Brain research
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We investigated in different experimental rat models the potential facilitatory contribution of the medullary dorsal reticular nucleus (DRt) descending pathway to the expressions of the sensory spinal neuron sensitization such as increased spontaneous and noxious evoked activities, responsivity to heterotopic afferences stimulation and long lasting afterdischarges (ADs). We carried out experiments by recording from ipsilateral lumbar Wide Dynamic Range (WDR) neurons and by simultaneously monitoring the DRt neuron activity in neuropathic pain rats with chronic constriction injury of one sciatic nerve (CCI), in sham-operated and in "intact" rats. In particular, we recorded the spinal neuron spontaneous activities and the activities evoked by noxious stimulations of ipsi- and contralateral sciatic supplied areas before and during DRt activity blockade. ⋯ We found that during DRt activity blockade in CCI rat neurons and in "intact" rat NMDA-treated neurons, the spontaneous activity was significantly reduced, the responses to contralateral sciatic area stimulation were reduced or suppressed, the responses to ipsilateral sciatic area were poorly affected (slightly reduced or unaffected), except for the poststimulus afterdischarges that were mostly suppressed. In sham-operated rats, the neuronal activity was not affected by DRt blockade. The finding that during the DRt nucleus blockade some expressions of spinal neurons sensitization, seemingly associated to sensory disorders in neuropathic pain, fade or extinguish designates a likely facilitatory role of DRt in the maintenance of neuronal sensitization and thus a contribution to neuropathic pain state.
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There is compelling evidence indicating that reduction of high-density lipoprotein (HDL) level is associated with increased risk of Alzheimer's disease (AD). It is known that the levels of HDL are regulated by cholesteryl ester transfer protein (CETP) and several single nucleotide polymorphisms (SNPs) in the CETP gene have been shown to be associated with the levels of HDL. Therefore, it is assumed that the CETP gene is a reasonable candidate for modifying the susceptibility in AD. ⋯ When the sample was stratified by APOE epsilon4 carrier status, the same tendency (P=0.042 for DG genotype, P=0.046 for G allele) was observed in the presence of APOE epsilon4, but not in the absence of APOE epsilon4 (P=0.284 for DG genotype, P=0.298 for G allele). However, these results became not statistically significant after correcting for multiple testing (Bonferroni) because of limited number of our sample. Our current results suggest that G allele of CETP D442G may have a potential protective effect against the development of AD, especially in APOE epsilon4 carriers, in Northern Han-Chinese, possibly through regulating the HDL level in the brain.
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We examined calcitonin gene-related peptide (CGRP) expression dynamics in the dorsal root ganglia (DRGs) and spinal cords of adult rats subjected to one of the following three types of unilateral sciatic nerve injury: crush (SNC), ligation (SNL), or transection combined with subsequent neurorrhaphy (SNT). Following SNC, CGRP immunoreactivity (IR) was increased in ipsilateral primary sensory neurons of L4-L5 DRGs, laminae I-II and spinal motoneurons; an area of CGRP-labeled fibers in ipsilateral laminae III-V was also increased in size following SNC. CGRP up-regulation exhibited a distinct temporospatial pattern and expression levels had returned to baseline levels by the end of the 28-day test period. ⋯ Interestingly, SNL did not affect CGRP-IR in spinal motoneurons, but did result in an accumulation of nerve growth factor (NGF) distal to ligature that was apparent as early as 1 day post-injury and persisted throughout the experimental period. These findings indicate that the nature of peripheral nerve injury has an impact on CGRP expression dynamics and that the response involves target tissues in vivo. Our results have important implications for elucidating the mechanisms of nerve regeneration.
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An abnormal accumulation of cytosolic dopamine resulting in reactive oxygen species and dopamine-quinone products may play an important role in the rather selective degeneration of substantia nigra pars compacta (SNc) dopaminergic neurons in Parkinson's disease. The neuronal-specific vesicular monoamine transporter (VMAT2), responsible for uptake of dopamine into vesicles, has been shown to play a central role both in intracellular dopamine homeostasis and sequestration of dopaminergic neurotoxins. Direct or indirect enhancement of VMAT2 activity could therefore have neuroprotective effects by decreasing cytosolic dopamine levels. ⋯ The opposite was seen after downregulation of VMAT2 using virally delivered shRNAs. Furthermore, using this VMAT2 knockdown model, we are the first to report a direct link between enhanced cytoplasmic dopamine levels, measured following mild permeabilization of the plasma membrane using digitonin, and neurite degeneration in primary dopaminergic neurons. In conclusion, our data support the hypothesis that an increase in vesicular sequestration of dopamine by modulation of VMAT2 activity could restore neuronal function and enhance dopaminergic cell survival in conditions of dysregulated dopamine homeostasis such as Parkinson's disease.
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Numerous studies have shown that the beta-amyloid peptide (Abeta) or beta-amyloid deposits impact many processes that can contribute to neurodegeneration, ranging from immune and inflammatory processes to cell death and apoptosis, processes characteristic of both Alzheimer's disease and head injury. Human and animal studies of traumatic brain injury (TBI) have shown that Abeta production is increased acutely following injury, and there is evidence for increased amyloid deposition and risk for Alzheimer's disease following TBI. Given the poorer outcome after injury observed both in transgenic mice overproducing Abeta, as well as in humans subjected to repetitive head injury, one may conclude that the presence of elevated brain levels of Abeta, whether endogenous or as a consequence of previous injury, exacerbates many of the deleterious processes triggered by TBI. ⋯ We focused our analyses by creating a "genotype-dependent" data set of response to injury which contained the genes that were uniquely altered in response to injury in either wild-type or APPsw mice, as well as those which were significantly differently modulated following TBI in one genotype compared to the other. The cellular functions predicted to be influenced by these changes in gene expression thus indicate the adverse pathways triggered by increased levels of Abeta, and the potentially favorable (recovery) pathways which are activated in wild-type mice but suppressed when Abeta levels are high. The results show that the cellular functions most influenced by the cerebral Abeta levels following TBI include inflammation, immune response, and cell death, which suggest a particular vulnerability to head injury in the Alzheimer brain.