Journal of molecular neuroscience : MN
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Dopamine D2 receptor (D2R) signalling has been shown to modulate seizure-induced hippocampal cell death. D2R knockout (D2R-/-) mice are more susceptible to kainic acid (KA)-induced excitotoxicity, displaying cell death in the CA3 subfield of the hippocampus at KA doses not damaging in wild-type (WT) animals. Absence of D2R signalling in the hippocampus leads to activation (dephosphorylation) of glycogen synthase kinase 3β (GSK-3β) after KA (20 mg/kg), which is not associated with a change in the phosphorylation of the GSK-3β regulator Akt at the canonical threonine 308 residue. ⋯ Additionally, the vulnerability in the CA3 is not associated with changes to p38MAPK and Dishevelled activation, and β-catenin does not appear to be a downstream target of the GSK-3β. Thus, we propose that GSK-3β phosphorylation-mediated hippocampal cell survival may depend on Akt (Ser473) phosphorylation; loss of D2R-mediated signalling in the CA3 region of D2R-/- mice leads to reduced Akt (Ser473) phosphorylation rendering neurons more vulnerable to apoptosis. Further investigation is required to fully elucidate the GSK-3β targets involved in D2R-dependent response to excitotoxicity.
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Caffeine has been reported to enhance cognition in animal and humans. Additionally, caffeine alleviates cognitive impairment associated with a number of disorders including Alzheimer's disease. The lipophilic nature of caffeine allows for rapid absorption into the bloodstream where it freely crosses the blood-brain barrier. ⋯ It appears that the neuroprotective effect of caffeine involves preservation of the levels of essential kinases and phosphatases in stressed rats. This may include preservation of basal levels of BDNF by chronic caffeine treatment in stressed animals. These findings highlight the critical role of P-CaMKII and BDNF in caffeine-induced prevention of stress-induced LTP impairment.
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The circadian time-keeping system consists of clocks in the suprachiasmatic nucleus (SCN) and in peripheral organs including an adrenal clock linked to the rhythmic corticosteroid production by regulating steroidogenic acute regulatory protein (StAR). Clock cells contain an autonomous molecular oscillator based on a group of clock genes and their protein products. Mice lacking the VPAC2 receptor display disrupted circadian rhythm of physiology and behaviour, and therefore, we using real-time RT-PCR quantified (1) the mRNAs for the clock genes Per1 and Bmal1 in the adrenal gland and SCN, (2) the adrenal Star mRNA and (3) the serum corticosterone concentration both during a light/dark (L/D) cycle and at constant darkness in wild type (WT) and VPAC2 receptor-deficient mice (VPAC2-KO). ⋯ The loss of adrenal clock gene rhythm in the VPAC2 receptor knockout mice after transfer into constant darkness was accompanied by disappearance of rhythmicity in Star mRNA expression and serum corticosterone concentration. Double immunohistochemistry showed that the PER1 protein and StAR were co-localised in the same steroidogenic cells. Circulating corticosterone plays a role in the circadian timing system and the misaligned corticosterone rhythm in the VPAC2 receptor knockout mice could be involved in their abnormal rhythms of physiology.
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We have previously demonstrated nerve growth factor (NGF) regulation of pituitary adenylate cyclase-activating polypeptide (PACAP)/receptors in bladder reflex pathways using a transgenic mouse model of chronic NGF overexpression in the bladder using the urothelial-specific uroplakin II promoter. We have now explored the contribution of target-derived NGF in combination with cyclophosphamide (CYP)-induced cystitis to determine whether additional changes in neuropeptides/receptors are observed in micturition reflex pathways due to the presence of additional inflammatory mediators in the urinary bladder. Quantitative PCR was used to determine PACAP/vasoactive intestinal polypeptide (VIP), substance P, galanin, and receptor transcript expression in the urinary bladder (urothelium, detrusor) in mice with overexpression of NGF in the urothelium (NGF-OE) and wild-type (WT) mice with CYP-induced cystitis (4 h, 48 h, and chronic). ⋯ Using conscious cystometry, NGF-OE mice treated with CYP exhibited significant (p ≤ 0.01) increases in voiding frequency above that observed in control NGF-OE mice. In addition, no changes in the electrical properties of the major pelvic ganglia neurons of NGF-OE mice were detected using intracellular recording, suggesting that the urinary bladder phenotype in NGF-OE mice is not influenced by changes in the efferent limb of the micturition reflex. These studies are consistent with target-derived NGF and other inflammatory mediators affecting neurochemical plasticity and the reflex function of micturition pathways.
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Induction of demyelination in the central nervous system induce the oligodendrocyte progenitors to proliferate, migrate, and differentiate for restoring new myelin sheathes around demyelinated axons. Factors which increase the response of endogenous progenitor cells could be used to improve remyelination. In the current study, the effect of bFGF on lysolecithin-induced demyelination and remyelination processes in mouse optic chiasm and nerves was investigated. ⋯ Lysolecithin decreased MBP and increased Olig2 expression in different days post-lesion. Lysolecithin-induced changes in VEPs were partially ameliorated by endogenous repair. bFGF reduced the increased delay, increased the reduced amplitude of P1-N1 wave, increased MBP gene expression, and accelerated the increasing pattern of Olig2. bFGF seems to be able to potentiate the endogenous repair mechanisms of myelin. Its effect on demyelination and remyelination processes seems to be mediated by oligodendrocyte progenitor cells and their differentiation to myelinating cells.