Neuroscience
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Mitochondrial division inhibitor 1 (mdivi-1), a selective inhibitor of mitochondrial fission protein dynamin-related protein 1 (Drp1), has been reported to display neuroprotective properties in different animal models. In the present study, we investigated the protective effect of mdivi-1 on β-amyloid protein (Aβ)-induced cytotoxicity and its potential mechanisms in BV-2 and primary microglial cells. ⋯ Moreover, we also found that mdivi-1 treatment markedly reversed mitochondrial membrane potential loss, cytochrome c (CytC) release and caspase-3 activation. Altogether, our data suggested that mdivi-1 exerts neuroprotective effects against Aβ-induced microglial apoptosis, and the underlying mechanism may be through inhibiting mitochondrial membrane potential loss, CytC release and suppression of the mitochondrial apoptosis pathway.
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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.
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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.