Neuroscience
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High-mobility group box-1 (HMGB1) acts as a proinflammatory molecule once released into the extracellular space and inhibition of HMGB1 signaling has been reported be neuroprotective in neurodegenerative diseases. Besides, chronic cerebral hypoperfusion (CCH) causes cognitive impairment in neurodegenerative diseases. Here we tested the protective role of HMGB1 inhibition using anti-HMGB1 neutralizing antibody (Ab) against CCH in rats after bilateral common carotid artery occlusion (2VO). 169 male Sprague-Dawley rats underwent 2VO or sham operation. ⋯ Besides, anti-HMGB1 Ab preserved BBB integrity and reduced glial activation, in association with the related changes in oxidative stress (increased activities of superoxide dismutase (SOD) and catalase (CAT), and decreased malondialdehyde (MDA) production) and inflammatory cytokines (increased gene expression of IL-1β, IL-6 and TNF) at 3 d. Additionally, anti-HMGB1 neutralizing Ab improved hippocampal CA1 neuronal survival and behavioral outcomes in the chronic phase (4 w and 12 w). Taken together, these findings suggest that HMGB1 neutralization suppresses hippocampal inflammatory responses and oxidative stress in the acute phase, and these changes exert long-lasting beneficial effects in the chronic phase of CCH.
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Developmental exposure to ethanol leads to a constellation of cognitive and behavioral abnormalities known as Fetal Alcohol Spectrum Disorders (FASDs). Many cell types throughout the central nervous system are negatively impacted by gestational alcohol exposure, including inhibitory, GABAergic interneurons. Little evidence exists, however, describing the long-term impact of fetal alcohol exposure on survival of interneurons within the hippocampal formation, which is critical for learning and memory processes that are impaired in individuals with FASDs. ⋯ In adulthood, interneuron populations were reduced in every hippocampal region examined. Moreover, we found that a single exposure to ethanol at P7 caused robust activation of apoptotic neurodegeneration of interneurons in the hilus, granule cell layer, CA1 and CA3 regions of the hippocampus. These studies demonstrate that developmental ethanol exposure has a long-term impact on hippocampal interneuron survivability, and may provide a mechanism partially explaining deficits in hippocampal function and hippocampus-dependent behaviors in those afflicted with FASDs.
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NMDA receptor (NMDAr) hypofunction has been widely used as a schizophrenia model. Decreased activation of NMDAr is associated with a disrupted excitation/inhibition balance in the prefrontal cortex and with alterations in gamma synchronization. Our aim was to investigate whether this phenomenon could be reproduced in the spontaneous oscillatory activity generated by the local prefrontal network in vitro and, if so, to explore the effects of antipsychotics on the resulting activity. ⋯ The increased beta/gamma power with NMDAr blockade implies that NMDAr activation in physiological conditions prevents hypersynchronization in this frequency range. High-frequency hypersynchronization following NMDAr blockade occurring in cortical slices suggests that-at least part of-the underlying mechanisms of this schizophrenia feature persist in the local cortical circuit, even in the absence of long-range cortical or subcortical inputs. The observed action of clozapine decreasing hypersynchronization in the local circuit may be one of the mechanisms of action of clozapine in preventing schizophrenia symptoms derived from NMDA hypofunction.
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Oxidative stress secondary to excitotoxicity is a common factor in the physiopathology of a variety of neurological disorders. In response to oxidative stress, several signaling pathways, such as MAPK, are activated or inactivated. Mitogen-activated protein kinase (MAPK) family activation must be finely regulated in time and intensity, as this pathway may either preserve cell survival or promote cell death. ⋯ No significant difference in p38 activation with QUIN was observed. QUIN (120 and 240 nmol) decreased BDNF/TrkB levels at 7 days post-injury. JNK inhibition (by an intracerebroventricular injection of SP600125) prevented the QUIN-induced reduction in BDNF and TrkB at 7 day post-injury, suggesting a role for the QUIN-induced JNK activation on the observed decrease in BDNF levels.
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Cellular mechanisms underlying the antinociceptive properties of orexins, a group of neuropeptides produced by the hypothalamus, in the spinal dorsal horn have not been thoroughly investigated. We examined how orexin B affects spontaneous synaptic transmission in lamina II neurons, which play a pivotal role in regulating nociceptive transmission, by applying a whole-cell patch-clamp technique to lamina II neurons in adult rat spinal cord slices. In 66% of neurons tested, bath-applied orexin B concentration dependently produced an inward current at -70 mV and/or increased the frequency of glutamatergic spontaneous excitatory postsynaptic current (sEPSC) without changing its amplitude, in a manner resistant to the voltage-gated Na+-channel blocker tetrodotoxin (TTX). ⋯ These results indicate that orexin B produces membrane depolarization and/or increased spontaneous l-glutamate release in lamina II neurons by activating orexin-2 receptors, leading to increased excitability of these neurons. Such increases potentially produce an action potential, resulting in enhancement of glycinergic transmission in lamina II neurons. This activity of orexin B, and possibly orexin A, may contribute to its antinociceptive effects, which are partly shared by oxytocin.