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Mechanism Underlying Organophosphate Paraoxon-Induced Kinetic Tremor

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Abstract

Organophosphates (OPs) inhibit cholinesterase and hyperactivate the acetylcholinergic nervous system in the brain, causing motor disorders (e.g., tremor and seizures). Here, we performed behavioral and immunohistochemical studies in mice and rats to investigate the tremorgenic mechanism of paraoxon, an active metabolite of parathion. Treating animals with paraoxon (0.15–0.6 mg/kg, i.p.) elicited kinetic tremor in a dose-dependent manner. Expressional analysis of Fos protein, a biomarker of neural excitation, revealed that a tremorgenic dose of paraoxon (0.6 mg/kg) significantly and region-specifically elevated Fos expression in the cerebral cortex (e.g., sensory cortex), hippocampal CA1, globus pallidus, medial habenula, and inferior olive (IO) among 48 brain regions examined. A moderate increase in Fos expression was also observed in the dorsolateral striatum while the change was not statistically significant. Paraoxon-induced tremor was inhibited by the nicotinic acetylcholine (nACh) receptor antagonist mecamylamine (MEC), but not affected by the muscarinic acetylcholine receptor antagonist trihexyphenidyl (THP). In addition, paraoxon-induced Fos expression in the IO was also antagonized by MEC, but not by THP, and lesioning of the IO markedly suppressed tremorgenic action of paraoxon. The present results suggest that OPs elicit kinetic tremor at least partly by activating IO neurons via nACh receptors.

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Funding

This study was supported in part by a research grant from the Smoking Research Foundation (YO) and by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (YO:17K08324, SS:16K21501).

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Authors and Affiliations

  1. Department of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan

    Higor Alves Iha, Naofumi Kunisawa, Saki Shimizu, Misaki Onishi, Yuji Nomura, Nami Matsubara, Chihiro Iwai, Mizuki Ogawa, Mai Hashimura, Kazuaki Sato, Masaki Kato & Yukihiro Ohno

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  1. Higor Alves Iha
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  2. Naofumi Kunisawa
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  12. Yukihiro Ohno
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Correspondence to Yukihiro Ohno.

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The experimental protocols were approved by the Experimental Animal Research Committee at the Osaka University of Pharmaceutical Sciences.

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Iha, H.A., Kunisawa, N., Shimizu, S. et al. Mechanism Underlying Organophosphate Paraoxon-Induced Kinetic Tremor. Neurotox Res 35, 575–583 (2019). https://doi.org/10.1007/s12640-019-0007-7

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