Neurobehavioral, neurochemical and synaptic plasticity perturbations during postnatal life of rats exposed to chloroquine in-utero

Olayemi Joseph Olajide; Zainab Omolara Alliy; Daniel Oluwapelumi Ojo; Olajumoke Olamipe Osinubi; Sofiyat Opeyemi Bello; Faaizah Eniola Ibrahim; Faith Ojochenemi Adukwu; Tolulope Olabisi Abikoye; Ismail Temitayo Gbadamosi; Nafisat Yetunde Mutholib; Olawande Bamisi; Olaolu Joseph Ajiboye; Akeem Ayodeji Okesina; Abdulmusawwir Alli-Oluwafuyi; Aboyeji Lukuman Oyewole; Abdulrazaq Bidemi Nafiu; Olugbenga Akinola

doi:10.1016/j.ntt.2021.106982

Neurobehavioral, neurochemical and synaptic plasticity perturbations during postnatal life of rats exposed to chloroquine in-utero

Neurotoxicol Teratol. 2021 Jul-Aug:86:106982. doi: 10.1016/j.ntt.2021.106982. Epub 2021 Apr 16.

Authors

Olayemi Joseph Olajide¹, Zainab Omolara Alliy², Daniel Oluwapelumi Ojo², Olajumoke Olamipe Osinubi², Sofiyat Opeyemi Bello², Faaizah Eniola Ibrahim², Faith Ojochenemi Adukwu², Tolulope Olabisi Abikoye², Ismail Temitayo Gbadamosi³, Nafisat Yetunde Mutholib³, Olawande Bamisi⁴, Olaolu Joseph Ajiboye⁵, Akeem Ayodeji Okesina⁶, Abdulmusawwir Alli-Oluwafuyi⁷, Aboyeji Lukuman Oyewole⁸, Abdulrazaq Bidemi Nafiu⁹, Olugbenga Akinola¹⁰

Affiliations

¹ Department of Anatomy, Faculty of Basic Medical Sciences, University of Ilorin, Ilorin, Nigeria; Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montreal, Canada; Biotranslational Research Group, University of Ilorin, Ilorin, Nigeria. Electronic address: olajide.oj@unilorin.edu.ng.
² Department of Anatomy, Faculty of Basic Medical Sciences, University of Ilorin, Ilorin, Nigeria.
³ Department of Anatomy, Faculty of Basic Medical Sciences, University of Ilorin, Ilorin, Nigeria; Central Research Laboratories Ltd, 132b University Road, Ilorin, Nigeria.
⁴ Department of Anatomy, Faculty of Basic Medical Sciences, University of Ilorin, Ilorin, Nigeria; Department of Anatomy, Faculty of Basic Medical Sciences, Ekiti State University, Ado-Ekiti, Nigeria.
⁵ Anatomy Department, School of Basic Medical Sciences, Babcock University, Ilishan-remo, Nigeria.
⁶ Department of Human Anatomy, Kampala International University, Western Campus, Uganda.
⁷ Biotranslational Research Group, University of Ilorin, Ilorin, Nigeria; Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, University of Ilorin, Ilorin, Nigeria.
⁸ Biotranslational Research Group, University of Ilorin, Ilorin, Nigeria; Department of Physiology, Faculty of Basic Medical Sciences, University of Ilorin, Ilorin, Nigeria.
⁹ Biotranslational Research Group, University of Ilorin, Ilorin, Nigeria; Department of Human Physiology, Federal University Dutse, Jigawa, Nigeria.
¹⁰ Biotranslational Research Group, University of Ilorin, Ilorin, Nigeria; Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, University of Ilorin, Ilorin, Nigeria; Malaria Research Laboratories, Institute for Advanced Medical Research and Training, College of Medicine, University of Ibadan, Ibadan, Nigeria; Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Ibadan, Ibadan, Nigeria. Electronic address: olugbenga.akinola@ui.edu.ng.

PMID: 33845156
DOI: 10.1016/j.ntt.2021.106982

Abstract

Despite reports that quinoline antimalarials including chloroquine (Chq) exhibit idiosyncratic neuropsychiatric effects even at low doses, the drug continues to be in widespread use during pregnancy. Surprisingly, very few studies have examined the potential neurotoxic action of Chq exposure at different points of gestation or how this phenomenon may affect neurophysiological well-being in later life. We therefore studied behavior, and the expression of specific genes and neurochemicals modulating crucial neural processes in offspring of rats exposed to prophylactic dose of Chq during different stages of gestation. Pregnant rats were injected 5 mg/kg/day (3 times) of Chq either during early- (first week), mid- (second week), late- (third week), or throughout- (all weeks) gestation, while controls received PBS injection. Behavioral characterization of offspring between postnatal days 15-20 in the open field, Y-maze, elevated plus and elevated zero mazes revealed that Chq evoked anxiogenic responses and perturbed spatial memory in rats, although locomotor activity was generally unaltered. In the prefrontal cortex (PFC), hippocampus and cerebellum of rats prenatally exposed to Chq, RT-qPCR analysis revealed decreased mRNA expression of presynaptic marker synaptophysin, which was accompanied by downregulation of postsynaptic marker PSD95. Synaptic marker PICK1 expression was also downregulated in the hippocampus but was unperturbed in the PFC and cerebellum. In addition to recorded SOD downregulation in cortical and hippocampal lysates, induction of oxidative stress in rats prenatally exposed to Chq was corroborated by lipid peroxidation as evinced by increased MDA levels. Offspring of rats infused with Chq at mid-gestation and weekly treatment throughout gestation were particularly susceptible to neurotoxic changes, especially in the hippocampus. Interestingly, Chq did not cause histopathological changes in any of the brain areas. Taken together, our findings causally link intrauterine exposure to Chq with postnatal behavioral impairment and neurotoxic changes in rats.

Keywords: Anxiety; Chloroquine; Neurotoxicity; Oxidative stress; Spatial memory; Synaptic plasticity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anxiety / chemically induced
Anxiety / psychology
Behavior, Animal / drug effects*
Brain Chemistry / drug effects*
Chloroquine / toxicity*
Female
Gene Expression / drug effects
Gestational Age
Maze Learning / drug effects
Motor Activity / drug effects
Neuronal Plasticity / drug effects*
Pregnancy
Prenatal Exposure Delayed Effects / metabolism*
Prenatal Exposure Delayed Effects / psychology*
Rats
Spatial Memory / drug effects

Substances

Chloroquine