Neuroscience
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Painful peripheral neuropathy is a major dose-limiting adverse effect of many cancer chemotherapeutic agents, such as the vinca alkaloids and taxanes. Recent studies demonstrate sexual dimorphism in second-messenger signaling for primary afferent nociceptor sensitization, and a role of second messengers in the models of metabolic and toxic painful peripheral neuropathies. This study tested the hypothesis that sexual dimorphism alters the severity and second-messenger signaling pathways for enhanced nociception in an animal model of vincristine-induced painful peripheral neuropathy. ⋯ Inhibition of protein kinase C epsilon (PKC epsilon ) attenuated vincristine-induced hyperalgesia in males and ovariectomized females, but not in normal females or in estrogen-replaced ovariectomized females. Inhibitors of protein kinase A, protein kinase G, p42 / p44-mitogen activated protein kinase and nitric oxide synthase also attenuated vincristine-induced hyperalgesia, but to a similar degree in both sexes. These data demonstrate an estrogen-dependent sexual dimorphism in vincristine-induced hyperalgesia (female>male) and an unexpected opposite sexual dimorphism in the contribution of PKC epsilon to the severity of this hyperalgesia (male>female).
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The metabolic events of neuronal energetics during functional activity are still partially unexplained. In particular, lactate (and not glucose) was recently proposed as the main substrate for neurons during activity. ⋯ In the present study we used a time-resolved proton magnetic resonance spectroscopy strategy in order to analyse the evolution of lactate during the early seconds following a brief visual stimulation (event-related design). A significant decrease in lactate concentration was observed 5 s after the stimulation, while a recovering of the baseline was observed at 12 s.
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Comparative Study
Methamphetamine-induced deficits of brain monoaminergic neuronal markers: distal axotomy or neuronal plasticity.
We examined the effects of methamphetamine (METH) on monoaminergic (i.e. dopamine and serotonin) axonal markers and glial cell activation in the rat brain. Our findings indicate that the loss of dopamine transporters (DAT), serotonin transporters (5-HTT), vesicular monoamine transporter type-2 (VMAT-2) and glial cell activation induced by METH in the striatum and in the central gray are consistent with a degenerative process. Our novel finding of METH effects on monoaminergic neurons in the central gray may have important implications on METH-induced hyperthermia. ⋯ In summary, our findings suggest two neurotoxic endpoints in the brain of METH-exposed animals. Brain regions exhibiting DAT and 5-HTT deficits that co-localize with decreased VMAT-2 levels and glial cell activation may represent monoaminergic terminal degeneration. However, the DAT and 5-HTT deficits in brain regions lacking a deficit in VMAT-2 and glial cell activation may reflect drug-induced modulation of these plasma membrane proteins.
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Comparative Study
The influence of the extracellular matrix on the morphology and intracellular pH of cultured astrocytes exposed to media lacking bicarbonate.
In previous work we showed that the polygonal shape of hippocampal astrocytes cultured on poly-L-lysine changes to a stellate morphology with loss of actinomyosin stress fibers on exchanging the culture medium for saline buffered with HEPES [Brain Res 946 (2002)12]. By contrast, in bicarbonate-buffered saline containing Ca(2+) astrocytes remained polygonal and continued to express stress fibers. Evidence suggests that stellation induced by saline buffered with HEPES is related to intracellular acidification due to the absence of bicarbonate. ⋯ Two observations suggested the involvement of integrins and focal adhesions. (1) Treatment of cultures on collagens with a blocking antibody to the beta1 integrin subunit abolished protection against HEPES-induced stellation. (2) Compared with polylysine, astrocytes cultured on collagens expressed increased contents of phosphotyrosine proteins, focal adhesion proteins vinculin and paxillin, the beta1 integrin subunit and increased numbers of focal adhesions labelled with anti-vinculin. The observation that astrocytes cultured on collagen I or IV, in contrast to polylysine, express stress fibers and a constant intracellular pH in the absence of buffering by bicarbonate may be related to the fact that in the intact brain astrocytic processes (or end-feet) encounter and bind to collagen IV and laminin in the basement membrane of the endothelial cells which surround the cerebral capillaries. It is also possible that astrocytes retain this capacity from early development when fibrous matrix proteins are present.
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The immunomodulatory thymic hormone thymulin has been shown previously to possess anti-inflammatory actions in the periphery. In this study, we have examined the effect of i.c.v. injections of either endotoxin (ET) or thymulin, in separate groups of conscious rats, on pain-related behavior and cytokine levels in different areas of the brain. Furthermore, we investigated the effect of pretreatment with either i.c.v. or i.p. injections of thymulin on endotoxin-induced hyperalgesia and the effect of pretreatment with i.c.v. thymulin on endotoxin-induced up-regulation of cytokine levels. ⋯ However, thymulin at different doses, when injected (i.c.v.), had no significant effect on pain related behavior. Pretreatment (i.c.v.) with thymulin (0.1, 0.5 and 1 microg in 5 microl saline) 20 min before endotoxin (i.c.v.) injection (1 microg in 5 microl saline) reduced, in a dose dependent manner, the endotoxin-induced hyperalgesia and exerted differential effects on the up-regulated levels of cytokines in different areas of the brain. The results provide behavioral and immunochemical characterization of a rat model for intracerebral inflammation and indicates a neuroprotective role for thymulin in the CNS.