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Neuroprotective Activity (neuroprotective + activity)
Selected AbstractsIbuprofen and Lipoic Acid Diamides as Potential Codrugs with Neuroprotective ActivityARCHIV DER PHARMAZIE, Issue 3 2010Piera Sozio Abstract Current evidences support the hypothesis that non-steroidal anti-inflammatory drugs (NSAIDs) and antioxidant therapy might protect against the development of Alzheimer's disease (AD). In the present work, our attention was focused on ibuprofen (IBU) used in clinical trails to prevent Alzheimer's disease, and (R)-,-lipoic acid (LA) considered as a potential neuroprotective agent in AD therapy. In particular, we investigated a series of lipophilic molecular combinations obtained by joining (R)-,-lipoic acid and ibuprofen via an amide bond. These new entities might allow targeted delivery of the parent drugs to neurons, where cellular oxidative stress and inflammation seem related to Alzheimer's disease. Our study included the synthesis of conjugates 1,3 and the evaluation of their physicochemical and in-vitro antioxidant properties. The new compounds are extremely stable in aqueous buffer solutions (pH = 1.3 and 7.4), and in rat and human plasma they showed a slow bioconversion to ibuprofen and (R)-,-lipoic acid. Codrugs 1,3 displayed in vitro free radical scavenging activity and were hydrolyzed more rapidly in brain tissue than in rat serum indicating that these new entities might allow targeted delivery of the parent drugs to neurons. The immunohistochemical analysis of A, (1-40) protein showed that A,-injected cerebral cortices treated with ibuprofen or compound 1 showed few plaques within capillary vessels and, in particular, A, (1-40) protein was less expressed in codrug- 1 -treated than in ibuprofen-treated cerebral cortex. [source] Green tea catechins as brain-permeable, natural iron chelators-antioxidants for the treatment of neurodegenerative disordersMOLECULAR NUTRITION & FOOD RESEARCH (FORMERLY NAHRUNG/FOOD), Issue 2 2006Silvia Mandel Abstract Neurodegeneration in Parkinson's, Alzheimer's, or other neurodegenerative diseases appears to be multifactorial, where a complex set of toxic reactions, including oxidative stress (OS), inflammation, reduced expression of trophic factors, and accumulation of protein aggregates, lead to the demise of neurons. One of the prominent pathological features is the abnormal accumulation of iron on top of the dying neurons and in the surrounding microglia. The capacity of free iron to enhance and promote the generation of toxic reactive oxygen radicals has been discussed numerous times. The observations that iron induces aggregation of inert ,-synuclein and beta-amyloid peptides to toxic aggregates have reinforced the critical role of iron in OS-induced pathogenesis of neurodegeneration, supporting the notion that a combination of iron chelation and antioxidant therapy may be one significant approach for neuroprotection. Tea flavonoids (catechins) have been reported to possess divalent metal chelating, antioxidant, and anti-inflammatory activities, to penetrate the brain barrier and to protect neuronal death in a wide array of cellular and animal models of neurological diseases. This review aims to shed light on the multipharmacological neuroprotective activities of green tea catechins with special emphasis on their brain-permeable, nontoxic, transitional metal (iron and copper)-chelatable/radical scavenger properties. [source] Protective effects of 3,-deoxy-4-O-methylepisappanol from Caesalpinia sappan against glutamate-induced neurotoxicity in primary cultured rat cortical cellsPHYTOTHERAPY RESEARCH, Issue 3 2010Hyung-In Moon Abstract To examine the neuroprotective effects of Caesalpinia sappan L., we tested its protection against the glutamate-induced neurotoxicity in primary cortical cultured neurons. We found that an aqueous extract of this medicinal plant exhibited significant protection against glutamate-induced toxicity in primary cultured rat cortical cells. In order to clarify the neuroprotective mechanism(s) of this observed effect, isolation was performed to seek and identify active fractions and components. By such fractionation, two known compounds , sappanchalcone and 3,-deoxy-4-O-methylepisappanol , were isolated from the methanol extracts from the air-dried and chipped C. sappan. Among these two compounds, 3,-deoxy-4-O-methylepisappanol exhibited significant neuroprotective activities against glutamate-induced toxicity, exhibiting cell viability of about 50%, at concentrations ranging from 0.1,,M to 10,,M. Therefore, the neuroprotective effect of C. sappan might be due to the inhibition of glutamate-induced toxicity by the protosappanin derivative it contains. Copyright © 2009 John Wiley & Sons, Ltd. [source] The Effects of Ascorbic Acid on Penicillin-induced Epileptiform Activity in RatsEPILEPSIA, Issue 7 2007Mustafa Ayyildiz Summary:,Purpose: Epileptic seizure results from excessive discharge in a population of hyperexcitable neurons. A number of studies help to document the effects of active oxygen free radical scavengers such as ,-tocopherol or ascorbic acid (vitamin C). In the present study, we examined the effects of ascorbic acid, at the six different doses, on penicillin-induced epileptiform activity. Methods: A single microinjection of penicillin (2.5 ,l, 500 units, intracortically) into the left sensorimotor cortex induced epileptiform activity within 2,5 min, progressing to full seizure activity lasting ,3,5 h. In the first set of experiments, 30 min after penicillin injection, six different doses of ascorbic acid (25, 50, 100, 200, 400, or 800 mg/kg) were administered intraperitoneally (IP). The other group of animals received the effective dose of ascorbic acid (100 mg/kg, IP) for 7 days. Ascorbic acid administration was stopped 24 h before penicillin treatment. Another group of rats received the effective dose of ascorbic acid (100 mg/kg, IP) 30 min before penicillin treatment. In the second set of experiments, the lipid peroxidation (MDA) and reduced glutathione (GSH) levels of brain were measured in the control, control + ascorbic acid, penicillin, and penicillin + ascorbic acid groups. Results: Ascorbic acid, at the low dose (50, 100 mg/kg, 30 min after penicillin injection), decreased both the frequency and amplitude of penicillin-induced epileptiform activity in rats. Ascorbic acid, at intermediate doses (200, 400 mg/kg, 30 min after penicillin injection), decreased the frequency of epileptiform activity without changing the amplitude. Ascorbic acid, at the lowest dose (25 mg/kg) and highest dose (800 mg/kg) (30 min after penicillin injection), did not change either the frequency or amplitude of epileptiform activity. Ascorbic acid, at the low dose (100 mg/kg) was the most effective dose in changing the frequency and amplitude of penicillin-induced epileptiform activity. Pretreatment with ascorbic acid (100 mg/kg) 30 min before penicillin treatment caused a significant delay in the onset of penicillin-induced epileptiform activity. Pretreatment with ascorbic acid (100 mg/kg) for 7 days did not change the latency of epileptiform activity. The most effective dose of ascorbic acid (100 mg/kg) prevented both the decrease in GSH level and the increase in lipid peroxidation level (MDA) occurring after penicillin-induced epileptiform activity. Conclusions: These data indicate that ascorbic acid has neuroprotective activity against penicillin-induced epileptiform electrocorticogram activity. [source] Schwann cells express erythropoietin receptor and represent a major target for Epo in peripheral nerve injuryGLIA, Issue 4 2005Xiaoqing Li Abstract Erythropoietin (Epo) expresses potent neuroprotective activity in the peripheral nervous system; however, the underlying mechanism remains incompletely understood. In this study, we demonstrate that Epo is upregulated in sciatic nerve after chronic constriction injury (CCI) and crush injury in rats, largely due to local Schwann cell production. In uninjured and injured nerves, Schwann cells also express Epo receptor (EpoR), and its expression is increased during Wallerian degeneration. CCI increased the number of Schwann cells at the injury site and the number was further increased by exogenously administered recombinant human Epo (rhEpo). To explore the activity of Epo in Schwann cells, primary cultures were established. These cells expressed cell-surface Epo receptors, with masses of 71 and 62 kDa, as determined by surface protein biotinylation and affinity precipitation. The 71-kDa species was rapidly but transiently tyrosine-phosphorylated in response to rhEpo. ERK/MAP kinase was also activated in rhEpo-treated Schwann cells; this response was blocked by pharmacologic antagonism of JAK-2. RhEpo promoted Schwann cell proliferation, as determined by BrdU incorporation. Cell proliferation was ERK/MAP kinase-dependent. These results support a model in which Schwann cells are a major target for Epo in injured peripheral nerves, perhaps within the context of an autocrine signaling pathway. EpoR-induced cell signaling and Schwann cell proliferation may protect injured peripheral nerves and promote regeneration. © 2005 Wiley-Liss, Inc. [source] PPAR: a therapeutic target in Parkinson's diseaseJOURNAL OF NEUROCHEMISTRY, Issue 2 2008Rajnish K. Chaturvedi Abstract Parkinson's disease (PD) is a progressive and chronic neurodegenerative disorder, characterized by progressive loss of dopaminergic neurons in substantia nigra. The etiology and pathogenesis of PD is still elusive, however, a large body of evidence suggests a prominent role of oxidative stress, inflammation, apoptosis, mitochondrial dysfunction and proteosomal dysfunction in the pathogenesis of PD. Due to multifactorial nature of the disease, currently available drug therapy cannot halt / slow down the disease progression, and only provides symptomatic relief. Peroxisome proliferator-activated receptor (PPAR), a member of nuclear receptor superfamily, regulates development, tissue differentiation, inflammation, mitochondrial function, wound healing, lipid metabolism and glucose metabolism. Recently, several PPAR agonists were shown to exert neuroprotective activity against oxidative damage, inflammation and apoptosis in several neurodegenerative disorders including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis and multiple sclerosis. Similarly, regular intake of PPAR activating non-steroidal anti-inflammatory drugs such as indomethacin and ibuprofen was associated with reduced incidence and progression of neurodegenerative disorders in several epidemiological studies. In this article, we review studies relating to the neuroprotective effect of PPAR agonists in in vitro and in vivo models of PD. Similarly, the pharmacological mechanism in neuroprotective actions of PPAR agonists is also reviewed. In conclusion, PPAR agonists exert neuroprotective actions by regulating the expression of a set of genes involved in cell survival processes, and could be a therapeutic target in debilitating neurodegenerative illnesses such as PD. [source] Brain-derived neurotrophic factor stimulates the transcriptional and neuroprotective activity of myocyte-enhancer factor 2C through an ERK1/2-RSK2 signaling cascadeJOURNAL OF NEUROCHEMISTRY, Issue 3 2007Yupeng Wang Abstract Neurotrophin activation of myocyte-enhancer factor (MEF) 2C is one of the strongest pro-survival signaling pathways in developing neurons. To date, neurotrophin stimulation of MEF2C has been largely attributed to its direct phosphorylation by extracellular signal-regulated kinase (ERK) 5. Because MEF2C is not directly phosphorylated by ERK1/2 in vitro, it is generally assumed that the ERK1/2 signaling cascade does not regulate MEF2C. Surprisingly, we discovered that ERK1/2 are required for both the transcriptional and neuroprotective activity of MEF2C in cortical neurons stimulated by brain-derived neurotrophic factor. ERK1/2 stimulation of MEF2C is mediated by p90 ribosomal S6 kinase 2 (RSK2), a Ser/Thr protein kinase downstream of ERK1/2. RSK2 strongly phosphorylates purified recombinant MEF2C protein in vitro. Furthermore, RSK2 can directly phosphorylate MEF2C on S192, a consensus RSK2-phosphorylation site located in the transactivation domain of MEF2C. Substitution of S192 with a non-phosphorylatable alanine diminishes both the transcriptional and neuroprotective activity of MEF2C to an extent similar to mutation on S387, an established activating phosphorylation site. Together, our data identifies ERK1/2-RSK2 signaling as a novel mechanism by which neurotrophins activate MEF2C and promote neuronal survival. [source] Mitochondrial localization of DJ-1 leads to enhanced neuroprotectionJOURNAL OF NEUROSCIENCE RESEARCH, Issue 1 2009Eunsung Junn Abstract Mutations in DJ-1 (PARK7) cause recessively inherited Parkinson's disease. DJ-1 is a multifunctional protein with antioxidant and transcription modulatory activity. Its localization in cytoplasm, mitochondria, and nucleus is recognized, but the relevance of this subcellular compartmentalization to its cytoprotective activity is not fully understood. Here we report that under basal conditions DJ-1 is present mostly in the cytoplasm and to a lesser extent in mitochondria and nucleus of dopaminergic neuroblastoma SK-N-BE(2)C cells. Upon oxidant challenge, more DJ-1 translocates to mitochondria within 3 hr and subsequently to the nucleus by 12 hr. The predominant DJ-1 species in both mitochondria and nucleus is a dimer believed to be the functional form. Mutating cysteine 106, 53, or 46 had no impact on the translocation of DJ-1 to mitochondria. To study the relative neuroprotective activity of DJ-1 in mitochondria and nucleus, DJ-1 cDNA constructs fused to the appropriate localization signal were transfected into cells. Compared with 30% protection against oxidant-induced cell death in wild-type DJ-1-transfected cells, mitochondrial targeting of DJ-1 provided a significantly stronger (55%) cytoprotection based on lactate dehydrogenase release. Nuclear targeting of DJ-1 preserved cells equally as well as the wild-type protein. These observations suggest that the time frame for the translocation of DJ-1 from the cytoplasm to mitochondria and to the nucleus following oxidative stress is quite different and that dimerized DJ-1 in mitochondria is functional as an antioxidant not related to cysteine modification. These findings further highlight the multifaceted functions of DJ-1 as a cytoprotector in different cellular compartments. © 2008 Wiley-Liss, Inc. [source] ESP-102, a combined extract of Angelica gigas, Saururus chinensis and Schizandra chinensis, protects against glutamate-induced toxicity in primary cultures of rat cortical cellsPHYTOTHERAPY RESEARCH, Issue 11 2009Choong Je Ma Abstract It was reported previously that ESP-102, a combined extract of Angelica gigas, Saururus chinensis and Schizandra chinensis, significantly improved scopolamine-induced memory impairment in mice and protected primary cultured rat cortical cells against glutamate-induced toxicity. To corroborate this effect, the action patterns of ESP-102 were elucidated using the same in vitro system. ESP-102 decreased the cellular calcium concentration increased by glutamate, and inhibited the subsequent overproduction of cellular nitric oxide and reactive oxygen species to the level of control cells. It also preserved cellular activities of antioxidative enzymes such as superoxide dismutase, glutathione peroxidase and glutathione reductase reduced in the glutamate-injured neuronal cells. While a loss of mitochondrial membrane potential was observed in glutamate treated cells, the mitochondrial membrane potential was maintained by ESP-102. These results support that the actual mechanism of neuroprotective activity of ESP-102 against glutamate-induced oxidative stress might be its antioxidative activity. Copyright © 2009 John Wiley & Sons, Ltd. [source] Pinusolide and 15-methoxypinusolidic acid attenuate the neurotoxic effect of staurosporine in primary cultures of rat cortical cellsBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2007K A Koo Background and purpose: Apoptosis is a fundamental process required for neuronal development but also occurs in most of the common neurodegenerative disorders. In an attempt to obtain an anti-apoptotic neuroprotective compound from natural products, we isolated the diterpenoids, pinusolide and 15-MPA, from B. orientalis and investigated their neuroprotective activity against staurosporine (STS) -induced neuronal apoptosis. In addition, we determined the anti-apoptotic mechanism of these compounds in rat cortical cells. Experimental approach: Primary cultures of rat cortical cells injured by STS were used as an in vitro assay system. Cells were pretreated with pinusolide or 15-MPA before exposure to STS. Anti-apoptotic activities were evaluated by the measurement of cytoplasmic condensation and nuclear fragmentation. The levels of cellular peroxide, malondialdehyde (MDA) and [Ca2+]i, as well as the activities of superoxide dismutase (SOD) and caspase-3/7, were measured. Key results: Pinusolide and 15-MPA, at a concentration of 5.0 ìM, reduced the condensed nuclei and rise in [Ca2+]i that accompanies apoptosis induced by 100 nM STS. Pinusolide and 15-MPA also protected the cellular activity of SOD, an antioxidative enzyme reduced by STS insult. Furthermore, the overproduction of reactive oxygen species and lipid peroxidation induced by STS was significantly reduced in pinusolide and 15-MPA treated cells. In addition, pinusolide and 15-MPA inhibited STS-induced caspase-3/7 activation. Conclusions and Implications: These results show that pinusolide and 15-MPA protect neuronal cells from STS-induced apoptosis, probably by preventing the increase in [Ca2+]i and cellular oxidation caused by STS, and indicate that they could be used to treat neurodegenerative diseases. British Journal of Pharmacology (2007) 150, 65,71. doi:10.1038/sj.bjp.0706944 [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] Searching for Disease Modifiers,PKC Activation and HDAC Inhibition,A Dual Drug Approach to Alzheimer's Disease that Decreases A, Production while Blocking Oxidative StressCHEMMEDCHEM, Issue 7 2009Abstract A series of benzolactam compounds were synthesized, some of which caused a concentration-dependent increase in sAPP, and decrease in A, production in the concentration range of 0.1,10,,M. Moreover, some compounds showed neuroprotective effects in the 10,20,,M range in the HCA cortical neuron model of oxidative stress and no toxicity in measurements of neuron viability by MTT assay, even at the highest concentrations tested (20,,M). Alzheimer's disease (AD) is a well-studied neurodegenerative process characterized by the presence of amyloid plaques and neurofibrillary tangles. In this study, a series of protein kinase,C (PKC) activators were investigated, some of which also exhibit histone deacetylase (HDAC) inhibitory activity, under the hypothesis that such compounds might provide a new path forward in the discovery of drugs for the treatment of AD. The PKC-activating properties of these drugs were expected to enhance the ,-secretase pathway in the processing of amyloid precursor protein (APP), while their HDAC inhibition was anticipated to confer neuroprotective activity. We found that benzolactams 9 and 11,14 caused a concentration-dependent increase in sAPP, and decrease in ,-amyloid (A,) production in the concentration range of 0.1,10,,M, consistent with a shift of APP metabolism toward the ,-secretase-processing pathway. Moreover, compounds 9,14 showed neuroprotective effects in the 10,20,,M range in the homocysteate (HCA) cortical neuron model of oxidative stress. In parallel, we found that the most neuroprotective compounds caused increased levels of histone acetylation (H4), thus indicating their likely ability to inhibit HDAC activity. As the majority of the compounds studied also show nanomolar binding affinities for PKC, we conclude that it is possible to design, de,novo, agents that combine both PKC-activating properties along with HDAC inhibitory properties. Such agents would be capable of modulating amyloid processing while showing neuroprotection. These findings may offer a new approach to therapies that exhibit disease-modifying effects, as opposed to symptomatic relief, in the treatment of AD. [source] | ||||||||||||||||