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Journal of Environmental Pathology, Toxicology and Oncology
インパクトファクター: 1.625 5年インパクトファクター: 1.63 SJR: 0.402 SNIP: 0.613 CiteScore™: 2.3

ISSN 印刷: 0731-8898
ISSN オンライン: 2162-6537

Journal of Environmental Pathology, Toxicology and Oncology

DOI: 10.1615/JEnvironPatholToxicolOncol.2019030362
pages 1-12

Clozapine Improves Behavioral and Biochemical Outcomes in a MK-801-Induced Mouse Model of Schizophrenia

Syed Suhail Andrabi
Department of Medical Elementology and Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi 110062, India
Shruti Vishnoi
Department of Medical Elementology and Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi 110062, India
Riya Madan
Department of Medical Elementology and Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi 110062, India
Neha Bhardwaj
Department of Medical Elementology and Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi 110062, India
Heena Tabassum
Division of Biomedical Sciences, Indian Council of Medical Research, Ministry of Health and Family Welfare, Government of India, V. Ramalingaswamy Bhawan, New Delhi 110029, India
Mohd. Akram
Dept. of Tahaffuzi wa Samaji Tibb, School of Unani Medical Education and Research, Jamia Hamdard, New Delhi 110062, India
Suhel Parvez
Department of Medical Elementology and Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi 110062, India


Glutamatergic N-methyl-D-aspartate (NMDA) receptors have critical roles in several neurological and psychiatric diseases. Dizocilpine (MK-801) is a ligand at phencyclidine recognition sites that is associated with NMDA receptor-coupled cation channels, where it acts as a potent noncompetitive antagonist of central glutamate receptors. In this study, we investigate the effect of clozapine on MK-801-induced neurochemical and neurobehavioral alterations in the prefrontal cortex of mice. Acute administration of NMDA noncompetitive antagonist MK-801 impairs motor coordination, grip strength, and locomotor activity. Clozapine is the only medication that is indicated for treating refractory schizophrenia, due to its superior efficacy among all antipsychotic agents; however, its mechanism is not well understood. To understand its mechanism, we investigated the effects of clozapine on motor coordination, locomotor activity, and grip strength in mice against the NMDA receptor antagonist MK-801. MK-801 induced elevations in acetylcholinesterase (AChE) activity, monoamine oxidase (MAO) activity, and c-fos expression. The administration of clozapine inhibited the effects caused by MK-801 (0.2 mg/kg body weight). Motor coordination and grip strength paradigms that had been altered by MK-801 were restored by clozapine. Moreover, clozapine also ameliorated MK-801-induced elevation in AChE and MAO activity. Our immunostaining results demonstrated that clozapine treatment reduced overexpression of the neuronal activity marker c-fos in cortices of the brain. Results of the current study determine that clozapine ameliorated cognition in MK-801-treated mice via cholinergic and neural mechanisms. These findings show that clozapine possesses the potential to augment cognition in diseases such as schizophrenia.


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