The role of oxidative stress in ovarian toxicity induced by haloperidol and clozapine—a histological and biochemical study in albino rats

Khalaf, Hanaa Attia; Elmorsy, Ekramy; Mahmoud, El-Hassanin Mohamed; Aggour, Amal Misbah; Amer, Saad A.

Abstract

Oxidative stress has been implicated in reproductive toxicity induced by antipsychotics (APs). This study aims to further investigate the role of AP-induced oxidative stress in reproductive dysfunction. Thirty adult female albino rats were divided into three groups including a control group (n = 10) receiving distilled water, HAL group (n = 10) receiving haloperidol (HAL) (2 mg/kg/day), and CLZ group (n = 10) receiving clozapine (CLZ) (20 mg/kg/day). After 28 days, the rats were anesthetized, blood was withdrawn from their hearts, and ovaries were removed before they were sacrificed. Serum prolactin concentrations were measured. For each rat, one ovary was used for biochemical studies including mitochondrial complexes I and III activities and oxidative stress markers (lipid peroxidation, super oxide dismutase [SOD], catalase [CAT], and reduced glutathione [GSH]). The other ovary was used for histopathological examination and immunohistochemistry staining for p53 and Ki-67. HAL-treated rats showed significantly (p ≤0.001) higher serum prolactin concentrations compared with other groups. HAL significantly inhibited complexes I (p ≤ 0.001) and III activities (p ≤ 0.05), while CLZ inhibited only complex I (p ≤ 0.001). Lipid peroxidation was increased by HAL (p ≤ 0.001) and CLZ (p ≤ 0.01). HAL caused significant (p ≤ 0.001) reductions in SOD, CAT, and GSH. CLZ caused a significant decrease in SOD (p ≤ 0.001) and GSH (p ≤ 0.01) with no effect on CAT. Histopathological studies of CLZ- and HAL-treated ovaries showed features suggestive of hyperprolactinemia and oxidative stress. Ki-67- and P53-immunostained sections were suggestive of disruption of cellular proliferation. These findings support the hypothesis that HAL and CLZ induce reproductive dysfunction through mechanisms involving ovarian mitochondrial dysfunction and oxidative stress.

Citation

Khalaf, H. A., Elmorsy, E., Mahmoud, E. M., Aggour, A. M., & Amer, S. A. (2019). The role of oxidative stress in ovarian toxicity induced by haloperidol and clozapine—a histological and biochemical study in albino rats. Cell and Tissue Research, 378(2), 371-383. https://doi.org/10.1007/s00441-019-03067-x

• Journal Article Type: Article
• Acceptance Date: Jul 1, 2019
• Online Publication Date: Jul 24, 2019
• Publication Date: Jul 24, 2019
• Deposit Date: Aug 4, 2019
• Publicly Available Date: Aug 5, 2019
• Journal: Cell and Tissue Research
• Print ISSN: 0302-766X
• Electronic ISSN: 1432-0878
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 378
• Issue: 2
• Pages: 371-383
• DOI: https://doi.org/10.1007/s00441-019-03067-x
• Keywords: Antipsychotics; Oxidative stress; Reproductive toxicity; Ovarian toxicity; Menstrual irregularities
• Public URL: https://nottingham-repository.worktribe.com/output/2386173
• Publisher URL: https://link.springer.com/article/10.1007%2Fs00441-019-03067-x
• Additional Information: Received: 26 October 2018; Accepted: 1 July 2019; First Online: 24 July 2019; : ; : The authors declare that they have no conflict of interest.; : N/A; : All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All rats’ experimental protocols and procedures were approved by the institutional review board (IRB), Faculty of Medicine, University of Mansoura (Ref: R.18.03.110).