Neuroscience
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A secondary consequence of spinal cord injury (SCI) is debilitating chronic neuropathic pain, which is commonly morphine resistant and inadequately managed by current treatment options. Consequently, new pain management therapies are desperately needed. We previously reported that dopamine D3 receptor (D3R) dysfunction was associated with opioid resistance and increases in D1 receptor (D1R) protein expression in the spinal cord. ⋯ Following SCI, morphine + pramipexole and morphine + SCH 39166 significantly increased both thermal and mechanical thresholds. Morphine alone induced conditioned place preference, but when combined with either the D3R agonist or D1R antagonist preference was not induced. The data suggest that adjunct therapy with receptor-specific dopamine modulators can restore morphine analgesia and decrease reward potential and thus, represents a new target for pain management therapy after SCI.
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Profiling the Gene Expression and DNA Methylation in the Mouse Brain after Ischemic Preconditioning.
Ischemic preconditioning (IPC) is a phenomenon in which a short-term sublethal ischemic exposure induces tolerance to a subsequent lethal ischemic insult; however, the detailed mechanism underlying IPC-induced neuroprotection remains obscure. Here, we applied middle cerebral artery occlusion, a preconditioning ischemic insult mouse model, to investigate the molecular mechanism underlying cerebral IPC. RNA sequencing and whole-genome bisulfite sequencing were performed to explore the gene expression profile and DNA methylation changes after cerebral IPC treatment. ⋯ The involvement of several genes in IPC-induced neuroprotection was first reported. Genes induced by IPC, including Arid5a, Nptx2 and Stc2, demonstrated a neuroprotective effect against oxygen-glucose deprivation induced neurotoxicity in vitro. Thus, our findings provide new insights into IPC signaling pathways and offer a novel therapeutic strategy towards stroke.
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The over-activation of N-methyl-D-aspartate receptors (NMDARs) is the main cause of neuronal death in brain ischemia. Both the NMDAR and the Acid-sensing ion channel 1a (ASIC1a) are present in the postsynaptic membrane of the central nervous system (CNS) and participate in physiological and pathological processes. However, the specific role played by ASIC1a in these processes remains elusive. ⋯ Furthermore, brain infarct sizes were reduced by a greater degree in older mice compared to younger ones when ASIC1a activity was suppressed. These data suggest that ASIC1a activity selectively enhances the function of triheteromeric NMDARs and exacerbates ischemic neuronal death especially in older animal brains. We propose ASIC1a as a novel therapeutic target for preventing and reducing the detrimental effect of brain ischemia in humans.
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Myeloid-derived suppressor cells (MDSCs) have strong immunosuppressive characteristics, which allow them to limit inflammation and facilitate wound healing and recovery. Although MDSCs are a newly-determined cell type that is gaining attention in the immunology field, their neuroimmunological characteristics remain unstudied. ⋯ MDSCs are among the first responders to tissue injury, responding even prior to microglial activation. Positron emission tomography imaging of translocator protein results suggest that infiltrating MDSCs suppress neuronal inflammation and interact with resident immune cells, like microglia, following focal TBI.
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Valproic acid (VPA) is widely used in the treatment of epilepsy. However, VPA has been revealed to impair memory of both humans and animals. The adverse effects of VPA are associated with reductions in hippocampal neurogenesis and memory. ⋯ It is noteworthy that rats receiving melatonin alone showed a significant diversity of proliferation, survival and immature neurons compared to the control rats. These findings suggest that melatonin is able to prevent the spatial and non-spatial memory impairments and a reduction in hippocampal neurogenesis simultaneously induced by VPA. Our results provide a feasible way to prevent this loss using melatonin.