Neuroscience
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Spontaneous neural hyperactivity in the central auditory pathway is often associated with deafness, the most common form of which is partial hearing loss. We quantified both peripheral hearing loss and spontaneous activity in single neurons of the contralateral inferior colliculus in a guinea-pig model 1 week after a unilateral partial deafness induced by cochlear mechanical lesion. We also measured mRNA levels of candidate genes in the same animals using quantitative real-time PCR. ⋯ A member of RAB family of small GTPase (RAB3A) was decreased in both ipsilateral cochlear nucleus and contralateral inferior colliculus. RAB3 GTPase activating protein subunit 1 (RAB3GAP1) and glycine receptor subunit alpha-1 (GLRA1) were reduced ipsilaterally in the cochlear nucleus only. These results suggest that a decrease in inhibitory neurotransmission and an increase in membrane excitability may contribute to elevated neuronal spontaneous activity in the auditory brainstem following unilateral partial hearing loss.
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To comprehend the role of pyridoxal 5'-phosphate (PLP) in epilepsy or seizure, we investigated whether the expressions of two PLP synthetic enzymes (pyridoxal kinase, PLK; pyridoxine-5'-phosphate oxidase, PNPO) are altered in the hippocampus and whether changes in paired-pulse responses in the hippocampus are associated with altered PLP synthetic enzyme expressions following status epilepticus (SE). PLK and PNPO immunoreactivities were significantly increased in the rat hippocampus accompanied by reductions in paired-pulse inhibition at 1 day and 1 week after SE. ⋯ Linear regression analysis identified a direct proportional relationship between PLK/PNPO immunoreactivity and normalized population spike amplitude ratio in the dentate gyrus and the CA1 region as excluded the data obtained from 4 weeks after SE. These findings indicate that the upregulation of PLK and PNPO immunoreactivities in principal neurons may not be involved in gamma-aminobutyric acid (GABA)ergic inhibition, but rather in enhanced excitability during epileptogenic periods.
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Resveratrol is a natural polyphenol found in grapes and wine and has been associated with protective effects against cardiovascular diseases. In vitro, both resveratrol preconditioning (RPC) and ischemic preconditioning (IPC) require activation of sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase, to induce neuroprotection against cerebral ischemia. In the present study, we tested two hypotheses: (a) that neuroprotection against cerebral ischemia can be induced by RPC in vivo; and (b) that RPC neuroprotection involves alterations in mitochondrial function via the SIRT1 target mitochondrial uncoupling protein 2 (UCP2). ⋯ The SIRT1-specific inhibitor sirtinol abolished the neuroprotection afforded by RPC and the decrease in UCP2 levels. Finally, RPC significantly increased the ADP/O ratio in hippocampal mitochondria reflecting enhanced ATP synthesis efficiency. In conclusion, in vivo resveratrol pretreatment confers neuroprotection similar to IPC via the SIRT1-UCP2 pathway.
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It has been proposed that alterations in spinal inhibitory neurotransmission are critically involved in the pathophysiology of neuropathic pain. The mechanisms by which a relief from inhibitory tone contributes to pathological pain are not fully understood. Hitherto it is still under debate whether there is a loss of inhibitory neurons in the spinal cord in neuropathic pain. ⋯ Although all animals that had undergone CCI showed pathological nociceptive behavior, stereology revealed no significant difference in glycinergic neurons-neither between the different groups nor between the ipsilateral and contralateral side of the thoracic and lumbar spinal segments. Our findings suggest that a loss of glycinergic neurons is not necessary for the development of pathological nociceptive behavior in the chronic constriction injury model of neuropathic pain in mice. A different mechanism may account for the decrease in inhibitory transmission in neuropathic pain.
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Increasing evidence implicates the c-Jun NH(2)-terminal kinase (JNK) pathway in the regulation of apoptosis in neurodegenerative diseases. In this study, we examined the neuroprotective effect of SP600125, a selective JNK inhibitor, in cerebellar granule cells (CGNs) deprived of serum and potassium (S/K withdrawal). S/K withdrawal-induced apoptosis occurs via activation of multiple pro-apoptotic pathways, including re-entry into the cell cycle, activation of glycogen synthase kinase-3 beta (GSK-3beta), cyclin-dependent kinase 5 (cdk5/p35) breakdown, formation of cdk5/p25 and JNK activation. ⋯ In addition, the specific PI3K/Akt inhibitor LY294002 greatly diminished the antiapoptotic effects of SP600125 upon S/K withdrawal, confirming that Akt is involved in the neuroprotection achieved by SP600125. These results suggest that the maintenance of the PI3-kinase/Akt pathway by inhibition of JNK contributes to the prevention of apoptosis in rat cerebellar granule neurons mediated by S/K withdrawal. Furthermore, we propose that JNK may regulate the cell cycle re-entry by a novel mechanism that involves Akt, GSK-3beta and Rb phosphorylation.