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

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 After 28 days, the rats were anesthetized, blood was withdrawn from their hearts, and ovaries were removed before they were sacrificed.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.

The effect of taxifolin on oxidative ovarian damage and reproductive dysfunctions induced by antipsychotic drugs in female rats

“…All this information suggests that TAP‐induced hyperprolactinemia does not cause reproductive dysfunction on its own, therefore, other possible mechanisms need to be investigated. Khalaf et al support the hypothesis that TAPs and AAPs induce mitochondrial and reproductive dysfunction through mechanisms involving oxidative stress in ovarian cells 6 . In their study, Elmorsy et al suggest that oxidative stress is a possible mechanism causing ovarian and reproductive toxicity associated with TAP and AAP 7 .…”

Do platelet rich plasma and folic acid reverse experimental induced ovarian failure: Emphasis on folliculogenesis, and ovarian steroidogenesis

“…Our results showed that VPA exposure for 90 days is associated with ovarian carbohydrate depletion as evidenced by PAS ovarian stained sections. Similarly, prior studies showed an intense positive PAS reaction in the zona pellucida surrounding the oocyte following exposure to antipsychotics as ovotoxin agents [59] . Ahmed et al reported a strong positive PAS reaction following PRP therapy in a rat model of induced renal ischemia-reperfusion injury [60] .…”

The Emerging Role of the Innate Immune Response in Idiosyncratic Drug Reactions

“…The effects of clozapine on various other organs, including the brain, heart, and kidney, have been investigated using several rodent models. In studies characterizing the effects of clozapine in the absence of induced injury or disease, decreased splenic white pulp was observed in both female mice and male rats (Abdelrahman et al, 2014;Mohammed et al, 2020), and both ovarian and kidney injury were reported in rats (Khalaf et al, 2019;Mohammed et al, 2020). Moreover, significant cardiac inflammation and morphologic aberrations were observed during the first few weeks of treatment (Wang et al, 2008;Nikoli c-Koki c et al, 2018;Mohammed et al, 2020).…”

“…The majority of rodent studies demonstrated evidence of apoptosis (e.g., increased terminal deoxynucleotide transferase dUTP nick-end labeling staining or caspase-3 activation) between weeks 1 and 4 of treatment (Wasti et al, 2006;Jarskog et al, 2007;Huang et al, 2012;Jia et al, 2014;Zlatkovi c et al, 2014;Hsu and Fu, 2016;Khalaf et al, 2019) using doses that would approximate therapeutic concentrations in patients (Lobach and Uetrecht, 2014a). One study also noted that clozapine induced autophagy within hours of administration (Kim et al, 2018), and others noted decreased proliferation within the first few weeks of treatment (Huang et al, 2012;Hsu and Fu, 2016;Khalaf et al, 2019) as well. Translocation of apoptosis-inducing factor was not observed in the striatum of clozapine-treated patients or in rodents after 1 month of treatment (Skoblenick et al, 2006), suggesting against the involvement of caspase-independent cell death with clozapine.…”

“…Several rodent studies have also been conducted to evaluate changes in mitochondrial function due to clozapine. Clozapine often caused attenuated mitochondrial function or oxidative stress (e.g., increased malondialdehyde levels), which was noted most frequently in male rats after 3-4 weeks of treatment in various brain regions (Lara et al, 2001;La et al, 2006;Mehler-Wex et al, 2006;Streck et al, 2007;Bullock et al, 2008;Martins et al, 2008;Ji et al, 2009;Bishnoi et al, 2011;Zlatkovi c et al, 2014;Cai et al, 2017), although cardiacspecific (Nikoli c-Koki c et al, 2018) and ovarian-specific (Khalaf et al, 2019) aberrations were also reported. Additionally, another study reported increased markers of ER stress in the liver 1 hour after clozapine treatment (Lauressergues et al, 2012).…”