Neuroscience
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Microglial cells are the pivotal immune cells of the central nervous system. Adult microglia cells under physiological conditions are in a ramification state with extensively branched processes. Upon disease stimulation, they retract their processes and become activated. ⋯ Mechanistic studies confirmed that the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) signal, extracellular signal-regulated kinase 1/2 (ERK1/2) or small RhoGTPase activation mediated the effect of CC on microglial shape change based on the following observations: (i) CC induced a significant activation of the small RhoGTPase Rac1 and Cdc42; (ii) CC promoted the phosphorylation of ERK1/2 and Akt; (iii) inhibition of Rac1, Cdc42, ERK1/2, or the PI3K-Akt signal abolished the effect of CC on microglial shape change. These signal mechanisms were also ascertained in primary microglia. Our results explore a potential agent that promotes microglial ramification, and provide an alternative explanation for the neuroprotective effects of CC in various disease models such as brain ischemia and subarachnoid hemorrhage.
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For years, the prevailing hypothesis for Alzheimer's Disease (AD) has proposed a mechanism by which deposition of amyloid-beta (Aβ) in the brain is independent of tau-pathologies and cognitive decline. However, despite extensive research on the disease, the mechanisms underlying the etiology of tau-pathology remain unknown. Previous research in our lab has shown that imatinib methanesulfonate (IM) blocks the peripheral production of Aβ in response to LPS, thereby preventing the buildup of Aβ in the hippocampus, and rescuing the cognitive dysfunction that normally follows. ⋯ In addition, 7days of LPS-induced inflammation and Aβ production also leads to elevated total tau protein expression. Our results may provide support for the hypothesis that enhanced expression of tau following LPS administration is a protective measure by hippocampal neurons to compensate for the loss of the microtubule-stabilizing protein due to phosphorylation. More importantly, our results support the hypothesis that blocking the production of Aβ that follows inflammation also leads to reduced tau phosphorylation, lending credence to a model in which Aβ initiates tau phosphorylation.
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To investigate the neuroprotective role of sodium valproate (VPA) in a hippocampal neuronal cell line (HT22) and the hippocampus of zebrafish after exposure to radiation. ⋯ ROS generation after radiation exposure contributes to DNA damage in the zebrafish brain. VPA inhibits ROS generation by activating the Nrf2/HO-1 pathway, which improves cognitive behavior following radiation-induced neuronal injury.
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Migraine affects predominantly women. Furthermore, epidemiological studies suggest that obesity is a risk factor for migraine and this association is influenced by sex. However, the biological basis for this bias is unclear. ⋯ This is in contrast to what we have previously shown in males and indicates a sex difference in the photophobic behavior of mice. Comparison of 20-25-week-old RD mice with 8-11-week-old RD mice suggests that age or age-related weight gain may contribute to capsaicin-evoked photophobic behavior in males, but not in females. These findings suggest that obesity exacerbates photophobia in both sexes, but additional work is needed to understand the sex- and age-specific mechanisms that may contribute to photophobia and trigeminal pain.
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Sigma-1 receptor (S1R) is a unique pluripotent modulator of living systems and has been reported to be associated with a number of neurological diseases including pathological pain. Intrathecal administration of S1R antagonists attenuates the pain behavior of rodents in both inflammatory and neuropathic pain models. However, the S1R localization in the spinal cord shows a selective ventral horn motor neuron distribution, suggesting the high likelihood of S1R in the dorsal root ganglion (DRG) mediating the pain relief by intrathecally administered drugs. ⋯ Using immuno-electron microscopy, we showed that S1R is detected in the nuclear envelope and endoplasmic reticulum (ER) of DRG cells. In contrast to other cells, S1R is also located directly at the plasma membrane of the DRG neurons. The presence of S1R in the nuclear envelope of all DRG neurons suggests an exciting potential role of S1R as a regulator of neuronal nuclear activities and/or gene expression, which may provide insight toward new molecular targets for modulating nociception at the level of primary afferent neurons.