Neurotoxicology
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Here, I will review accumulating evidence that during the developmental period of synaptogenesis, also known as the brain growth spurt period, neurons are very sensitive to specific disturbances in their synaptic environment. During this period, abnormal increases in NMDA glutamate (Glu) receptor activity triggers excitotoxic neurodegeneration, and abnormal inhibition of neuronal activity (by blockade of NMDA Glu receptors or excessive activation of GABAA receptors) triggers neuronal suicide (apoptosis). Only a transient disturbance, lasting for a few hours, is sufficient to trigger either excitotoxic or apoptotic neurodegeneration during this developmental period. ⋯ Thus, there is a period in fetal and neonatal human development, lasting for several years, during which immature central nervous system (CNS) neurons are exquisitely sensitive to environmental agents (the specific number and variety of which remains to be established) that can trigger widespread neurodegeneration by inducing specific abnormal changes in the synaptic environment. Agents identified thus far include drugs that may be abused by pregnant mothers (ethanol, phencyclidine (PCP) (angel dust), ketamine (Special K), nitrous oxide (laughing gas), barbiturates, benzodiazepines) and many medicinals used in obstetric and pediatric medicine as sedatives, anti-convulsants or anesthetics (all general anesthetics are either NMDA antagonists or GABAmimetics). Many other chemicals in the human environment remain to be evaluated for their ability to cause developing CNS neurons to commit suicide, and this provides an exciting challenge for the field of developmental neurotoxicology.
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Idiopathic Parkinson's disease (PD) is associated with advanced age, but it is still unclear whether dopaminergic neuronal death results from events initiated during development, adulthood, or represents a cumulative effect across the span of life. This study hypothesized that paraquat (PQ) and maneb (MB) exposure during critical periods of development could permanently change the nigrostriatal dopamine (DA) system and enhance its vulnerability to subsequent neurotoxicant challenges. C57BL/6 mice were treated daily with saline, 0.3 mg/kg PQ, 1 mg/kg MB or PQ + MB from post-natal (PN) days 5 to 19. ⋯ Developmental exposure to PQ or MB alone produced minimal changes. However, following adult re-challenge, significant decreases in DA and nigral cell counts were observed, suggesting that exposure to either neurotoxicant alone produced a state of silent toxicity that was unmasked following adult re-exposure. Taken together, these findings indicate that exposure to pesticides during the PN period can produce permanent and progressive lesions of the nigrostriatal DA system, and enhanced adult susceptibility to these pesticides, suggesting that developmental exposure to neurotoxicants may be involved in the induction of neurodegenerative disorders and/or alter the normal aging process.
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Comparative Study
Clostridium botulinum neurotoxins act with a wide range of potencies on SH-SY5Y human neuroblastoma cells.
We have described, in undifferentiated SH-SY5Y human neuroblastoma cells, the relative potency of Clostridium botulinum neurotoxin (BoNT) serotypes A-F Sensitivity of stimulated [3H]-noradrenaline ([3H]-NA) release to the toxins had a rank order of potency of: C > D > A > B > F after 3 days exposure. The difference between the most potent (BoNT/C: IC50 0.54 nM) and the least (BoNT/F: IC50 > 300 nM) was approximately 1,000-fold. Though fluid phase endocytosis may have been the mechanism of entry for low potency toxins the far higher potency of BoNT/C would suggest receptor-driven entry. ⋯ SNAP-25 cleavage by BoNT/A was shown to be a dose-dependent and correlated closely with reduction of release, supporting proteolysis as the mechanism by which toxin inhibited secretion. Comparison of the SH-SY5Y cell line sensitivity to BoNT/A with glycine releasing rat primary spinal cord neuron cultures, revealed a massive difference in potency; the primary cultures being approximately 200,000-fold more sensitive. The demonstration, using BoNTs, of the crucial role of SNAP-25, VAMP and syntaxin in SH-SY5Y cells suggests the use of this neuroblastoma as a model in the study of these proteins in neurotransmitter release.
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Cisplatin (cis-diamminedichloroplatinum(II) (CDDP)) is a widely used, highly effective, oncolytic agent that has serious ototoxic side-effects. To test the effectiveness of local delivery, of L-methionine (L-Met) as an otoprotective agent against CDDP ototoxicity, we used a rat model of a highly metastatic breast cancer tumor, i.e. Fisher 344 rats implanted with MTLn3 breast cancer cells. ⋯ CDDP was effective in controlling the MTLn3 initiated breast cancer tumors in the CDDP-treated (II) and the local L-Met protection, CDDP-treated (IV) Groups. In contrast, the tumors in the systemic L-Met protection, CDDP-treated Group (III) were not controlled by the CDDP treatment regime. This study demonstrates that local delivery of L-Met to the scala tympani of the cochlea via the round window membrane (IV) provides effective protection against CDDP ototoxicity without compromising its ability to control a highly metastatic form of cancer.