Brain research
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Dexmedetomidine (Dex) has been demonstrated to provide neuroprotection against ischemia/reperfusion (I/R) injury. However, the exact mechanism of this protection remains unknown. Here, we explored the neuroprotective effect of Dex in rats exposed to cerebral I/R-induced by middle cerebral artery occlusion (MCAO) and the role of phosphatidylinositol 3-kinase (PI3K)/Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), and glycogen synthase kinase-3β (GSK-3β) in this protective action. ⋯ The increasing expressions of p-Akt and p-ERK1/2 induced by Dex in the ischemic hemisphere were markedly inhibited by LY294002 (or wortmannin) and U0126 (or PD98059), respectively. The up-regulation of p-GSK-3β by Dex in the ischemic hemisphere was significantly decreased by both LY294002 (or wortmannin) and U0126 (or PD98059). Our data demonstrated that treatment with Dex reduced cerebral injury in rats exposed to transient focal I/R, and this was mediated by the activation of the PI3K/Akt and ERK1/2 pathways as well the phosphorylation of downstream GSK-3β.
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Neuronal cell death via apoptosis or necrosis underlies several devastating neurodegenerative diseases associated with aging. Mitochondrial dysfunction resulting from oxidative or nitrosative stress often acts as an initiating stimulus for intrinsic apoptosis or necrosis. These events frequently occur in conjunction with imbalances in the mitochondrial fission and fusion equilibrium, although the cause and effect relationships remain elusive. ⋯ N-terminal cleavage of OPA1 is also observed in vivo in aged rat and mouse midbrain and hippocampal tissues. We conclude that N-terminal cleavage and subsequent inactivation of OPA1 may be a contributing factor in the neuronal cell death processes underlying neurodegenerative diseases, particularly those associated with aging. Furthermore, these data suggest that OPA1 cleavage is a likely convergence point for mitochondrial dysfunction and imbalances in mitochondrial fission and fusion induced by oxidative or nitrosative stress.
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Comparative Study
Amphetamine increases phosphorylation of MAPK/ERK at synaptic sites in the rat striatum and medial prefrontal cortex.
Mitogen-activated protein kinases (MAPKs) play a central role in cell signaling. Extracellular signal-regulated kinase (ERK) is a prototypic subclass of MAPKs and is densely expressed in postmitotic neurons of adult mammalian brains. Active ERK translocates into the nucleus to regulate gene expression. ⋯ In both synaptic and extrasynaptic compartments, total ERK1/2 proteins remained stable in response to amphetamine. Our data establish the subsynaptic distribution pattern of MAPK/ERK in striatal and cortical neurons. Moreover, the synaptic pool of ERK2 in these neurons can be selectively activated by amphetamine.
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It has been confirmed that gabapentin (GBP) induced a inhibition of the voltage-gated persistent sodium current in chronically compressed dorsal root ganglion (DRG) neurons. The persistent sodium current is found in excitable DRG neurons of painful diabetic neuropathy (PDN) rats where it is mediated by tetrodotoxin (TTX) sensitive sodium channels. Recently, many groups have used models of neurological disorder to explore the mechanism of GBP in neuropathic pain. ⋯ Diabetes significantly increased the excitability of DRG neurons and the expression of Nav1.7 and p-ERK1/2, and GBP significantly inhibited these changes. These results suggest that the inhibitory effect of GBP on the expression of Nav1.7 and p-ERK1/2 might be one of the analgesic mechanisms of action of GBP. This may partially explain the antinociceptive action of GBP in the PDN rats.
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Traumatic brain injury (TBI) remains the leading cause of injury-related death and disability. Brain edema, one of the most major complications of TBI, contributes to elevated intracranial pressure, and poor prognosis following TBI. Nerve growth factor (NGF) appears to be a viable strategy to treat brain edema and TBI. ⋯ An electrophoretic mobility shift assay (EMSA) displayed a significant activation of nuclear factor-κB following TBI, which was, however, much lowered in the NGF-treated rats. Furthermore, upon intranasal NGF supplementation, mitochondria-mediated apoptosis following TBI was minimized, as indicated by upregulation of Bcl-2 and downregulation of caspase-3. Collectively, our findings suggested that intranasal NGF may be a promising strategy to treat brain edema and TBI.