Neuroscience
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Pyramidal neurons in the hippocampal CA3 area interconnect intensively via recurrent axonal collaterals, and such CA3-to-CA3 recurrent circuitry plays important roles in the generation of hippocampal network activities. In particular, the CA3 circuitry is able to generate spontaneous sharp waves (SPWs) when examined in vitro. These in vitro SPWs are thought to result from the network activity of GABAergic inhibitory interneurons as SPW-correlating intracellular activities are featured with strong IPSPs in pyramidal neurons and EPSPs or spikes in GABAergic interneurons. ⋯ In addition, aged CA3 pyramidal neurons displayed more positive resting potentials and had a higher propensity of burst firing than adult neurons. We postulate that alterations of GABAergic network activity may explain the reduced IPCS contributions to in vitro SPWs in aged CA3 pyramidal neurons. Overall, our present observations are supportive of the notion that excitability of hippocampal CA3 circuitry is increased in aged mice.
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Metformin a well known antidiabetic drug has been recently investigated and proposed to promote neurogenesis and enhance the spatial memory formation. In the present study, we aim to investigate the neuroprotective effect of metformin with respect to Parkinson's disease (PD). MPTP (Sigma-Aldrich, St. ⋯ TH-positive cells decreased up to 16% in MPTP-treated mice as compared to normal mice (P<0.001) and were found to be protected from degeneration in metformin-treated mice (47%, P<0.01). Interestingly, BDNF levels were found to be significantly elevated in metformin treatment group as compared to MPTP treatment mice (P<0.001). In conclusion, metformin possesses neuroprotective activity and provides preclinical support for therapeutic prospective of this compound in the treatment of PD.
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Hemokinin-1 (HK-1) is a new mammalian tachykinin peptide consisting of the amino acid sequence similar to substance P (SP). Although the function of SP, a representative tachykinin peptide, has been well established in the pain system, that of HK-1 has not yet been elucidated. [Leu(11)]-SP had an antagonistic effect on SP-induced scratching behavior, suggesting that [Leu(11)]-HK-1 may also attenuate the induction of scratching behavior by HK-1. Thus, the effects of a pretreatment with [Leu(11)]-HK-1 were evaluated to clarify the function of HK-1. ⋯ To evaluate the involvement of HK-1 and SP in pruritic processing, the effect of [Leu(11)]-HK-1 and [Leu(11)]-SP on the induction of scratching behavior and c-Fos expression by serotonin (5-HT) and histamine was evaluated. The increased induction of scratching behavior and c-Fos expression by 5-HT and histamine was markedly attenuated by pretreatment with both [Leu(11)]-HK-1 and [Leu(11)]-SP, suggesting that HK-1 and SP may be involved in pruritic processing. These results indicate that HK-1 is involved in pruritic processing and [Leu(11)]-HK-1 is a valuable tool for clarifying the mechanisms underlying pruritic processing.
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P2X7 receptors play an important role in inflammatory hyperalgesia, but the mechanisms involved in their hyperalgesic role are not completely understood. In this study, we hypothesized that P2X7 receptor activation induces mechanical hyperalgesia via the inflammatory mediators bradykinin, sympathomimetic amines, prostaglandin E2 (PGE2), and pro-inflammatory cytokines and via neutrophil migration in rats. We found that 2'(3')-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate triethylammonium salt (BzATP), the most potent P2X7 receptor agonist available, induced a dose-dependent mechanical hyperalgesia that was blocked by the P2X7 receptor-selective antagonist A-438079 but unaffected by the P2X1,3,2/3 receptor antagonist TNP-ATP. ⋯ Co-administration of DALBK or bradyzide with BzATP significantly reduced BzATP-induced IL-1β and CINC-1 release. These results indicate that peripheral P2X7 receptor activation induces mechanical hyperalgesia via inflammatory mediators, especially bradykinin, which may contribute to pro-inflammatory cytokine release. These pro-inflammatory cytokines in turn may mediate the contributions of PGE2, sympathomimetic amines and neutrophil migration to the mechanical hyperalgesia induced by local P2X7 receptor activation.
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Alzheimer's disease (AD) is a progressive and degenerative disorder accompanied by cognitive impairment, but effective strategies against AD are currently not available. Interestingly, glucagon-like peptide-1 (GLP-1) used in type 2 diabetes mellitus (T2DM) has shown neuroprotective effects in preclinical studies of AD. Lixisenatide, an effective GLP-1 receptor (GLP-1R) agonist with much longer half life than GLP-1, has been licensed in the EU as a treatment for T2DM. ⋯ In the present study, we report for the first time the effects of lixisenatide on the amyloid β (Aβ) protein-induced impairments in spatial learning and memory of rats, and investigated its electrophysiological and molecular mechanisms. We found that: (1) bilateral intrahippocampal injection of Aβ25-35 resulted in a significant decline in spatial learning and memory of rats, as well as a suppression of in vivo hippocampal long-term potentiation (LTP); (2) lixisenatide treatment effectively prevented the Aβ25-35-induced impairments; (3) lixisenatide inhibited the Aβ25-35 injection-induced activation of glycogen synthase kinase 3β (GSK3β), with a significant increase in the phosphorylation of ser9 and a significant decrease in the phosphorylation of Y216. These results indicate that lixisenatide, by affecting the PI3K-Akt-GSK3β pathway, can prevent Aβ-related impairments in synaptic plasticity and spatial memory of rats, suggesting that lixisenatide may be a novel and effective treatment for AD.