Neuroscience
-
We have previously demonstrated that glucagon-like peptide-1 (GLP-1) receptor agonist ameliorated neurodegenerative changes in rat models of diabetes-related Alzheimer's disease (AD), and protected neurons from glucose toxicity in vitro. Herein, we investigated the effects of GLP-1 receptor mediates on cell toxicity and tau hyperphosphorylation induced by advanced glycation end products (AGEs), which are associated with glucose toxicity, and the molecular mechanism in PC12 cells and the primary hippocampal neurons. Our study demonstrated that the similar protection effects of GLP-1 existed in PC12 cells treated with glucose-bovine serum albumin (BSA) in hyperglycemic conditions or with glycoaldehyde-BSA alone. ⋯ And we found that GLP-1 could reduce cell tau phosphorylation induced by high glucose or glucose-BSA. Furthermore, our data in the present study suggested that GLP-1 regulated tau phosphorylation induced by AGEs through a signaling pathway involving glycogen synthase kinase 3β (GSK-3β), similarly to the GSK-3β inhibitor, lithium chloride. Our findings suggest that GLP-1 can protect neurons from diabetes-associated AGE insults in vitro, and provide new evidence for a potential therapeutic value of GLP-1 receptor agonist in the treatment of AD especially diabetes-related AD.
-
The apolipoprotein E4 (apoE4) allele is consistently associated with increased risk for Alzheimer's disease (AD). We investigated the molecular mechanism of this susceptibility by analyzing the levels of genes involved in AD pathogenesis in transgenic mice expressing human apoE3 or apoE4 isoforms. mRNA and protein levels of Pin1, Sirtuin 1 (Sirt1), Presenilin 1 (PS1), and pro-Brain-derived Neurotrophic Factor (BDNF) were analyzed in brain regions affected by neuropathological changes in AD. Pin1 mRNA was significantly higher in the hippocampus of apoE4 mice than in apoE3 controls, whereas lower expression was detected in the entorhinal and parietal cortices. ⋯ Lower PS1 expression may hamper γ-secretase function, thus affecting amyloid precursor protein processing. Pro-BDNF mRNA levels did not differ between apoE3 and apoE4 mice in any region analyzed. This study showed dysregulated expression of Pin1, Sirt1, and PS1 genes in different cerebral areas of apoE4 mice, suggesting that these changes may play a role in the mechanism of AD vulnerability.
-
One of the major consequences of stroke is brain injury caused by glutamate-mediated excitotoxicity. Glutamate-mediated excitatory activities are partially driven by β2-containing nicotinic acetylcholine receptors (β2-nAChRs). In examining the role of β2-nAChRs in cerebral ischemic injury, excitotoxicity and stroke outcome, we found that deficiency of β2-nAChRs attenuated brain infarction and neurological deficit at 24 and 72 h after transient middle cerebral artery occlusion (MCAO). ⋯ Pharmacologic pretreatment with a selective β2-nAChRs antagonist reduced brain infarction, neurological deficit, and MCAO-induced glutamate release. These findings suggest that deficiency of β2-nAChRs, also achievable by pharmacological blockade, can decrease brain infarction and improve the neurological status in ischemic stroke. The improved outcome is associated with reduced extracellular glutamate level and lower excitatory inputs into ischemic neurons, suggesting a reduction of glutamate-mediated excitotoxicity in the mechanisms of neuroprotection.
-
Progesterone (PROG) is promising as an important protective agent against various injuries to the nervous system. The present study was designed to investigate whether starting PROG administration, when symptomatology is already established, would alleviate the expression of nociceptive behaviors (mechanical allodynia and thermal hyperalgesia) and electrophysiological changes in a chronic constriction injury (CCI) model of neuropathic pain in rats. Male rats were given PROG (1.5, 3, 6 and 12 mg/kg, i.p.) 12 days after CCI induction, and dosing continued daily until day 26. ⋯ PROG at doses of 6 or 12 mg/kg induced a significant recovery of all electrophysiological changes. Our data indicated that starting PROG therapy when symptomatology is already established, and continuing it for a sufficient period of time, may have a therapeutic effect. This suggests that PROG may offer new strategies for the treatment of neuropathic pain.
-
Modulation of L-type Ca²⁺-channel function by dopamine is a major determinant of the rate of action potential firing by striatal medium spiny neurons. However, the role of these channels in modulating GABA release by nerve terminals in the basal ganglia is unknown. We found that depolarization-induced [³H]GABA release in both the substantia nigra reticulata and the external globus pallidus (GPe), was depressed by about 50% by either the selective L-channel dihydropyridine blocker nifedipine or the P/Q channel blocker ω-agatoxin TK. ⋯ In the GP nifedipine blocked the effects of D2 and A2(A) receptor coactivation as well as the effects of activating adenylyl cyclase with forskolin. ω-Agatoxin TK did not interfere with the action of these modulatory agents. The L-type Ca²⁺-channel agonist BAYK 8644 stimulated GABA release in both substantia nigra reticulata and GP. Because dihydropyridine sensitivity is a key criterion to identify L-type Ca²⁺-channel activity, our results imply that these channels are determinant of GABA release modulation by dopamine in striatonigral, striatopallidal and pallidonigral terminals.