Neuroscience
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Nuclear respiratory factor 1 (NRF-1) is one of the key transcription factors implicated in mitochondrial biogenesis by activating the transcription of mitochondrial transcription factor A (mtTFA) and subunit genes of respiratory enzymes. NRF-1 transactivation activity can be enhanced by interaction with transcription coactivator peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha). The expression of PGC-1alpha, NRF-1 and mtTFA in neurons is known to be tightly regulated by neuronal activity. ⋯ Conversely, 1 week of MD significantly reduces AMPK phosphorylation and activity, dramatically down-regulates PGC-1alpha and NRF-1 expression in deprived primary visual cortex. Administration of resveratrol in vivo significantly activates AMPK activity and attenuates the effects of MD on mitochondria by significant increase in PGC-1alpha and NRF-1 levels, mitochondria amount, and coupled respiration. These results strongly indicate that AMPK is an essential upstream mediator that couples neuronal activity to mitochondrial energy metabolism by regulation of PGC-1alpha-NRF-1 pathway in neurons.
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The purposes of this study were to clarify the involvement of P-glycoprotein in the absorption of levosulpiride in knockout mice that lack the Abcb1a/ 1b gene, and to evaluate the relationship between genetic polymorphisms in ABCB1 (exon 12, 21 and 26) and levosulpiride disposition in healthy subjects. The plasma and brain samples were obtained after oral administration (10 microg/g) of levosulpiride to abcb1a/1b(-/-) and wild-type mice (n=3 approximately 6 at each time point). The average brain-to-plasma concentration ratio and blood-brain barrier partitioning of levosulpiride were 2.3- and 2.0-fold higher in Abcb1a/1b(-/-) mice than in wild-type mice, respectively. ⋯ The subjects were evaluated for polymorphisms of the ABCB1 exon 12 C1236T, exon 21 G2677A/T (Ala893Ser/Thr) and exon 26 C3435T using polymerase chain reaction restriction fragment length polymorphism. The PK parameters (AUC(0-4h), AUC(0-infinity) and C(max.)) of ABCB1 2677TT and 3435TT subjects were significantly higher than those of subjects with at least one wild-type allele (P<0.05). The results indicate that levosulpiride is a P-glycoprotein substrate in vivo, which is supported by the effects of SNPs 2677G>A/T in exon 21 and 3435C>T in exon 26 of ABCB1 on levosulpiride disposition.
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The cognitive impairment in Alzheimer's disease (AD) is associated with synaptic loss, neuritic sprouting and altered neuroplasticity. Compensatory neuritic sprouting might be beneficial, while aberrant sprouting could contribute to the neurodegenerative process. Nogo (or Rtn4) is a major myelin-derived inhibitor of axonal sprouting in adult CNS. ⋯ Furthermore, deleting Nogo restored the expression levels of markers for synapto-dendritic complexity and axonal sprouting including synaptophysin, MAP2, GAP43 and neurofilament that are otherwise reduced in APP transgenic mice. Other aspects of disease progression including neuronal loss, astrogliosis, microgliosis and, importantly, Abeta levels and amyloid deposits were not significantly altered by Nogo deletion. These data support the hypothesis that Nogo-mediated inhibition of neuritic sprouting contributes to the disease progression in an APP transgenic model of AD in a way that is mechanistically distinct from what has been proposed for Rtn3 or NgR.
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We have previously described a rat model for the contribution of neuroplastic changes in nociceptors to the transition from acute to chronic pain. In this model a prior injury activates protein kinase C epsilon (PKCepsilon), inducing a chronic state characterized by marked prolongation of the hyperalgesia induced by inflammatory cytokines, prototypically prostaglandin E(2) (PGE(2)), referred to as hyperalgesic priming. In this study we evaluated the population of nociceptors involved in priming, by lesioning isolectin B4-positive (IB4(+)) nociceptors with intrathecal administration of a selective neurotoxin, IB4-saporin. ⋯ Thus, while PKCepsilon is present in most dorsal root ganglion neurons, where it can contribute to acute mechanical hyperalgesia, priming is restricted to IB4(+)-nociceptors, including those that are TrkA(+). While PKCepsilon activation can induce acute hyperalgesia in the IB4(+) population, it fails to induce priming. We suggest that hyperalgesic priming occurs only in IB4(+) nociceptors, and that in the peripheral terminals of nociceptors separate intracellular pools of PKCepsilon mediate nociceptor sensitization and the induction of hyperalgesic priming.
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Hyperglycemia is one of the major factors for hemorrhagic transformation after ischemic stroke. In this study, we tested the effect of hydrogen gas on hemorrhagic transformation in a rat focal cerebral ischemia model. Sprague-Dawley rats (n=72) were divided into the following groups: sham; sham treated with hydrogen gas (H(2)); Middle Cerebral Artery Occlusion (MCAO); and MCAO treated with H(2) (MCAO+H(2)). ⋯ However, the treatment had no significant effect on the expression of ZO-1, occludin, collagen IV or aquaporin4 (AQP4). In conclusion, hydrogen gas reduced brain infarction, hemorrhagic transformation, and improved neurological function in rats. The potential mechanisms of decreased oxidative stress and glucose levels after hydrogen treatment warrant further investigation.