Effects of Manganese on Inositol Polyphosphate Receptors and Nitric Oxide Synthase Activity in Rat Brain

Abstract

The neurotoxic effects of excessive exposure to manganese (Mn) include degeneration of dopaminergic neurons, impairment of energy metabolism, and perturbations in phosphoinositide (PI) hydrolysis leading to altered calcium (Ca²⁺) homeostasis. This study is designed to assess the in vitro and in vivo effects of Mn on Ca²⁺/cahnodulin-dependent neuronal nitric oxide synthase (nNOS) activity and on the regulation of inositol 1,4,5-trisphosphate (InsP₃) and inositol 1,3,4,5-tetrakisphosphate (InsP₄) receptors involved in intracellular and extracellular mobilization of Ca²⁺. In vivo Mn exposure significantly increased ³H-InsP₃ and ³H-InsP₄ binding in the cerebellum and the cerebral cortex in a dose-dependent manner. However, in vitro Mn decreased ³H-InsP₃ binding and increased ³H-InsP₄ binding. In vitro and in vivo exposure of Mn inhibited nNOS activity in the cerebellum and the cerebral cortex. Immunohistochemical studies also showed a notable decrease in nNOS immunoreactivity in the granule cell layer of the cerebellum, whereas no significant changes were observed in the cerebral cortex. These data suggest that Mn neurotoxicity may be due to altered calcium homeostasis by its modulation of inositol polyphosphate receptors. Further, the inhibition of nNOS by Mn is of considerable importance because NO regulates a number of neurotransmitter functions.

Keywords

Cerebellum Cerebral Cortex Inositol Polyphosphate Receptors Manganese Nitric Oxide Synthase

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