Neuroscience
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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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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.
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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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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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Comparative Study
Association of the Jun dimerization protein 2 gene with intracranial aneurysms in Japanese and Korean cohorts as compared to a Dutch cohort.
In a previous study a linkage region for association to IA patients was found on chromosome 14q22. In this study, we report the findings of a positional candidate gene, Jun dimerization Protein 2 (JDP2), and single nucleotide polymorphisms (SNP) of that gene that are associated with intracranial aneurysms in different ethnic populations. We screened the linkage region around chromosome 14q22 and narrowed it down to JDP2. ⋯ The allelic and genotypic frequency of one intronic SNP (rs175646; P=0.0135 and P=0.0137, respectively) and the genotypic frequency for the SNP in the UTR region (rs8215; P=0.049) was also significantly different between cases and controls of the Korean cohort. There was no difference in allelic or genotypic frequencies in the Dutch population. These SNPs in JDP2 are associated with intracranial aneurysms, suggesting that variation in or near JDP2 play a role in susceptibility to IAs in East Asian populations.