Haloperidol elicits oxidative damage in the brain of rats submitted to the ketamine-induced model of schizophrenia

Highlights

• Several side effects were assigned to haloperidol, an antipsychotic drug.

• Molecular alterations underlying the side effects of this drug are poorly understood.

• Haloperidol induced remarkable oxidative damage to lipids and proteins in rat brain.

• Redox imbalance is one of the potential mechanisms involved in the oxidative damage.

Abstract

The present study aims to evaluate the effects of haloperidol, an important first-generation antipsychotic, on the antioxidant system parameters in the brain of animals subjected to a model of schizophrenia induced by ketamine. Adult rats intraperitoneally received saline (1 mL/kg) or ketamine (25 mg/kg body weight) for 15 days, and saline or haloperidol (0.1 mg/kg body weight) via gavage once a day, between the 9th and 14th days. In the frontal cortex, hippocampus, and striatum, assessments of lipid (4-hydroxy-2-nonenal and 8-isoprostane levels) and protein (protein carbonyl content) oxidative damage were conducted. It was also measured the glutathione peroxidase and glutathione reductase activities in the same cerebral structures. Increases in the 4-hydroxy-2-nonenal and 8-isoprostane levels were detected in rats receiving haloperidol and ketamine. An increase in the carbonyl content was also observed in animals receiving ketamine, haloperidol, or a combination thereof. In animals receiving the antipsychotic, there was a decrease in the activity of the enzymes. Therefore, both ketamine and haloperidol induced oxidative damage. A possible energy dysfunction or a haloperidol effect targeting the glutathione enzymes, and then disrupting the redox homeostasis in neurons, could not be ruled out, although further studies are required to confirm or refute a direct interaction.

Introduction

Schizophrenia (SZ) is a lifelong mental disorder characterized by positive and negative symptoms, as well as cognitive impairment (Krzystanek and Pałasz, 2019). The SZ prevalence is 0.3–1% worldwide (Cattane et al., 2018; World Health Organization (WHO), 2018). SZ pathophysiology remains poorly understood, while the alterations observed in several brain structures and the lack of responsiveness of negative and cognitive symptoms to antipsychotics are still a challenge (Dean, 2017; Rodrigues-Amorim et al., 2017). Nevertheless, it was hypothesized that an excess or depletion of dopamine, serotonin, glutamate, and γ-aminobutyric acid (GABA) collaborates for the pathophysiology of the disorder (Patel et al., 2014). There is evidence of immune system dysfunction in schizophrenic patients, which could lead to neuroinflammation (Miller et al., 2011). Moreover, studies have indicated that an impairment in the antioxidant defenses is also detectable in patients (Pavlović et al., 2002; Gysin et al., 2007; Dadheech et al., 2008).

In the present study, an SZ model was induced using ketamine (Ket), a well-known anesthetic drug (Canever et al., 2010). Ket administration is regarded as a suitable SZ animal model since it mimics the pathogen mechanisms associated with the symptoms of the disorder. Indeed, Ket administration enables the study of positive, negative, and cognitive alterations observed in SZ, which contributes to providing face validity to this model (Chatterjee et al., 2011; Frohlich and Van Horn, 2014). Neurochemical effects induced by Ket include oxidative stress and blockade of N-methyl-D-aspartic acid (NMDA) receptors, preventing the influx of calcium in neurons, which induces behavioral changes similar to that observed in the patients, collaborating to provide construct validity to the model (Chatterjee et al., 2011). Additional evidence about how to induce the Ket model and how it works regarding the behavioral analysis is showed in recent studies (Zugno et al., 2016; Damazio et al., 2017; Canever et al., 2018; Supp et al., 2020). Data from these papers enable the reproduction of the model to assess potential neurochemical alterations similar to that observed in schizophrenic patients using haloperidol or other drugs.

The therapy of SZ and other psychotic disorders can be carried out by first-generation antipsychotics. These drugs primarily act by inhibiting dopaminergic receptors (Dean, 2017). Among the drugs of this class, haloperidol (Hal) is recommended for acute episodes of positive symptoms and as maintenance therapy for SZ (Haddad and Correll, 2018; Chokhawala and Stevens, 2019). Although the antipsychotics have persisted as the standard therapy for SZ and are effective in treating the positive symptoms, these drugs may induce several side effects, including tardive dyskinesia, muscle rigidity, and tremors (Buchanan et al., 2007; Chatterjee et al., 2011; Dean, 2017). At least in part, oxidative stress seems to be involved in such effects.

In this regard, Hal (2 mg kg⁻¹ day⁻¹) was found to impair the activity of enzymes such as catalase and superoxide dismutase as well as elicit an increase in the levels of the lipid peroxidation by-product hydroxyalkenal in rat brain (Parikh et al., 2003). Besides, Hal (1.5 mg kg⁻¹ day⁻¹) induced significant increases in the content of thiobarbituric acid-reactive species (TBARS) in the striatum as well as in the protein carbonyl content in hippocampus of rats (Reinke et al., 2004). Hal was also linked to increased serum TBARS in SZ patients, in comparison with olanzapine (Singh et al., 2008). In the Raudenska and coworkers' review (2013) is outlined a more detailed picture of the mechanisms involved in the cytotoxicity of Hal-induced oxidative stress.

Other antipsychotics with a possible role in oxidative stress include clozapine, chlorpromazine, risperidone, and ziprasidone (Martins et al., 2008; Elmorsy et al., 2017; Dietrich-Muszalska and Kolińska-Łukaszuk, 2018). The first-generation drugs are more prone to induce lipid peroxidation than the most recent ones (Kropp et al., 2005). Despite the repertory of alterations mediated by reactive oxygen species described to date, the precise mechanisms underlying the toxicity of antipsychotics are still incomplete, even at the lowest doses of the drugs. In this scenario, the present study aimed to evaluate the effects of a low dose of Hal on oxidative stress parameters in the brain of rats submitted to an animal model of SZ induced by Ket.