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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Sound envelope plays a crucial role in perception: ramped sounds (slow attack and quick decay) are louder in strength and longer in subjective duration than damped sounds (quick attack and slow decay) even if they are equal in intensity and physical duration. To explain the asymmetrical perception, the perceptual constancy hypothesis supposes that the listener eliminates the slow decay of damped sounds from the judgment of perception, while the persistence of perception hypothesis supposes asymmetrical neural responses after the source has stopped. To understand neural mechanisms underlying the perceptual asymmetry, we explored response properties of the primary auditory cortex (A1) neurons during ramped and damped stimuli in awake cats. ⋯ The former needs a short (<2.5 ms) period of stimulus duration for evoking maximal peak responses, while the latter needs a long (20 ms) period, suggesting that the timescale of processing underlies differential sensitivity between the cell types. The findings suggest that perceptual constancy is not yet be executed at A1 because the specific cells distinguishing the direction of amplitude change (attack or decay) are lacking in A1. On the other hand, there is evidence of persistence of perception: overall response duration during ramped sound reached 1.4 times longer than that during damped sound, originating mainly from the response asymmetry of the edge cell (sensitive to the quick decay of ramped sounds but not to the slow decay of damped sounds), and neuronal persistence of excitation after the termination of ramped sounds was substantially longer than that of damped sounds, corresponding to the psychological evidence of persistence of perception.
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Perinatal nutrient restriction exerts profound influences on brain development. Animals that suffer undernutrition during lactation also display impaired weight gain. Feeding behavior is mainly modulated by neural and hormonal inputs to the hypothalamus. ⋯ Our results showed a NPY immunostaining peak at P10 in all nuclei in CG animals. In UFG animals this peak was observed by P15, while, in the PFG animals only by P20. Our results suggest that the neuropeptidergic arcuate-paraventricular pathway suffered a delay in NPY distribution in undernourished animals, particularly those fed a 0% protein diet, reflecting an effect on this pathway maturation that could explain previously reported alterations on feeding behavior in these animals.
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The mood-stabilizing drug lithium is the most commonly used treatment for bipolar disorder. Previous studies have shown that chronic treatment with lithium produces a protective effect against oxidative stress. Nuclear factor E2-related factor 2 (Nrf2) is a gene transcription factor that binds to the electrophile response element (EpRE) and triggers expression of various genes with antioxidant properties. ⋯ Electrophorectic gel shift analysis further showed that chronic treatment with lithium increased Nrf-2-EpRE binding activity. We also found that knocking down Nrf2 with its short hairpin RNA inhibited lithium-increased expression of Nrf2 and suppressed the protective effect of lithium against hydrogen peroxide (H₂O₂)-reduced cell viability and H₂O₂-increased DNA fragmentation. Because Nrf2 can induce expression of various genes that play important roles in cytoprotection, the current findings suggest that Nrf2 may mediate the neuroprotective effect of lithium against oxidative stress.
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Neuroinflammatory disturbances have been closely associated with depression and many other neuropsychiatric diseases. Although targeting neuroinflammatory mediators with centrally acting drugs has shown certain promise, its translation is faced with several challenges especially drug delivery and safety concerns. Here, we report that neuroinflammation-induced behavioral abnormality could be effectively attenuated with immunomodulatory agents that need not to gain brain penetration. ⋯ Furthermore, these peripheral regulatory effects were accompanied by dampened microglial activation, mitigated expression of pro-inflammatory mediators and neurotoxic species in the central compartment. Taken together, our work suggested that targeting the peripheral immune system may serve as a novel therapeutic approach to neuroinflammation-induced neuropsychiatric disorders. Moreover, our findings provided the rationale for employing peripherally active agents like Rg1 to combat mental disturbances.