Neuroscience
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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.
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Adaptation is an important process of sensory systems to adjust sensitivity to ensure the appropriate information encoding. Sensitivity and kinetics of retinal ganglion cell (RGC) responses have been studied extensively using a brief flash superimposed on different but steady backgrounds. However, it is still unclear if light adaptation exerts any effect on more complex response properties, such as response nonlinearity. ⋯ We further excluded GABAergic and glycinergic inhibition, N-methyl-D-aspartate receptor rectification and voltage-gated Na(+) channels as potential sources of this nonlinearity by pharmacological experiments. Our results indicate the bipolar cell terminals as the potential site of nonlinearity. Computational modeling constrained by experimental data supports that conclusion and suggests the voltage-sensitive Ca(++) channels and Ca(++)-dependent vesicle release in the bipolar cell terminals as mechanistic basis.
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Calcium/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the transmission of nociceptive input in diabetic neuropathy. The aim of this study was to test whether intraganglionic (i.g.) injection of CaMKII inhibitors may alleviate pain-related behavior in diabetic rats. Diabetes was induced in Sprague-Dawley rats using 55 mg/kg streptozotocin intraperitoneally. ⋯ Attenuation of nociceptive behavior was accompanied with a corresponding decrease of CaMKII alpha expression in DRG neurons on the side of injection. A significant decrease of CaMKII alpha expression was seen in small- and medium-sized neurons. In conclusion, our study provides evidence that CaMKII inhibitors are potential pharmacological agents that should be further explored for treatment of diabetic neuropathy symptoms.
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Activity-dependent hyperpolarization of EGABA is absent in cutaneous DRG neurons from inflamed rats.
A shift in GABA(A) signaling from inhibition to excitation in primary afferent neurons appears to contribute to the inflammation-induced increase in afferent input to the CNS. An activity-dependent depolarization of the GABA(A) current equilibrium potential (E(GABA)) has been described in CNS neurons which drives a shift in GABA(A) signaling from inhibition to excitation. The purpose of the present study was to determine if such an activity-dependent depolarization of E(GABA) occurs in primary afferents and whether the depolarization is amplified with persistent inflammation. ⋯ The shift in E(GABA) was not blocked by 10 μM bumetanide. Furthermore, because activity-dependent hyperpolarization of E(GABA) was fully manifest in the absence of HCO₃⁻ in the bath solution, this shift was not dependent on a change in HCO₃⁻-Cl⁻ exchanger activity, despite evidence of HCO₃⁻-Cl⁻ exchangers in DRG neurons that may contribute to the establishment of E(GABA) in the presence of HCO₃⁻. While the mechanism underlying the activity-dependent hyperpolarization of E(GABA) has yet to be identified, because this mechanism appears to function as a form of feedback inhibition, facilitating GABA-mediated inhibition of afferent activity, it may serve as a novel target for the treatment of inflammatory pain.
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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.