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Comparison of Novel and Known Neuroprotectants for Treating Exposure to Different Types of Toxins

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Annual rept. 16 Aug 2001-15 Aug 2002

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Studies using cultured brain slices have found that compensatory signals are activated in response to different types of excitotoxicityseizures related to environmental toxin or military threat agent exposure. Surprisingly, glutamate receptors, cannabinoid receptors, and proteoglycan-binding adhesion receptors activated common pathways involving MAP kinase, focal adhesion kinase FAK, and transcription factors that facilitate endogenous repair mechanisms. Inhibition of the receptors potentiated excitotoxic vulnerability and, correspondingly, promoting receptor-mediated responses enhanced cellular and synaptic repair. The receptors seem to act through transcription regulators to explain common signaling elements including MAPK and FAK. NF-kappaB is one such regulator, activated in response to both excitotoxicity and receptor activation. Interestingly, NF-kappaB activation is biphasic properties of the initial phase are consistent with neuroprotection and the second phase with neurodegeneration. Microarray analyses have confirmed that genes activated initially are those that promote survival, while genes activated during the delayed phase can enhance neuronal vulnerability. The latter phase may explain why months after an insult, select brain regions remain acutely vulnerable to stroke events and age-related neurodegeneration. Studies with receptor modulators are helping to identify key signal transduction pathways that lead to neuroprotection vs. those that enhance neuronal vulnerability, and what determines the direction of the signaling path.

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  • Medicine and Medical Research
  • Toxicology

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