Journal of pharmacological sciences
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Sepsis remains the leading cause of death in critically ill patients. A major problem contributing to sepsis-related high mortality is the lack of effective medical treatment. ⋯ The pivotal role of cell apoptosis is now highlighted by multiple studies demonstrating that prevention of cell apoptosis can improve survival in clinically relevant animal models of sepsis. In this review article, we address the scientific rationale for remedying apoptotic cell death in sepsis and propose that therapeutic efforts aimed at blocking cell signaling pathways leading to apoptosis may represent an attractive target for sepsis therapy.
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Tissue-type plasminogen activator (t-PA) administration has been approved for treating acute ischemic stroke, but delayed treatment is associated with increased risk of cerebral hemorrhage and brain injury. t-PA, a serine proteinase, converts plasminogen to plasmin. Plasmin participates not only in the degradation of fibrin, causing clot lysis, but also in the degradation of various extracellular matrix proteins, either directly or via the activation of matrix metalloproteinase (MMPs). We established an animal stroke model and observed a phenomenon of spontaneous rethrombosis and thrombolysis in the cerebral vessels after vessel damage. ⋯ On studying intracranial hemorrhage (ICH) induced by t-PA treatment of ischemic stroke, we observed that MMP-3 is relatively important for the enhanced ICH induced by t-PA. MMP-3 was upregulated by t-PA in endothelial cells, but the upregulation was prevented by the inhibition of either low-density lipoprotein receptor-related protein (LRP) or nuclear factor kappa-B (NF-kappaB) activation. Thus, t-PA causes ICH via MMP-3 induction in endothelial cells, which is regulated through the LRP/NF-kappaB pathway, and could be targeted to improve the therapeutic efficacy of t-PA for acute ischemic stroke.
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Comparative Study
Blockade of glycine transporter (GlyT) 2, but not GlyT1, ameliorates dynamic and static mechanical allodynia in mice with herpetic or postherpetic pain.
Glycine is an inhibitory neurotransmitter in the spinal dorsal horn and its extracellular concentration is regulated by glial glycine transporter (GlyT) 1 and neuronal GlyT2. This study was conducted to elucidate the effects of intrathecal injections of GlyT1 and GlyT2 inhibitors on two distinct types of mechanical allodynia, dynamic and static allodynia, in mice with herpetic or postherpetic pain. The GlyT2 inhibitor ALX1393, but not the GlyT1 inhibitor sarcosine, suppressed dynamic and static allodynia at the herpetic and postherpetic stages. ⋯ Glycine receptor alpha1-subunit mRNA was decreased in the lumbar dorsal horn at the herpetic, but not postherpetic stage, without alteration in alpha3-subunit mRNA. The results suggest that GlyT2 is a potential target for treatment of dynamic and static allodynia in patients with herpes zoster and postherpetic neuralgia. The lack of efficacy of GlyT1 inhibitor may be explained by activation of NMDA receptors and the down-regulation of GlyT1 in the lumbar dorsal horn.
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Oxaliplatin is a platinum-based chemotherapy drug characterized by the development of acute and chronic peripheral neuropathies. Mexiletine, an orally available Na(+)-channel blocker, has widely been used in patients with chronic painful diabetic neuropathy. ⋯ Lidocaine (30, but not 3 and 10, mg/kg, i.p.) also significantly relieved both pain behaviors. These results suggest that mexiletine may be effective in relieving the oxaliplatin-induced neuropathic pain clinically.
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The activity of pyruvate dehydrogenase (PDH) is reduced in diabetic patients. Phosphorylation of the PDH E1alpha subunit by PDH kinase contributes to the suppression of PDH activity. PDH requires thiamine as a coenzyme. ⋯ The O-glycosylated protein was markedly increased in RCFs exposed to high glucose, which was inhibited by thiamine. These results suggest that thiamine ameliorates diabetes-induced PDH inhibition by suppressing the increased expression of the O-glycosylated protein. The O-glycosylation of PDH E1alpha may be involved in the regulation of the PDH activity.