Chemical hypoxia-induced neurodegeneration: Studies of acute and repeated exposure

Goran Pavlakovic, Purdue University

Abstract

Hypoxia of the CNS results in neurodegeneration of select brain areas. It is of interest to investigate pathophysiological consequences of chemical hypoxia induced by cyanide in order to understand the mechanism of this neurodegeneration. The studies presented in this thesis focused on consequences of repeated exposure to cyanide-induced chemical hypoxia on the GABAergic neurotransmitter system in the CNS and the potential role of PKC and immediate-early genes (IEGs) in neurodegeneration. The results demonstrate that repeated exposure to cyanide over 8-day period results in pathohistological changes in substantia nigra and corpus striatum. Dopaminergic neurons degenerate and a disbalance of inhibitory and excitatory neurotransmitter systems develops. The GABAergic tonus is increased and this may explain decreased locomotor activity previously seen following this paradigm of cyanide exposure. Cyanide induces expression of Fos, but not expression of c-Jun. This effect is mediated by the EAA neurotransmitter system, since NMDA antagonist MK-801 blocks this effect. Furthermore, in vitro studies indicate that cyanide does not affect Fos expression independently of the EAA system. Finally, the role of PKC in cyanide-induced neurodegeneration in vitro was demonstrated. Confocal microscopy and western blotting studies showed that cyanide causes PKC translocation and this process is dependent on influx of extracellular Ca$\sp{2+}.$ PKC down-regulation and inhibition resulted in partial protection of differentiated PC12 cells against cyanide-induced chemical hypoxia. This indicates that PKC activation plays a role in neurodegeneration induced by chemical hypoxia, but is not the only biochemical pathway activated by cyanide that causes cell injury.

Degree

Ph.D.

Advisors

Isom, Purdue University.

Subject Area

Pharmacology|Neurology|Environmental science|Occupational safety

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