Neuroscience
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Synaptotagmin (syt) I is a Ca(2+) sensor that has been thought to trigger all vesicle secretion with similar mechanisms. However, given the calcium and stimulation requirements of small clear, and large dense core vesicles, we hypothesized that syt I expression differentially regulates vesicle release. Therefore, in this study, we generated multiple stable cell lines of PC12 cells that each had a different and stable level of syt I expression. ⋯ We used an immunoassay to measure NPY release and found that NPY release was abolished in cells that had abolished syt I expression, but cell lines that expressed 50-60% of control levels of syt I exhibited NPY release levels comparable to release of NPY from control cells. Furthermore, the vesicle fusion pore exhibited a reduced open duration when syt I was abolished, but a longer open duration time for 50% syt I expression than control cells. Therefore, vesicles have a threshold for syt I that is required to control opening of the fusion pore, expansion, and full fusion to release large dense core proteins, but not for full fusion of the small molecules like NE.
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Hydrogen sulfide (H(2)S), an endogenous gasotransmitter, modulates various biological functions, including nociception. It is known that H(2)S causes neurogenic inflammation and elicits hyperalgesia. Here we show that H(2)S activates mouse transient receptor potential ankyrin 1 (TRPA1) channels and elicits acute pain, using TRPA1-gene deficient mice (TRPA1(-/-)) and heterologous expression system. ⋯ The [Ca(2+)](i) responses to H(2)S in sensory neurons and in heterologously expressed channels, and pain-related behavior induced by H(2)S were enhanced under acidic conditions. These results suggest that H(2)S functions as a nociceptive messenger through the activation of TRPA1 channels. TRPA1 may be a therapeutic target for H(2)S-related algesic action, especially under inflammatory conditions.
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Comparative Study
The differential profiles of withdrawal symptoms induced by morphine and beta-endorphin administered intracerebroventricularly in mice.
In the present study, withdrawal symptoms induced by morphine or β-endorphin administered intracerebroventricularly (i.c.v.) were compared in ICR mice. Naloxone (10mg/kg) was post-treated intraperitoneally (i.p.) 3h after either a single or repeated (1 time/day for 3 days) i.c.v. injections with opioids. Withdrawal symptoms such as jumping frequency, diarrhea, weight loss, rearing, penile licking and paw tremor were observed for 30 min immediately after naloxone treatment. ⋯ In contrast with the findings in morphine-treated group, only pCaMK-IIα expression was decreased by naloxone treatment in repeatedly administered β-endorphin group. Our results suggest that profiles of the withdrawal symptoms induced by morphine and β-endorphin administered supraspinally appear to be differentially regulated. The pCaMK-IIα and the c-FOS protein expression may play important roles for the regulation of naloxone-precipitated withdrawal symptoms such as jumping, diarrhea, weight loss, rearing, penile licking and paw tremor induced by morphine-treated group, whereas the phosphorylation of hypothalamic pCaMK-IIα appears to be involved only in the regulation of naloxone-precipitated withdrawal symptoms such as diarrhea, weight loss and rearing in β-endorphin-treated group.
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L-arginine, a semi-essential amino acid, can be metabolized to form a number of bioactive molecules. Nitric oxide (NO), generated by NO synthase (NOS) from L-arginine, has been strongly implicated in the aging process. Agmatine, decarboxylated arginine, regulates the production of NO and other metabolites of L-arginine, modulates behavioural function, and has anti-inflammatory and neuroprotective effects. ⋯ Agmatine (40 mg/kg) administered intraperitoneally significantly improved spatial working memory and object recognition memory in aged rats, suppressed age-related elevation in total NOS activity, and restored endothelial NOS protein to the normal level. However, agmatine supplementation was unable to improve exploratory activity and spatial reference learning and memory in aged rats. These findings suggest that exogenous agmatine selectively improves behavioural function in aged rats under the present experimental condition, and merit future investigation of its therapeutic potential in cognitive decline during aging.
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Neuroglobin (Ngb) is a new member of the globin family and a novel endogenous neuroprotective molecule, but its neuroprotective mechanisms remain largely undefined. Previous studies suggest Ngb is both physically and functionally related to mitochondria, however without direct evidence. Our recent discovery has shown that Ngb can physically interact with a number of mitochondrial proteins. ⋯ Complementary approaches including confocal imaging and immuno-electron microscopy confirmed Ngb distribution in mitochondria under both basal-resting condition and OGD. Inhibitors of mitochondria permeability transition pore (mPTP) and Voltage-Dependent Anion Channel (VDAC) blocked OGD-induced increase of mitochondrial Ngb level, demonstrating a possible role of mPTP in Ngb's mitochondrial translocation. We further found that Ngb overexpression-conferred neuroprotection was correlated with increased mitochondrial Ngb level, suggesting the mitochondria distribution of Ngb is clearly associated with and may contribute to Ngb's neuroprotection.