nervous system-specific p65-deleted mice revealing an accelerated prion disease in NF-,B2- and Bcl-3-deficient mice, which is in line with a reduced neuroprotective activity in prion infection. Based on our findings, we propose a model whereby the alteration of NF-,B activity at the early stages of infection with pathological prion protein leads to neuronal cell death mediated by mitochondrial apoptosis. [source] MAPKs are differentially modulated in arctic ground squirrels during hibernationJOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2005Xiongwei Zhu Abstract Hibernating animals are very tolerant of trauma to the central nervous system such that dramatic fluctuations in cerebral blood flow occur during hibernation and arousal without apparent damage. Indeed, it was demonstrated that Arctic ground squirrels (AGS) experience acute and severe systemic hypoxia along with the dramatic fluctuation in cerebral blood flow when the animals are aroused from hibernation. While initial hypotheses concerned protective mechanisms in the hibernating state, recent evidence of sustained elevation of HIF1, in euthermic AGS from our laboratory suggests that a preparatory program of protective gene expression is chronically expressed in euthermic AGS. In this study we evaluated potential neuroprotective adaptations by examining the alteration of intracellular MAPK pathways that may be modulated by hypoperfusion/reperfusion in AGS during hibernation and arousal. We found that ERK and JNK are activated in both euthermic and aroused AGS compared to the hibernating group which positively correlated with HIF1, levels. The activation of ERK and JNK associated with HIF1, may play an important role in mediating neuroprotective adaptations that is essential for successful hibernation. Interestingly, p38 is activated in euthermic AGS but not in aroused AGS, which shows strong correlation with iNOS induction. Therefore, the attenuation of p38 activation and iNOS induction in hibernating and aroused animals may contribute to the attenuation of inflammation that plays important neuroprotective roles during hibernation. Taken together, the differential modulation of the MAPK pathways may be critical for neuroprotection of AGS necessary for fluctuations in oxygen and nutrient delivery during hibernation. © 2005 Wiley-Liss, Inc. [source] Glial reactions in Parkinson's diseaseMOVEMENT DISORDERS, Issue 4 2008Patrick L. McGeer MD Abstract Dopaminergic neurons of the substantia nigra are particularly vulnerable to oxidative and inflammatory attack. Such processes may play a crucial role in the etiology of Parkinson disease (PD). Since glia are the main generators of these processes, the possibility that PD may be caused by glial dysfunction needs to be considered. This review concentrates on glial reactions in PD. Reactive astrocytes and reactive microglia are abundant in the substantia nigra (SN) of PD cases indicating a robust inflammatory state. Glia normally serve neuroprotective roles but, given adverse stimulation, they may contribute to damaging chronic inflammation. Microglia, the phagocytes of brain, may be the main contributors since they can produce large numbers of superoxide anions and other neurotoxins. Their toxicity towards dopaminergic neurons has been demonstrated in tissue culture and various animal models of PD. The MPTP and ,-synuclein models are of particular interest. Years after exposure to MPTP, inflammation has been observed in the SN. This has established that an acute insult to the SN can result in a sustained local inflammation. The ,-synuclein model indicates that an endogenous protein can induce inflammation, and, when overexpressed, can lead to autosomal dominant PD. Less is known about the role of astrocytes than microglia, but they are known to secrete both inflammatory and anti-inflammatory molecules and may play a role in modulating microglial activity. Oligodendrocytes do not seem to play a role in promoting inflammation although, like neurons, they may be damaged by inflammatory processes. Further research concerning glial reactions in PD may lead to disease-modifying therapeutic approaches. © 2007 Movement Disorder Society [source] | |||||||||||||