Neurotoxicology
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Descending facilitation from the rostral ventromedial medulla (RVM) contributes to some pathological pain states. The intra-RVM microinjection with dermorphin-saporin could specifically abolish this facilitation in rodent models by selectively ablating the RVM neurons expressing mu opioid receptors. Thus, this targeted lesion may be an alternative mechanism-based approach for intractable pain. ⋯ Results showed though some acute cardiovascular signs were observed with dermorphin-saporin, the treatment exhibited no long-lasting significant influence on some physiological functions for up to 3-month observation period, including normal sensory function, locomotor activity, ingestive behaviors, body weight, rectal temperature, respiratory rate, heart rate, systolic blood pressure, cardiac structure and function. Moreover, there were only mild microglial responses on day 7 post-microinjection, while no significant increase in the immunostaining of astrocytes and no noticeable up-regulation in the production of proinflammatory cytokines were detected in the RVM treated with dermorphin-saporin. Taken together, these data would suggest that this selective ablation of mu opioid receptor bearing descending facilitatory neurons in the RVM with dermorphin-saporin did not elicit the long-standing evident adverse toxicity in terms of some physiological parameters and neurochemical alterations we determined, plausibly providing us a safe and reliable approach to treat some intractable pain.
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Neurotoxicity and mechanistic data were collected for six alpha-cyano pyrethroids (beta-cyfluthrin, cypermethrin, deltamethrin, esfenvalerate, fenpropathrin and lambda-cyhalothrin) and up to six non-cyano containing pyrethroids (bifenthrin, S-bioallethrin [or allethrin], permethrin, pyrethrins, resmethrin [or its cis-isomer, cismethrin] and tefluthrin under standard conditions. Factor analysis and multivariate dissimilarity analysis were employed to evaluate four independent data sets comprised of (1) fifty-six behavioral and physiological parameters from an acute neurotoxicity functional observatory battery (FOB), (2) eight electrophysiological parameters from voltage clamp experiments conducted on the Na(v)1.8 sodium channel expressed in Xenopus oocytes, (3) indices of efficacy, potency and binding calculated for calcium ion influx across neuronal membranes, membrane depolarization and glutamate released from rat brain synaptosomes and (4) changes in chloride channel open state probability using a patch voltage clamp technique for membranes isolated from mouse neuroblastoma cells. The pyrethroids segregated into Type I (T--syndrome-tremors) and Type II (CS syndrome--choreoathetosis with salivation) groups based on FOB data. ⋯ None of the non-cyano pyrethroids reduced open channel probability, except bioallethrin, which gave a weak response. Overall, based upon neurotoxicity data and the effect of pyrethroids on sodium, calcium and chloride ion channels, it is proposed that bioallethrin, cismethrin, tefluthrin, bifenthrin and permethrin belong to one common mechanism group and deltamethrin, lambda-cyhalothrin, cyfluthrin and cypermethrin belong to a second. Fenpropathrin and esfenvalerate occupy an intermediate position between these two groups.
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For 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to exert neurotoxicity on dopaminergic neurons, 1-methyl-4-phenylpyridinium (MPP+), a metabolite of MPTP, must be taken up into the dopaminergic neuron via the dopamine transporter (DAT). Previous reports have shown that MPTP also causes neuroblast apoptosis in the subventricular zone (SVZ) of adult mice. The aim of this study is to elucidate the role of DAT and other monoamine transporters including vesicular monoamine transporter 2 (VMAT2), the serotonin transporter (SERT), and the norepinephrine transporter (NET) on the neuroblast apoptosis induced by MPTP administration. ⋯ However, the injection of these transporter inhibitors had no influence on the MPTP-induced neuroblast apoptosis in the SVZ. It is likely that neither DAT nor other monoamine transporters are involved in MPTP-induced neuroblast apoptosis. The present findings suggest that the neurotoxicity of MPTP to neuroblasts in the SVZ does not require DAT or other monoamine transporters, and the apoptosis it induces may be executed through other unknown pathways.
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Neuronal cell death after general anesthesia has recently been demonstrated in neonatal animal models. The possibility of anesthesia-induced neurotoxicity during an uneventful anesthetic procedure in human neonates or infants has led to serious questions about the safety of pediatric anesthesia. However, the applicability of animal data to clinical anesthesia practice remains uncertain. ⋯ Published retrospective reviews demonstrate temporary neurological sequelae after prolonged anesthetic exposure in young children and larger studies identify long-term neurodevelopmental impairment after neonatal surgery and anesthesia. However, there are no prospective studies evaluating neurocognitive function in children after neonatal exposure to anesthetics. Given the potential magnitude of the public health importance of this issue, this review also discusses epidemiological approaches and several ongoing prospective studies that are assessing the long-term neurocognitive effects of general anesthesia on the neonate.
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Sodium channel blocker insecticides (SCBIs), such as indoxacarb and metaflumizone, are a new class of insecticides with a mechanism of action different from those of other insecticides that target sodium channels. SCBIs block sodium channels in a manner similar to local anesthetics (LAs) such as lidocaine. Several residues, particularly F1579 and Y1586, in the sixth transmembrane segment (S6) of domain IV (IV) of rat Na(v)1.4 sodium channels are required for the action of LAs and SCBIs and may form part of overlapping receptor sites. ⋯ The mutant channels showed no effect or a marked increase in channel sensitivity to both DCJW (the active metabolite of indoxacarb) and metaflumizone. Thus, it appeared that although the F1817 residue plays a role in the action of SCBIs and that both residues are involved in LA activity in mammalian sodium channels, neither F1817 nor Y1824 are integral determinants of SCBI binding on insect sodium channels. Our results suggest that the receptor site of SCBIs on insect sodium channels may be significantly different from that on mammalian sodium channels.