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Neuroprotective Strategies (neuroprotective + strategy)
Selected AbstractsNeuroprotective Strategies to Avert Seizure-Induced Neurodegeneration in EpilepsyEPILEPSIA, Issue 2007Janice R. Naegele Summary:, Neurodegeneration in limbic circuits is a hallmark feature of chronic temporal lobe epilepsy (TLE). Studies in experimental animal models and human patients indicate that seizure-induced neuronal injury involves some active, as well as passive cell death processes. Experimental approaches that inhibit active steps in cell death programs have been shown to reduce neuronal cell death and sclerosis, but not to prevent epileptogenesis in animal models of TLE. These findings suggest that we need additional research using both animal models and brain slices from human patients to understand the pathological mechanisms underlying seizure generation. Such comparative studies will also aid in evaluating the potential therapeutic value of inhibiting cell death in seizure disorders. [source] Thrombin potently enhances swelling-sensitive glutamate efflux from cultured astrocytesGLIA, Issue 9 2007Gerardo Ramos-Mandujano Abstract High concentrations of thrombin (Thr) have been linked to neuronal damage in cerebral ischemia and traumatic brain injury. In the present study we found that Thr markedly enhanced swelling-activated efflux of 3H -glutamate from cultured astrocytes exposed to hyposmotic medium. Thr (0.5,5 U/mL) elicited small 3H -glutamate efflux under isosmotic conditions and increased the hyposmotic glutamate efflux by 5- to 10-fold, the maximum effect being observed at 15% osmolarity reduction. These Thr effects involve its protease activity and are fully mimicked by SFFLRN, the synthetic peptide activating protease-activated receptor-1. Thr potentiation of 3H -glutamate efflux was largely dependent on a Thr-elicited increases in cytosolic Ca2+ (Ca2+i) concentration ([Ca2+]i). Preventing Ca2+i rise by treatment with EGTA-AM or with the phospholipase C blocker U73122 reduced the Thr-increased glutamate efflux by 68%. The protein kinase C blockers Go6976 or chelerythrine reduced the Thr effect by 19%,22%, while Ca/calmodulin blocker W7 caused a 63% inhibition. In addition to this Ca2+ -sensitive pathway, Thr effect on glutamate efflux also involved activation of phosphoinositide-3 kinase (PI3K), since it was reduced by the PI3K inhibitor wortmannin (51% inhibition). Treating cells with EGTA-AM plus wortmannin essentially abolished Thr-dependent glutamate efflux. Thr-activated glutamate release was potently inhibited by the blockers of the volume-sensitive anion permeability pathway, NPPB (IC50 15.8 ,M), DCPIB (IC50 4.2 ,M). These results suggest that Thr may contribute to the excitotoxic neuronal injury by elevating extracellular glutamate release from glial cells. Therefore, this work may aid in search of neuroprotective strategies for treating cerebral ischemia and brain trauma. © 2007 Wiley-Liss, Inc. [source] Long-term treadmill exposure protects against age-related neurodegenerative change in the rat hippocampusHIPPOCAMPUS, Issue 10 2009Rachel M. O'Callaghan Abstract The potential of exercise or environmental enrichment to prevent or reverse age-related cognitive decline in rats has been widely investigated. The data suggest that the efficacy of these interventions as neuroprotectants may depend upon the duration and nature of the protocols and age of onset. Investigations of the mechanisms underlying these neuroprotective strategies indicate a potential role for the neurotrophin family of proteins, including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). In this study, we have assessed the effects of 8 months of forced exercise, begun in middle-age, on the expression of long-term potentiation (LTP) and on spatial learning in the Morris water maze in aged Wistar rats. We also assessed these measures in a cage control group and in a group of rats exposed to the stationary treadmill for the same duration as the exercised rats. Our data confirm an age-related decline in expression of LTP and in spatial learning concomitant with decreased expression of NGF and BDNF mRNA in dentate gyrus (DG). The age-related impairments in both plasticity and growth factor expression were prevented in the long-term exercised group and, surprisingly, the treadmill control group. Given the extensive handling that the treadmill control group received and their regular exposure to an environment outside the home cage, this group can be considered to have experienced environmentally enriched conditions when compared with the cage control group. Significant correlations were observed between both learning and LTP and the expression of NGF and BDNF mRNA in the dentate gyrus. We conclude that decreased expression of NGF and BDNF in the dentate gyrus of aged rats is associated with impaired LTP and spatial learning. We suggest that the reversal of these age-related impairments by enrichment and exercise may be linked with prevention of the age-related decline in expression of these growth factors and, furthermore, that enrichment is as efficacious as exercise in preventing this age-related decline. © 2009 Wiley-Liss, Inc. [source] Glutamine synthetase enhances the clearance of extracellular glutamate by the neural retinaJOURNAL OF NEUROCHEMISTRY, Issue 3 2002Iftach Shaked Abstract Clearance of synaptic glutamate by glial cells is required for the normal function of excitatory synapses and for prevention of neurotoxicity. Although the regulatory role of glial glutamate transporters in glutamate clearance is well established, little is known about the influence of glial glutamate metabolism on this process. This study examines whether glutamine synthetase (GS), a glial-specific enzyme that amidates glutamate to glutamine, affects the uptake of glutamate. Retinal explants were incubated in the presence of [14C]glutamate and glutamate uptake was assessed by measurement of the amount of radioactively labeled molecules within the cells and the amount of [14C]glutamine released to the medium. An increase in GS expression in Müller glial cells, caused by induction of the endogenous gene, did not affect the amount of glutamate accumulated within the cells, but led to a dramatic increase in the amount of glutamine released. This increase, which was directly correlated with the level of GS expression, was dependent on the presence of external sodium ions, and could be completely abolished by methionine sulfoximine, a specific inhibitor of GS activity. Our results demonstrate that GS activity significantly influences the uptake of glutamate by the neural retina and suggest that this enzyme may represent an important target for neuroprotective strategies. [source] MAPK-pathway activity, Lrrk2 G2019S, and Parkinson's diseaseJOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2007Linda R. White Abstract The 6055G>A mutation in the leucine-rich repeat kinase 2 (LRRK2) gene results in a G2019S substitution in the mixed-lineage kinase domain of Lrrk2, causing autosomal dominant Parkinson's disease (PD). We hypothesized the mutation alters cellular mitogen-activated protein kinase (MAPK) signalling cascades, and might be detectable in tissues other than in the brain. We therefore compared total levels and activation of the signalling proteins Src, HSP27, p38 MAPK, JNK, and ERK, in extracts of leukocytes isolated from patients with PD carrying the G2019S mutation, healthy mutation carriers, patients with idiopathic PD, and healthy controls. Phosphorylation of Src, HSP27, and JNK was reduced significantly in cell extracts from patients with G2019S-associated PD compared to healthy controls. Similarly, phosphorylation was reduced significantly in Src and HSP27 in the group of healthy carriers of the mutation, as well as in patients with idiopathic PD. Significant reductions in total Src were also observed in these three groups compared to the controls. The results of this pilot project therefore indicate significant alterations in key signalling proteins in leukocytes from patients with PD, and were most pronounced in G2019S-associated PD. Changes in MAPK-signalling may thus be common to PD pathophysiology, regardless of aetiology. Such changes may also be shown in blood samples during the preclinical stage of LRRK2 -associated PD, which could be particularly important for the development of neuroprotective strategies to delay onset, or slow progression of PD. © 2007 Wiley-Liss, Inc. [source] Mixed lineage kinase,c-jun N-terminal kinase signaling pathway: A new therapeutic target in Parkinson's diseaseMOVEMENT DISORDERS, Issue 6 2005Robert M. Silva PhD Abstract There is growing evidence that the molecular pathways of programmed cell death play a role in neurodegenerative disease, including Parkinson's disease, so there has been increased interest in them as therapeutic targets for the development of neuroprotective strategies. One pathway of cell death that has attracted particular attention is the mixed lineage kinase (MLK) ,c-jun N-terminal kinase (JNK) signaling cascade, which leads to the phosphorylation and activation of the transcription factor c-jun. There is much evidence, from in vitro and in vivo studies, that this cascade can mediate cell death. In addition, there is evidence that it is operative upstream in the death process. It is possible that abrogation of this pathway may forestall death before irreversible cellular injury. One class of compounds that has shown promise for their ability to block cell death by inhibiting this cascade are the inhibitors of the MLKs, which are upstream in the activation of c-jun. One of these compounds, CEP1347, is now in a Phase II/III clinical trial for neuroprotection in PD. Whether this trial is successful or not, this signaling cascade is likely to be a focus of future therapeutic development. This review, therefore, outlines the principles of signaling within this kinase pathway, and the evidence for its role in cell death. We review the evidence that inhibition of the MLKs can prevent dopamine neuron cell death and the degeneration of their axons. These studies suggest important future directions for the development of therapies that will target this important cell death pathway. © 2005 Movement Disorder Society [source] Neuroprotective therapy in Parkinson's disease and motor complications: A search for a pathogenesis-targeted, disease-modifying strategyMOVEMENT DISORDERS, Issue S11 2005C. Warren Olanow MD, FRCPC Abstract The introduction of levodopa in the late 1960s represented a landmark in the therapy of Parkinson's disease (PD). However, motor complications of chronic levodopa therapy have emerged as a major limitation of this otherwise effective therapy. Advancing medical and surgical treatment of these complications has been the main objective of clinical trials during the past few decades. In addition, basic research has focused on better understanding of the mechanisms of motor complications and how to prevent them. Slowing or delaying the progression of the disease delays the need for levodopa therapy; therefore, neuroprotective strategies may play an important role in preventing the onset and reducing the severity of levodopa-related adverse effects. In this introductory review, we present the rationale for current and experimental therapies designed to favorably modify the progression of PD. If implemented early in the course of the disease, such treatments, if found effective, may not only alter the natural progression of the disease but may also delay or minimize motor and nonmotor complications associated with levodopa. © 2005 Movement Disorder Society [source] What is the basis of transmissible spongiform encephalopathy induced neurodegeneration and can it be repaired?NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 1 2002J. R. FraserArticle first published online: 8 APR 200 Once an animal becomes infected with a prion disease, or transmissible spongiform encephalopathy (TSE), the progression of infection is relentless and inevitably fatal, although often with such prolonged incubation periods that an alternative cause of death can intervene. Infection has been compared to ,setting a clock' which then runs inexorably as the disease spreads, usually through the lymphoreticular system and then via peripheral nerves to the central nervous system (CNS), although the mechanism controlling the protracted progression is not known. Clinical disease develops as characteristic degenerative changes in the CNS progress, but the molecular basis for this pathology is not clear, particularly the relationship between the deposition of abnormal PrP and neuronal dysfunction. Recent research has identified several means of slowing (if not stopping) the clock when infection has not yet reached the CNS; although the potential for later stage therapies seems limited, neuroprotective strategies which have been shown to be effective in other neurodegenerative conditions may also ameliorate TSE induced CNS pathology. This review focuses on our current knowledge of the key events following infection of the CNS and the opportunities for intervention once the CNS has become infected. [source] cGMP-dependent cone photoreceptor degeneration in the cpfl1 mouse retinaTHE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 17 2010Dragana Trifunovi Abstract Inherited retinal degeneration affecting both rod and cone photoreceptors constitutes one of the leading causes of blindness in the developed world. Such degeneration is at present untreatable, and the underlying neurodegenerative mechanisms are unknown, even though certain genetic causes have been established. The rd1 mouse is one of the best characterized animal models for rod photoreceptor degeneration, whereas the cpfl1 mouse is a recently discovered model for cone cell death. Because both animal models are affected by functionally similar mutations in the rod and cone phosphodiesterase 6 genes, respectively, we asked whether the mechanisms of photoreceptor degeneration in these two mouse lines share common pathways. In the present study, we followed the temporal progression of photoreceptor degeneration in the cpfl1 retina, correlated it with specific metabolic markers, and compared it with the wild-type and the rd1 situation. Similar to corresponding rd1 observations, cpfl1 cone photoreceptor cell death was associated with an accumulation of cyclic guanosine monophosphate (cGMP), activity of calpains, and phosphorylation of vasodilator-stimulated protein (VASP). Cone degeneration progressed rapidly, with a peak in cell death around postnatal day 24. Furthermore, cpfl1 cone photoreceptor migration during early postnatal development was delayed significantly compared with the corresponding wild-type retina. The finding that rod and cone photoreceptor degeneration was associated with the same metabolic markers suggests that in both cell types similar degenerative mechanisms are active. This raises the possibility that equivalent neuroprotective strategies may be used to prevent both rod and cone photoreceptor degeneration. J. Comp. Neurol. 518:3604,3617, 2010. © 2010 Wiley-Liss, Inc. [source] 2153: Can we treat glaucoma by non-IOP related approaches?ACTA OPHTHALMOLOGICA, Issue 2010I STALMANS Intra-ocular pressure is the main risk factor for the progression of glaucoma. However, intra-ocular pressure lowering is not always sufficient to halt the progressive ganglion cell loss. Indeed, additional risk factors have been identified for glaucoma progression that can explain why some patients progress despite rigourous intra-ocular pressure lowering. Vascular risk factors, such as low perfusion pressure, can be taken into account in the management of our glaucoma patients. The treatment options for these vascular risk factors will be discussed during the lecture. Moreover, neuroprotective strategies might open therapeutic perspectives to directly support the ganglion cells and thus help stabilizing the disease. Possible neuroprotective agents will be highlighted. [source] Inactivation of astroglial NF-,B promotes survival of retinal neurons following ischemic injuryEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2009Galina Dvoriantchikova Abstract Reactive astrocytes have been implicated in neuronal loss following ischemic stroke. However, the molecular mechanisms associated with this process are yet to be fully elucidated. In this work, we tested the hypothesis that astroglial NF-,B, a key regulator of inflammatory responses, is a contributor to neuronal death following ischemic injury. We compared neuronal survival in the ganglion cell layer (GCL) after retinal ischemia-reperfusion in wild-type (WT) and in GFAP-I,B,-dn transgenic mice, where the NF-,B classical pathway is suppressed specifically in astrocytes. The GFAP-I,B,-dn mice showed significantly increased survival of neurons in the GCL following ischemic injury as compared with WT littermates. Neuroprotection was associated with significantly reduced expression of pro-inflammatory genes, encoding Tnf-,, Ccl2 (Mcp1), Cxcl10 (IP10), Icam1, Vcam1, several subunits of NADPH oxidase and NO-synthase in the retinas of GFAP-I,B,-dn mice. These data suggest that certain NF-,B-regulated pro-inflammatory and redox-active pathways are central to glial neurotoxicity induced by ischemic injury. The inhibition of these pathways in astrocytes may represent a feasible neuroprotective strategy for retinal ischemia and stroke. [source] Cell proliferation and death in the brain of active and hibernating frogsJOURNAL OF ANATOMY, Issue 2 2009Silvia Cerri Abstract ,Binomial' cell proliferation and cell death have been studied in only a few non-mammalian vertebrates, such as fish. We thought it of interest to map cell proliferation/apoptosis in the brain of the frog (Rana esculenta L.) as this animal species undergoes, during the annual cycle, physiological events that could be associated with central nervous system damage. Therefore, we compared the active period and the deep underground hibernation of the frog. Using western blot analysis for proliferating cell nuclear antigen (PCNA), we revealed a positive 36 kDa band in all samples and found higher optical density values in the hibernating frogs than in active frogs. In both active and hibernating frogs, we found regional differences in PCNA-immunoreactive cells and terminal transferase dUTP nick-end labelling apoptotic cells in the ventricular zones and parenchyma areas of the main encephalon subdivisions. During the active period of the frogs, the highest concentration of PCNA-immunoreactive cells was found in the ventricle dorsal zone of the cerebral hemispheres but only some of the cells were apoptotic. By contrast, the tectal and cerebellar ventricular zones had a small or medium amount of PCNA-immunoreactive cells, respectively, and a higher number of apoptotic cells. During hibernation, an increased PCNA-immunoreactive cell number was observed in both the brain ventricles and parenchyma compared with active frogs. This increase was primarily evident in the lateral ventricles, a region known to be a proliferation ,hot spot'. Although differences existed among the brain areas, a general increase of apoptotic cell death was found in hibernating frogs, with the highest number of apoptotic cells being detected in the parenchyma of the cerebral hemispheres and optic tectum. In particular, the increased number of apoptotic cells in the hibernating frogs compared with active frogs in the parenchyma of these brain areas occurred when cell proliferation was higher in the corresponding ventricular zones. We suggest that the high number of dying cells found in the parenchymal regions of hibernating frogs might provide the stimulus for the ventricular zones to proliferate. Hibernating frogs could utilize an increased cell proliferation in the brain areas as a neuroprotective strategy to face cell death and the onset of neurological damages. Therefore, the hibernator promises to be a valuable model for studying the mechanisms naturally carried out by the central nervous system in order to adapt itself or survive adverse conditions. [source] A molecular basis for the increased vulnerability of substantia nigra dopamine neurons in aging and Parkinson's disease,MOVEMENT DISORDERS, Issue S1 2010C. Savio Chan PhD Abstract Parkinson's disease (PD) is a common neurodegenerative disorder of unknown etiology. There is no cure or proven strategy for slowing the progression of the disease. Although there are signs of pathology in many brain regions, the core symptoms of PD are attributable to the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta. A potential clue to the vulnerability of these neurons is an increasing reliance with age upon L-type Ca2+ channels with a pore-forming Cav1.3 subunit to support autonomous activity. This reliance could pose a sustained stress on mitochondrial ATP generating oxidative phosphorylation, accelerating cellular aging and death. Systemic administration of isradipine, a dihydropyridine blocker of these channels, forces dopaminergic neurons in rodents to revert to a juvenile, L-type Ca2+ channel independent mechanism to generate autonomous activity. This "rejuvenation" confers protection against toxins that produce experimental Parkinsonism, pointing to a potential neuroprotective strategy for PD. Their decades-long track record of safe use in the treatment of hypertension makes dihydropyridines particularly attractive as a therapeutic tool in PD. © 2010 Movement Disorder Society [source] Neuroprotective effect of riluzole in a primate model of Parkinson's disease: Behavioral and histological evidenceMOVEMENT DISORDERS, Issue 1 2002Maria C. Obinu PhD Abstract Our study aimed to determine whether riluzole, which has shown efficacy as a disease-modifying agent in amyotrophic lateral sclerosis (ALS), is neuroprotective in a marmoset model of Parkinson's disease (PD). Reduction of energy demand by riluzole could be a rational neuroprotective strategy with good tolerability. The efficacy of riluzole was evaluated in marmosets by testing its ability to reduce MPTP-induced behavioral deficits and loss of dopaminergic nigral neurons. Marmosets were divided into two groups of four animals each: animals in Group 1 were injected twice with MPTP (2 mg/kg subcutaneous) and treated with riluzole (10 mg/kg per os b.i.d.), animals in Group 2 (controls) were injected with MPTP and with the vehicle of riluzole. A third group of marmosets which did not receive MPTP or riluzole drug was introduced for neurohistopathological studies (normal animals). Marmosets treated with riluzole preserved a better motor function and neurological performance through the 26 days of assessment when compared with the controls. Histologically, there was sparing of TH- and Nissl-stained nigral neurons and of TH-stained terminals in the striatum and the putamen in the group treated with riluzole compared to the controls. We conclude that riluzole protects dopaminergic neurons and reduces behavioral deficits in a marmoset model of PD. © 2001 Movement Disorder Society. [source] In vivo gene delivery of glial cell line,derived neurotrophic factor for Parkinson's diseaseANNALS OF NEUROLOGY, Issue S3 2003Jeffrey H. Kordower PhD Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects approximately 1,000,000 Americans. The cause of the disease remains unknown. The histopathological hallmarks of the disease are dopaminergic striatal insufficiency secondary to a loss of dopaminergic neurons in the substantia nigra pars compacta and intracellular inclusion called Lewy bodies. Currently, only symptomatic treatment for PD is available. Although some treatments are efficacious for many years, all have significant limitations and new therapeutic approaches are needed. Gene therapy is ideal for delivering therapeutic molecules to site-specific regions of the central nervous system. Via gene therapy, a piece or pieces of DNA placed into a carrying vector encoding for a substance of interest can be introduced into specific cells. Although there are several ways that gene therapy can be applied for PD, this review focuses on in vivo gene delivery of glial cell line,derived neurotrophic factor (GDNF) as a neuroprotective strategy for PD. Ann Neurol 2003;53 (suppl 3):S120,S134 [source] EFFECT OF NAPROXEN, A NON-SELECTIVE CYCLO-OXYGENASE INHIBITOR, ON PENTYLENETETRAZOL-INDUCED KINDLING IN MICECLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 7 2005Ashish Dhir SUMMARY 1.,Epilepsy is one of the major neurological disorders of the brain, affecting approximately 0.5,1.0% of the population worldwide. Various neurotransmitter abnormalities, especially of GABA and glutamate, have been reported to play a key role in the pathophysiology of epilepsy. 2.,Cyclo-oxygenase (COX) is the rate-limiting enzyme in the production of prostaglandins and, as such, is a key target for many anti-inflammatory drugs. Cyclo-oxygenase has been reported to play a significant role in neurodegeneration. Recent studies have reported that COX plays a significant role in the pathophysiology of epilepsy. 3.,The aim of the present study was to explore the possible role of COX and the effect of COX inhibitors in epilepsy. 4.,Kindling is a chronic model of epilepsy. In the present study, kindling was induced in mice by chronic administration of a subconvulsive dose of pentylenetetrazole (PTZ; 40 mg/kg) on every other day for a period of 15 days. Naproxen was administered daily 45 min before PTZ or vehicle. The kindling score was recorded after PTZ administration. Seizure severity was measured according to a prevalidated scoring scale. Biochemical estimations were performed immediately after recording behavioural parameters on the 16th day of PTZ treatment. 5.,Chronic treatment with PTZ significantly induced kindling in mice. Pretreatment with the non-selective COX inhibitor naproxen (7 and 14 mg/kg, i.p.) showed significant protection against PTZ-induced kindling in mice. Biochemical analysis revealed that chronic treatment with PTZ significantly increased lipid peroxidation and nitrite levels (NO levels), but decreased reduced glutathione (GSH) levels in brain homogenates. 6.,In conclusion, the results of the present study strongly suggest that COX plays an important role in the pathophysiology of PTZ-induced kindling in mice and that COX inhibitors could be a useful neuroprotective strategy for the treatment of epilepsy. [source] | |||||||||||||