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Neuroprotective Properties (neuroprotective + property)
Selected AbstractsTacrine,Melatonin Hybrids as Multifunctional Agents for Alzheimer's Disease, with Cholinergic, Antioxidant, and Neuroprotective PropertiesCHEMMEDCHEM, Issue 5 2009María Isabel Fernández-Bachiller Dr. Abstract Tacrine,melatonin hybrids are potential multifunctional drugs for Alzheimer's disease that may simultaneously palliate intellectual deficits and protect the brain against both ,-amyloid peptide and oxidative stress. Molecular modeling studies show that they target both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. They are nontoxic and may be able to penetrate the CNS, according to in,vitro PAMPA-BBB assays. Tacrine,melatonin hybrids were designed and synthesized as new multifunctional drug candidates for Alzheimer's disease. These compounds may simultaneously palliate intellectual deficits and protect the brain against both ,-amyloid (A,) peptide and oxidative stress. They show improved cholinergic and antioxidant properties, and are more potent and selective inhibitors of human acetylcholinesterase (hAChE) than tacrine. They also capture free radicals better than melatonin. Molecular modeling studies show that these hybrids target both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. At sub-micromolar concentrations they efficiently displace the binding of propidium iodide from the PAS and could thus inhibit A, peptide aggregation promoted by AChE. Moreover, they also inhibit A, self-aggregation and display neuroprotective properties in a human neuroblastoma line against cell death induced by various toxic insults, such as A,25,35, H2O2, and rotenone. Finally, they exhibit low toxicity and may be able to penetrate the central nervous system according to an in,vitro parallel artificial membrane permeability assay for the blood,brain barrier (PAMPA-BBB). [source] Pre-clinical studies of pramipexole: clinical relevanceEUROPEAN JOURNAL OF NEUROLOGY, Issue 2000J. P. Hubble This paper reviews the preclinical study of the novel dopamine agonist pramipexole and its use in early Parkinson's disease (PD). Emphasis will be given to those properties distinguishing this drug from other dopamine agonists, the relevance of the preclinical data to clinical trial results in early PD, and the putative neuroprotective properties of the compound. The conventional dopamine agonists are ergot-derived compounds that are most widely used as adjunctive therapies in advancing Parkinson's disease (PD). Examples of conventional agonists are bromocriptine and pergolide. Pramipexole is an aminobenzothiazole compound, recently introduced for the treatment of both early and advanced PD. Its nonergot structure may reduce the risk of side-effects, considered unique to ergot drugs, such as membranous fibrosis. Pramipexole is a full dopamine agonist with high selectivity for the D2 dopamine receptor family. This family includes the D2, D3 and D4 receptor subtypes. Pramipexole has a 5- to 7-fold greater affinity for the D3 receptor subtype with lower affinities for the D2 and D4 receptor subtypes. The drug has only minimal ,2 -adrenoceptor activity and virtually no other receptor agonism or antagonism. The optimal dopamine receptor activation for the safe and effective treatment of PD is not known. Findings in animal models and clinical studies indicate that activation of the postsynaptic D2 receptor subtype provides the most robust symptomatic improvement in PD. Given its pharmacological profile, it is not surprising that pramipexole was found to be effective in ameliorating parkinsonian signs in animal models. This therapeutic effect has been confirmed in clinical trials in both early and advanced PD. In early disease, it provides a clear reduction in the chief motor manifestations of PD and improved activities of daily living. Perhaps most striking is the large number of clinical trial patients who have remained on pramipexole monotherapy for many months. The majority of these subjects have been maintained on pramipexole for an excess of 24 months without requiring additional symptomatic treatment with levodopa. This is in contrast to the general clinical experience with older conventional agonists. Pramipexole also has a favourable pharmacokinetic profile. It is rapidly absorbed with peak levels appearing in the bloodstream within 2 h of oral dosing. It has a high absolute bioavailability of > 90% and can be administered without regard to meals. It has no significant effects on other antiparkinson drugs such as levodopa or selegiline. Its excretion is primarily renal and, thus, has little or no impact on hepatic cytochrome P450 enzymes or other related metabolic pathways. Pramipexole has also been theorized to have ,neuroprotectant' properties. Oxyradical generation is posited as a cause or accelerant of brain nigral cell death in PD. Pramipexole stimulates brain dopamine autoreceptors and reduces dopamine synthesis and turnover which may minimize oxidative stress due to dopamine metabolism. Furthermore, the compound has a low oxidation potential that may serve as an oxyradical scavenger in the PD brain. In summary, pramipexole is a new antiparkinson medication found to have unique dopamine agonist characteristics and putative neuroprotective properties. [source] Exogenous agmatine has neuroprotective effects against restraint-induced structural changes in the rat brainEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 6 2008Meng-Yang Zhu Abstract Agmatine is an endogenous amine derived from decarboxylation of arginine catalysed by arginine decarboxylase. Agmatine is considered a novel neuromodulator and possesses neuroprotective properties in the central nervous system. The present study examined whether agmatine has neuroprotective effects against repeated restraint stress-induced morphological changes in rat medial prefrontal cortex and hippocampus. Sprague-Dawley rats were subjected to 6 h of restraint stress daily for 21 days. Immunohistochemical staining with ,-tubulin III showed that repeated restraint stress caused marked morphological alterations in the medial prefrontal cortex and hippocampus. Stress-induced alterations were prevented by simultaneous treatment with agmatine (50 mg/kg/day, i.p.). Interestingly, endogenous agmatine levels, as measured by high-performance liquid chromatography, in the prefrontal cortex and hippocampus as well as in the striatum and hypothalamus of repeated restraint rats were significantly reduced as compared with the controls. Reduced endogenous agmatine levels in repeated restraint animals were accompanied by a significant increase of arginine decarboxylase protein levels in the same regions. Moreover, administration of exogenous agmatine to restrained rats abolished increases of arginine decarboxylase protein levels. Taken together, these results demonstrate that exogenously administered agmatine has neuroprotective effects against repeated restraint-induced structural changes in the medial prefrontal cortex and hippocampus. These findings indicate that stress-induced reductions in endogenous agmatine levels in the rat brain may play a permissive role in neuronal pathology induced by repeated restraint stress. [source] Riluzole inhibits the persistent sodium current in mammalian CNS neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 10 2000Andrea Urbani Abstract The effects of 0.1,100 ,m riluzole, a neuroprotective agent with anticonvulsant properties, were studied on neurons from rat brain cortex. Patch-clamp whole-cell recordings in voltage-clamp mode were performed on thin slices to examine the effects of the drug on a noninactivating (persistent) Na+ current (INa,p). INa,p was selected because it enhances neuronal excitability near firing threshold, which makes it a potential target for anticonvulsant drugs. When added to the external solution, riluzole dose-dependently inhibited INa,p up to a complete blocking of the current (EC50 2 ,m), showing a significant effect at therapeutic drug concentrations. A comparative dose-effect study was carried out in the same cells for the other main known action of riluzole, the inhibitory effect on the fast transient sodium current. This effect was confirmed in our experiments, but we found that it was achieved at levels much higher than putative therapeutic concentrations. Only the effect on INa,p, and not that on fast sodium current, can account for the reduction in neuronal excitability observed in cortical neurons following riluzole treatment at therapeutic concentrations, and this might represent a novel mechanism accounting for the anticonvulsant and neuroprotective properties of riluzole. [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] Gene therapy approaches for Parkinson's diseaseJOURNAL OF NEUROCHEMISTRY, Issue 2003P. Aebischer The CNS delivery of glial cell line-derived neurotrophic factor (GDNF) for the treatment of Parkinson's disease constitutes one of the more promising clinical applications of neurotrophic factors. Crucial for clinical application will be the ability to deliver GDNF within the target structures, i.e. striatum and/or substantia nigra. We are developing both in vivo and ex vivo gene therapy approaches to reach this goal. We have shown in rodents that both lentiviral vectors coding for GDNF and polymer encapsulated cells genetically engineered to release GDNF are able to protect nigral dopaminergic neurons against various insults including axotomy and neurotoxins such as 6-hydroxydopamine. Even more important for clinical application is the ability to scale-up the technology to nonhuman primate application. Neurorestorative and/or neuroprotective properties of GDNF expression were demonstrated with both methods in various nonhuman primate models. [source] trans -Resveratrol Protects Embryonic Mesencephalic Cells from tert -Butyl HydroperoxideJOURNAL OF NEUROCHEMISTRY, Issue 1 2000Electron Param Abstract : In recent years, the antioxidant and other pharmacological properties of resveratrol, a natural product present in grapes and wine, have attracted considerable interest from the biomedical research community. In an examination of the potential neuroprotective properties of the compound, we have investigated the ability of resveratrol to protect rat embryonic mesencephalic tissue, rich in dopaminergic neurones, from the prooxidant tert -butyl hydroperoxide. Using the electron paramagnetic resonance (EPR) spin-trapping technique, the main radicals detected in cell suspensions were the tert -butoxyl radical and the methyl radical, indicating the one-electron reduction of the peroxide followed by a ,-scission reaction. The appearance of EPR signals from the trapped radicals preceded the onset of cytotoxicity, which was almost exclusively necrotic in nature. The inclusion of resveratrol in incubations resulted in the marked protection of cells from tert -butyl hydroperoxide. In parallel spin-trapping experiments, we were able to demonstrate the scavenging of radicals by resveratrol, which involved direct competition between resveratrol and the spin trap for reaction with the radicals. To our knowledge, this is the first example in which cytoprotection by resveratrol has been demonstrated by EPR spin-trapping competition kinetics to be due to its scavenging of the radicals responsible for the toxicity of a prooxidant. [source] Asiatic acid, a pentacyclic triterpene from Centella asiatica, is neuroprotective in a mouse model of focal cerebral ischemiaJOURNAL OF NEUROSCIENCE RESEARCH, Issue 11 2009Rajanikant G. Krishnamurthy Abstract Asiatic acid, a triterpenoid derivative from Centella asiatica, has shown biological effects such as antioxidant, antiinflammatory, and protection against glutamate- or ,-amyloid-induced neurotoxicity. We investigated the neuroprotective effect of asiatic acid in a mouse model of permanent cerebral ischemia. Various doses of asiatic acid (30, 75, or 165 mg/kg) were administered orally at 1 hr pre- and 3, 10, and 20 hr postischemia, and infarct volume and behavioral deficits were evaluated at day 1 or 7 postischemia. IgG (blood,brain barrier integrity) and cytochrome c (apoptosis) immunostaining was carried out at 24 hr postischemia. The effect of asiatic acid on stress-induced cytochrome c release was examined in isolated mitochondrial fractions. Furthermore, its effects on cell viability and mitochondrial membrane potential were studied in HT-22 cells exposed to oxygen-glucose deprivation. Asiatic acid significantly reduced the infarct volume by 60% at day 1 and by 26% at day 7 postischemia and improved neurological outcome at 24 hr postischemia. Our studies also showed that the neuroprotective properties of asiatic acid might be mediated in part through decreased blood,brain barrier permeability and reduction in mitochondrial injury. The present study suggests that asiatic acid may be useful in the treatment of cerebral ischemia. © 2009 Wiley-Liss, Inc. [source] ADAMs family members as amyloid precursor protein ,-secretasesJOURNAL OF NEUROSCIENCE RESEARCH, Issue 3 2003Tobias M.J. Allinson Abstract In the non-amyloidogenic pathway, the Alzheimer's amyloid precursor protein (APP) is cleaved within the amyloid-, domain by ,-secretase precluding deposition of intact amyloid-, peptide. The large ectodomain released from the cell surface by the action of ,-secretase has several neuroprotective properties. Studies with protease inhibitors have shown that ,-secretase is a zinc metalloproteinase, and several members of the adamalysin family of proteins, tumour necrosis factor-, convertase (TACE, ADAM17), ADAM10, and ADAM9, all fulfil some of the criteria required of ,-secretase. We review the evidence for each of these ADAMs acting as the ,-secretase. What seems to be emerging from numerous studies, including those with mice in which each of the ADAMs has been knocked out, is that there is a team of zinc metalloproteinases able to cleave APP at the ,-secretase site. We also discuss how upregulation of ,-secretase activity by muscarinic agonists, cholesterol-lowering drugs, steroid hormones, non-steroidal anti-inflammatory drugs, and metal ions may explain some of the therapeutic actions of these agents in Alzheimer's disease. © 2003 Wiley-Liss, Inc. [source] Histamine-3 receptor antagonists reduce superoxide anion generation and lipid peroxidation in rat brain homogenatesJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2005H. E. Badenhorst Using a cyanide model to induce neurotoxic effects in rat brain homogenates, we examined the neuroprotective properties of three H3 antagonists, namely clobenpropit, thioperamide and impentamine, and compared them to aspirin, a known neuroprotective agent. Superoxide anion levels and malondialdehyde concentration were assessed using the nitroblue tetrazolium and lipid peroxidation assays. Clobenpropit and thioperamide significantly reduced superoxide anion generation and lipid peroxidation. Impentamine reduced lipid peroxidation at all concentrations used, but only reduced superoxide anion generation at a concentration of 1 mM. In the lipid peroxidation assay, all the drugs compared favourably to aspirin. This study demonstrates the potential of these agents to be neuroprotective by exerting antioxidant effects. [source] The neuroprotective activities of melatonin against the Alzheimer ,-protein are not mediated by melatonin membrane receptorsJOURNAL OF PINEAL RESEARCH, Issue 3 2002Miguel A. Pappolla Exposure of neuronal cells to the Alzheimer's amyloid , protein (A,) results in extensive oxidative damage of bio-molecules that are profoundly harmful to neuronal homeostasis. It has been demonstrated that melatonin protects neurons against A, -mediated neurotoxicity, including cell death and a spectrum of oxidative lesions. We undertook the current study to determine whether melatonin membrane receptors are involved in the mechanism of neuroprotection against A, neurotoxicity. For this purpose, we characterized the free-radical scavenging potency of several compounds exhibiting various affinities for melatonin membrane receptors (MLT 1a and 1b). A, -mediated neurotoxicity was assessed in human neuroblastoma cells and in primary hippocampal neurons. In sharp contrast with melatonin, no neuroprotection against A, toxicity was observed when we used melatonin membrane receptor agonists that were devoid of antioxidant activity. In contrast, the cells were fully protected in parallel control experiments when either melatonin, or the structurally unrelated free-radical scavenger phenyl- N - t -butyl nitrone (PBN), were added to A, -containing culture media. This study demonstrates that the neuroprotective properties of melatonin against A, -mediated toxicity does not require binding of melatonin to a membrane receptor and is likely the result of the antioxidant and antiamyloidogenic features of the agent. [source] Acamprosate: Recent Findings and Future Research DirectionsALCOHOLISM, Issue 7 2008Karl Mann This article explores the mechanisms of action and the potential responder profile of acamprosate, a compound efficacious in relapse prevention of alcoholism. New evidence at the molecular and cellular level suggests that acamprosate attenuates hyper-glutamatergic states that occur during early abstinence and involves iono (NMDA)- and metabotrotropic (mGluR5) glutamate receptors along with augmented intracellular calcium release and electrophysiological changes. Thus mutant mice with enhanced glutamate levels exhibit higher alcohol consumption than wild type mice and respond better to acamprosate, demonstrating that acamprosate acts mainly on a hyper-glutamatergic system. This mode of action further suggests that acamprosate exhibits neuroprotective properties. In rats, cue-induced reinstatement behavior is significantly reduced by acamprosate treatment whereas cue-induced craving responses in alcohol-dependent patients seem not to be affected by this treatment. An ongoing study ("Project Predict") defines specific responder profiles for an individualized use of acamprosate and naltrexone. Neurophysiological as well as psychometric data are used to define 2 groups of patients: "reward cravers" and "relief cravers". While naltrexone should work better in the first group, acamprosate is hypothesized to be efficacious in the latter where withdrawal associated and/or cue induced hyper-glutamatergic states are thought to trigger relapse. Further research should target the definition of subgroups applying endophenotypic approaches, e.g. by detecting a hyperglutamatergic syndrome using MR spectroscopy. [source] Acetyl-l-carnitine in the treatment of painful antiretroviral toxic neuropathy in human immunodeficiency virus patients: an open label studyJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2006Maurizio Osio Abstract Antiretroviral toxic neuropathy causes morbidity in human immunodeficiency virus (HIV) patients under dideoxynucleoside therapy, benefits only partially from medical therapy, and often leads to drug discontinuation. Proposed pathogeneses include a disorder of mitochondrial oxidative metabolism, eventually related to a reduction of mitochondrial DNA content, and interference with nerve growth factor activity. Carnitine is a substrate of energy production reactions in mitochondria and is involved in many anabolic reactions. Acetyl carnitine treatment promotes peripheral nerve regeneration and has neuroprotective properties and a direct analgesic role related to glutamatergic and cholinergic modulation. The aim of this study was to evaluate acetyl-l-carnitine in the treatment of painful antiretroviral toxic neuropathy in HIV patients. Twenty subjects affected by painful antiretroviral toxic neuropathy were treated with oral acetyl-l-carnitine at a dose of 2,000 mg/day for a 4-week period. Efficacy was evaluated by means of the modified Short Form McGill Pain Questionnaire with each item rated on an 11-point intensity scale at weekly intervals and by electromyography at baseline and final visit. Mean pain intensity score was significantly reduced during the study, changing from 7.35 ± 1.98 (mean ± SD) at baseline to 5.80 ± 2.63 at week 4 (p = 0.0001). Electrophysiological parameters did not significantly change between baseline and week 4. In this study, acetyl-l-carnitine was effective and well tolerated in symptomatic treatment of painful neuropathy associated with antiretroviral toxicity. On the contrary, no effect was noted on neurophysiological parameters. [source] The effect of Ginkgo biloba on the cerebellum of aging SAMP mouse,A TUNEL, bcl-2, and fMRI studyMICROSCOPY RESEARCH AND TECHNIQUE, Issue 8 2007Maria S.M. Wai Abstract EGb 761, an extract from Ginkgo biloba that possesses neuroprotective properties, was fed to a strain of fast aging mice (SAMP-8) beginning at 3 weeks of age until they were sacrificed at 3 months and 11 months, respectively, along with an age-matched control group without herbal feeding. The aim of the study was to determine (1) the status of apoptosis and the status of bcl-2, a molecule involved in the fate of cells following injury, in the cerebella of these mice and (2) to analyze the functional changes as shown by fMRI images. The data indicated that there were no differences in apoptosis between the mice fed with EGb 761 and the control group at the two time points of 3 and 11 months of age. For bcl-2 positive cells, there was a decrease in density only in the cerebella of 11-month-old mice fed with the herbal extract when compared with controls. Functional studies indicated that while no changes were observed in the 3-month-old mice fed with Ginkgo biloba, an expansion of activated sites, possibly related to "synaptic reorganization and pathway alteration," was observed in the 11-month-old mice. Microsc. Res. Tech., 2007. © 2007 Wiley-Liss, Inc. [source] Erythropoietin improves neurodevelopmental outcome of extremely preterm infantsANNALS OF NEUROLOGY, Issue 5 2010Achim-Peter Neubauer MD Objective Erythropoietin has been reported to possess neuroprotective properties in animal studies. No previous studies have investigated the neurodevelopmental outcome of extremely low birth weight (ELBW) infants treated with recombinant human erythropoietin (rEpo) and evaluated it at school age. Methods Of 200 ELBW infants treated from 1993 to 1998, 171 (86%) survived, and 148 (87%) were followed up to the age of 10 to 13 years. The neurodevelopmental and school outcome of the ELBW infants receiving rEpo treatment for stimulation of erythropoiesis in the first weeks of life (n = 89) was compared to that of untreated children (n = 57). To test for a neuroprotective effect of erythropoietin therapy, analyses of variance (ANOVAs) were conducted with erythropoietin treatment and intraventricular hemorrhage (IVH) as independent variables and Hamburg-Wechsler Intelligence Test for Children-III (HAWIK-III) intelligence quotient (IQ) scores as dependent variables. Results The rEpo group scored significantly better than untreated children in the overall developmental assessment (55% vs 39% normally developed, p < 0.05) as well as in the psychological examination (mean composite HAWIK-III IQ score, 90.8 vs 81.3, p < 0.005). The results of ANOVAs show that these differences were ascribable to children with IVH. Whereas those children with IVH treated with rEpo scored significantly better than untreated children (52% vs 6% normally developed, composite HAWIK-III IQ score, 90.3 vs 67.0), treated and untreated children without IVH did not differ in their outcome. The treatment and control groups were comparable in perinatal parameters relevant to prognosis. Interpretation The results of our observational study confirm the hypothesis of a neuroprotective effect of rEpo in ELBW infants with IVH. This offers a promising preventative therapeutic option for the treatment of these high-risk infants. ANN NEUROL 2010;67:657,666 [source] Activation of metabotropic glutamate receptor 5 improves recovery after spinal cord injury in rodents,ANNALS OF NEUROLOGY, Issue 1 2009Kimberly R. Byrnes PhD Objective Activation of metabotropic glutamate receptor 5 (mGluR5) has neuroprotective properties in vitro and has been reported to limit postischemic lesion volume in vivo. Previously, mGluR5 has been identified on microglia in vitro, but the effects of mGluR5 activation on inflammation in vivo or on recovery after spinal cord injury is unknown. Methods Rats received intrathecal infusion of the selective mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) for 7 days after moderate impact spinal cord injury at T9. Complementary studies examined CHPG effects on activated spinal microglia cultures. Results Functional motor recovery was significantly increased by CHPG treatment up to 28 days after injury, with improvements in weight bearing, step taking, and coordination of stepping behavior. CHPG treatment significantly reduced lesion volume and increased white matter sparing at 28 days after injury. Administration of CHPG attenuated microglial-associated inflammatory responses in a dose-dependent fashion, including expression of ED1, Iba-1, Galectin-3, NADPH oxidase components, tumor necrosis factor-,, and inducible nitric oxide synthase. Because mGluR5 is expressed by microglial cells in the rat spinal cord, such effects may be mediated by direct action on microglial cells. mGluR5 stimulation also reduced microglial activation and decreased microglial-induced neurotoxicity in spinal cord microglia cultures; the latter effects were blocked by the selective mGluR5 antagonist MTEP. Interpretation These data demonstrate that mGluR5 activation can reduce microglial-associated inflammation, suggesting that the protective effects of mGluR5 agonists may reflect this action. Ann Neurol 2009;66:63,74 [source] Minocycline prevents cholinergic loss in a mouse model of Down's syndromeANNALS OF NEUROLOGY, Issue 5 2004Christopher L. Hunter PhD Individuals with Down's syndrome develop Alzheimer's-like pathologies comparatively early in life, including progressive degeneration of basal forebrain cholinergic neurons (BFCNs). Cholinergic hypofunction contributes to dementia-related cognitive decline and remains a target of therapeutic intervention for Alzheimer's disease. In light of this, partial trisomy 16 (Ts65Dn) mice have been developed to provide an animal model of Down's syndrome that exhibits progressive loss of BFCNs and cognitive ability. Another feature common to both Down's syndrome and Alzheimer's disease is neuroinflammation, which may exacerbate neurodegeneration, including cholinergic loss. Minocycline is a semisynthetic tetracycline with antiinflammatory properties that has demonstrated neuroprotective properties in certain disease models. Consistent with a role for inflammatory processes in BFCN degeneration, we have shown previously that minocycline protects BFCNs and improves memory in mice with acute, immunotoxic BFCN lesions. We now report that minocycline treatment inhibits microglial activation, prevents progressive BFCN decline, and markedly improves performance of Ts65Dn mice on a working and reference memory task. Minocycline is an established antiinflammatory and neuroprotective drug and may provide a novel approach to treat specific AD-like pathologies. Ann Neurol 2004 [source] 4412: Immunohistochemistry and Western blot methodologies to evaluate neuroprotective agents in models of retinopathiesACTA OPHTHALMOLOGICA, Issue 2010K THERMOS Purpose Many retinopathies that lead to visual loss and blindness are characterized by neovascularization and neural retinal defects, such as a marked loss in retinal neurons and an increase in apoptosis. There are no therapeutic agents for the treatment of the neurodegenerative component of retinal disease. Immunohistochemistry and western blot methodologies were employed to determine retinal viability and to elucidate the putative neuroprotective properties of new therapeutic targets, in animal models of retinopathy (chemical ischemia, excitotoxicity, STZ). Methods To assay retinal viability, the following antibodies for retinal markers were employed in immunohistochemical assays: PKC (rod bipolar cells), ChAT, bNOS, TH (cholinergic-, nitric oxide synthetase-, and dopamine- containing amacrine cells, respectively), calbindin-containing horizontal, amacrine and cone bipolar cells, NFL and MAP1 (ganglion axons and cells, respectively). Antibodies against various pro-survival or pro-death molecules (western blots), as well as the TUNEL-assay, were employed to examine retinal apoptosis and neuroprotection. Results Loss of retinal marker immunoreactivity was differentially observed according to the animal model employed. The neuroprotection of specific retinal neurons by the new therapeutic targets examined (somatostatin and neurosteroids) reflect the existence of protein substrates involved in the mechanism of action of these molecules. Conclusion Immunohistochemical and western blot analysis techniques provide important information on the retinal damage induced by ischemic insults and the neuroprotection afforded by new targets of retinal therapeutics. [source] Nitric oxide and cGMP protect the retina from ischemia and mediate somatostatin's neuroprotective effectsACTA OPHTHALMOLOGICA, Issue 2009K THERMOS Purpose The neuropeptide somatostatin has been shown to modulate retinal circuitry by activating its receptors (sst1-sst5) found in retinal neurons and to influence the levels of other neuroactive substances such as nitric oxide (NO) and cGMP. In addition, it displays neuroprotective properties against retinal chemical ischemia and excitotoxicity. In another paradigm, somatostatin was shown to protect cortical cultures against NMDA induced neuronal death via a cGMP mechanism. These findings led us to investigate whether NO and/or cGMP could protect the retina from ischemia, and possibly underlie somatostatin's neuroprotective actions. Methods A model of chemical ischemia was employed in rat retina in order to examine the neuroprotective effects of arginine, the substrate of nitric oxide synthase (NOS), and a number of NO donors. Subsequently, blockade of NOS and guanylyl cyclase in the presence of somatostatin receptor (sst2) agonists was attempted to investigate the role of NO/cGMP in somatostatin's protection of the retina in the chemical ischemia model and in a model of AMPA induced excitotoxicity. Results The NO donors SIN-1 and NONOate and 8-Br-cGMP protected the retina in a concentration-dependent manner, as shown by ChAT immunoreactivity and TUNEL staining. L-cysteine (the peroxynitrite scavenger) partially reduced the SIN-1 protective effect. NOS and guanyl cyclase inhibitors reversed the protective effect of sst2 agonists in the chemical ischemia and excitotoxicity model. Conclusion NO/peroxynitrite and cGMP appear to be important mediators in the protection of the retina from chemical ischemia. The NO/sGC/cGMP pathway is involved in the neuroprotective effects of the sst2 ligands in the same model and against AMPA excitotoxic insults. [source] Tacrine,Melatonin Hybrids as Multifunctional Agents for Alzheimer's Disease, with Cholinergic, Antioxidant, and Neuroprotective PropertiesCHEMMEDCHEM, Issue 5 2009María Isabel Fernández-Bachiller Dr. Abstract Tacrine,melatonin hybrids are potential multifunctional drugs for Alzheimer's disease that may simultaneously palliate intellectual deficits and protect the brain against both ,-amyloid peptide and oxidative stress. Molecular modeling studies show that they target both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. They are nontoxic and may be able to penetrate the CNS, according to in,vitro PAMPA-BBB assays. Tacrine,melatonin hybrids were designed and synthesized as new multifunctional drug candidates for Alzheimer's disease. These compounds may simultaneously palliate intellectual deficits and protect the brain against both ,-amyloid (A,) peptide and oxidative stress. They show improved cholinergic and antioxidant properties, and are more potent and selective inhibitors of human acetylcholinesterase (hAChE) than tacrine. They also capture free radicals better than melatonin. Molecular modeling studies show that these hybrids target both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. At sub-micromolar concentrations they efficiently displace the binding of propidium iodide from the PAS and could thus inhibit A, peptide aggregation promoted by AChE. Moreover, they also inhibit A, self-aggregation and display neuroprotective properties in a human neuroblastoma line against cell death induced by various toxic insults, such as A,25,35, H2O2, and rotenone. Finally, they exhibit low toxicity and may be able to penetrate the central nervous system according to an in,vitro parallel artificial membrane permeability assay for the blood,brain barrier (PAMPA-BBB). [source] Protection of Mouse Brain from Aluminum-induced Damage by Caffeic AcidCNS: NEUROSCIENCE AND THERAPEUTICS, Issue 1 2008Jun-Qing Yang The natural product caffeic acid is a specific inhibitor of 5-lipoxygenase (5-LOX); it also possesses antioxidant and antiinflammatory properties. The current study was designed to determine whether the neuroprotective properties of caffeic acid are due to inhibition of 5-LOX. Cerebral damage was induced in mice by intracerebroventricular microinjection of aluminum (5.0 ,g aluminum in 2.0 ,L, once a day, for 5 days). Caffeic acid was administered intragastrically at 30 min prior to aluminum and repeated daily for an additional 10 days. The brain injury was determined by observation of behavioral changes in mice, as well as by measuring biochemical and pathological changes in the cerebral tissue. The levels of 5-LOX proteins and 5-LOX mRNA expression were measured in brain tissue. Aluminum impaired learning and memory in mice produced neuronal death in hippocampi, elevated brain malondialdehyde levels, increased protein expression of amyloid precursor protein (APP), amyloid beta, and 5-LOX. It also increased 5-LOX mRNA expression and decreased choline acetyl transferase (ChAT) protein expression in the brain tissue of mice. Caffeic acid prevented brain damage as well as behavioral and biochemical changes caused by aluminum overload. The results of this study suggest that overexpression of 5-LOX accompanies the cerebral injury induced by aluminum overload in mice, and that selective inhibitors of 5-LOX may have potential value in the treatment of aluminum neurotoxicity and conceivably of diseases associated with neuronal injury. [source] Effect of mivazerol, a ,2 -agonist, on striatal norepinephrine concentration during transient forebrain ischemia in rats,ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 7 2008T. KIMURA Background: We have previously reported that mivazerol, a ,2 -agonist, possibly provides neuroprotection against transient forebrain ischemia in rats. This study was designed to investigate the ability of mivazerol to attenuate ischemia-induced increase in striatal norepinephrine concentration after transient forebrain ischemia in rats. Methods: Male Sprague,Dawley rats, anesthetized with halothane, were assigned to one of three groups (n=10 each); control (C, normal saline 1 ml/kg), mivazerol 20 ,g/kg (M20), and 40 ,g/kg (M40) groups. Monitored variables included temporal muscle temperature (maintained at 37.5±0.1 °C), electroencephalogram, systolic/diastolic blood pressure, heart rate, arterial blood gases, and blood glucose concentrations. Thirty minutes after subcutaneous drug administration, forebrain ischemia was induced with hemorrhagic hypotension (systolic arterial pressure: 40,50 mmHg) and bilateral carotid artery occlusion for 10 min, and then the brain was reperfused. Norepinephrine concentration in the interstitial fluids in the striatum was analyzed using in vivo microdialysis in combination with high-performance liquid chromatography. Results: Ischemia resulted in a prompt increase in norepinephrine concentrations in the striatum in all groups. However, there were no significant differences in norepinephrine concentrations in the striatum between the three groups at any period. Conclusions: Our results indicate that mivazerol did not attenuate ischemia-induced increase in striatal norepinephrine concentration. This suggests that the possible neuroprotective property of mivazerol is not related to inhibition of norepinephrine release in the brain. [source] | |||||||||||||