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Alzheimer's disease is a neurodegenerative disorder characterized by extracellular deposition of amyloid-β (Aβ) peptide and hyperphosphorylation of Tau protein, which ultimately leads to the formation of intracellular neurofibrillary tangles and cell death. Increasing evidence indicates that genistein, a soy isoflavone, has neuroprotective effects against Aβ-induced toxicity. However, the molecular mechanisms involved in its neuroprotection are not well understood. In this study, we have established a neuronal damage model using retinoic-acid differentiated SH-SY5Y cells treated with different concentrations of Aβ25-35 to investigate the effect of genistein against Aβ-induced cell death and the possible involvement of protein kinase B (PKB, also termed Akt), glycogen synthase kinase 3β (GSK-3β), and Tau as an underlying mechanism to this neuroprotection. Differentiated SH-SY5Y cells were pre-treated for 24 hr with genistein (1 and 10 nM) and exposed to Aβ25-35 (25 μM), and we found that genistein partially inhibited Aβ induced cell death, primarily apoptosis. Furthermore, the protective effect of genistein was associated with the inhibition of Aβ-induced Akt inactivation and Tau hyperphosphorylation. These findings reinforce the neuroprotective effects of genistein against Aβ toxicity and provide evidence that its mechanism may involve regulation of Akt and Tau proteins. [ABSTRACT FROM AUTHOR]

Accumulating evidence indicates that resveratrol potently protects against cerebral ischemia damage due to its oxygen free radicals scavenging and antioxidant properties. However, cellular mechanisms that may underlie the neuroprotective effects of resveratrol in brain ischemia are not fully understood yet. This study aimed to investigate the potential association between the neuroprotective effect of resveratrol and the apoptosis/survival signaling pathways, in particular the glycogen synthase kinase 3 (GSK-3β) and cAMP response element-binding protein (CREB) through phosphatidylinositol 3-kinase (PI3-K)-dependent pathway. An experimental model of global cerebral ischemia was induced in rats by the four-vessel occlusion method for 10 min and followed by different periods of reperfusion. Nissl staining indicated extensive neuronal death at 7 days after ischemia/reperfusion. Administration of resveratrol by i.p. injections (30 mg/kg) for 7 days before ischemia significantly attenuated neuronal death. Both GSK-3β and CREB appear to play a critical role in resveratrol neuroprotection through the PI3-K/Akt pathway, as resveratrol pretreatment increased the phosphorylation of Akt, GSK-3β and CREB in 1 h in the CA1 hippocampus after ischemia/reperfusion. Furthermore, administration of LY294002, an inhibitor of PI3-K, compromised the neuroprotective effect of resveratrol and decreased the level of p-Akt, p-GSK-3β and p-CREB after ischemic injury. Taken together, the results suggest that resveratrol protects against delayed neuronal death in the hippocampal CA1 by maintaining the pro-survival states of Akt, GSK-3β and CREB pathways. These data suggest that the neuroprotective effect of resveratrol may be mediated through activation of the PI3-K/Akt signaling pathway, subsequently downregulating expression of GSK-3β and CREB, thereby leading to prevention of neuronal death after brain ischemia in rats. [ABSTRACT FROM AUTHOR]

Abstract: Homocysteine is a neurotoxic amino acid that accumulates in several disorders including homocystinuria, neurodegenerative and neuroinflammatory diseases. In the present study we evaluated the effect of acute and chronic hyperhomocysteinemia on Akt, NF-κB/p65, GSK-3β, as well as Tau protein in hippocampus of rats. For acute treatment, rats received a single injection of homocysteine (0.6μmol/g body weight) or saline (control). For chronic treatment, rats received daily subcutaneous injections of homocysteine (0.3–0.6μmol/g body weight) or saline (control) from the 6th to the 28th days-of-age. One or 12h after the last injection, rats were euthanized, the hippocampus was removed and samples were submitted to electrophoresis followed by Western blotting. Results showed that acute hyperhomocysteinemia increases Akt phosphorylation, cytosolic and nuclear immunocontent of NF-κB/p65 subunit and Tau protein phosphorylation, but reduces GSK-3β phosphorylation at 1h after homocysteine injection. However, 12h after acute hyperhomocysteinemia there is no effect on Akt and GSK-3β phosphorylation. Furthermore, chronic hyperhomocysteinemia did not alter Akt and GSK-3β phosphorylation at 1h and 12h after the last administration of this amino acid. Our data showed that Akt, NF-κB/p65, GSK-3β and Tau protein are activated in hippocampus of rats subjected to acute hyperhomocysteinemia, suggesting that these signaling pathways may be, at least in part, important contributors to the neuroinflammation and/or brain dysfunction observed in some hyperhomocystinuric patients. [Copyright &y& Elsevier]

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by accumulation of extracellular deposits of amyloid-β (Aβ) peptide in brain regions that are important for memory and cognition. The buildup of Aβ aggregates in the AD is followed by the formation of intracellular neurofibrillary tangles and activation of neuroinflammatory reactions. The present study investigated whether melatonin possesses a neuroprotective effect against Aβ-induced toxicity. For this purpose, organotypic hippocampal slices were cultured and exposed to 25 μm of Aβ25–35 in the absence or in the presence of melatonin (25, 50, or 100 μm). In addition, the authors have investigated the involvement of GSK-3β, tau protein, astroglial, and microglial activation, and cytokine levels in the melatonin protection against Aβ-induced neurotoxicity. Melatonin prevented the cell damage in hippocampus induced by the exposure to Aβ25–35. In addition, melatonin significantly reduced the activation of GSK-3β, the phosphorylation of tau protein, the glial activation and the Aβ-induced increase of TNF-α and IL-6 levels. On the basis of these findings, we speculate that melatonin may provide an effective therapeutic strategy for AD, by attenuating Aβ-induced phosphorylation of tau protein, and preventing GSK-3β activation and neuroinflammation. [ABSTRACT FROM AUTHOR]

Abstract: In the present study we evaluated the effect of acute and chronic homocysteine administrations on glutamate uptake in parietal cortex of rats. The immunocontent of glial glutamate transporter (GLAST) and sodium-dependent glutamate/aspartate transporter (GLT-1) in the same cerebral structure was also investigated. For acute treatment, neonate or young rats received a single injection of homocysteine or saline (control) and were sacrificed 1, 8, 12h, 7 or 30 days later. For chronic treatment, homocysteine was administered to rats twice a day at 8h interval from their 6th to their 28th days old; controls and treated rats were sacrificed 12h, 1, 7 or 30 days after the last injection. Results show that acute hyperhomocysteinemia caused a reduction on glutamate uptake in parietal cortex of neonate and young rats, and that 12h after homocysteine administration the glutamate uptake returned to normal levels in young rats, but not in neonate. Chronic hyperhomocysteinemia reduced glutamate uptake, and GLAST and GLT-1 immunocontent. According to our results, it seems reasonable to postulate that the reduction on glutamate uptake in cerebral cortex of rats caused by homocysteine may be mediated by the reduction of GLAST and GLT-1 immunocontent, leading to increased extracellular glutamate concentrations, promoting excitotoxicity. [Copyright &y& Elsevier]

Glioma is the most frequent and malignant primary human brain tumor with dismal prognosis despite multimodal therapy. Resveratrol and quercetin, two structurally related and naturally occurring polyphenols, are proposed to have anticancer effects. We report here that resveratrol and quercetin decreased the cell number in four glioma cell lines but not in rat astrocytes. Low doses of resveratrol (10 µM) or quercetin (25 µM) separately had no effect on apoptosis induction, but had a strong effect on caspase 3/7 activation when administered together. Western blot analyses showed that resveratrol (10 µM) and quercetin (25 µM) caused a reduction in phosphorylation of Akt, but this reduction was not sufficient by itself to mediate the effects of these polyphenols. Most important, resveratrol and quercetin chronically administered presented a strong synergism in inducing senescence-like growth arrest. These results suggest that the combination of polyphenols can potentialize their antitumoral activity, thereby reducing the therapeutic concentration needed for glioma treatment. ( Cancer Sci 2009; 100: 1655–1662) [ABSTRACT FROM AUTHOR]

Abstract: In the present study we evaluate the effects of homocysteine on cellular damage using hippocampal slices from Wistar rats exposed to oxygen and glucose deprivation (OGD, followed by reoxygenation), an in vitro model of hypoxic–ischemic events. For chronic treatment, we induced elevated levels of homocysteine in blood (500μM), comparable to those of human homocystinuria, and in brain (60nmol/g wet tissue) of young rats by subcutaneous injections of homocysteine (0.3–0.6μmol/g of body weight), twice a day with 8h intervals, from the 6th to the 28th postpartum day and controls received saline. Rats were sacrificed 1, 3 or 12h after the last injection. For acute treatment, 29-day-old rats received one single injection of homocysteine (0.6μmol homocysteine/g body weight) or saline and were sacrificed 1h later. In another set of experiments rats were pretreated with Vitamins E (40mg/kg) and C (100mg/kg) or folic acid (5mg/kg) during 1 week; 12h after the last administration they received a single injection of homocysteine or saline and were sacrificed 1h later. Results showed that both chronic (1h after homocysteine administration) and acute hyperhomocysteinemia increased the cellular damage measured by LDH released to de incubation medium, suggesting an increase of tissue damage caused by OGD. Pretreatment with folic acid completely prevented the damage caused by acute hyperhomocysteinemia, whereas Vitamin E just partially prevented such effect. These findings may be relevant to explain, at least in part, the higher susceptibility of hyperhomocysteinemic patients to be susceptible to ischemic events and point to a possible preventive treatment. [Copyright &y& Elsevier]