Abstract
Schizophrenia remains one of the most chronic and highly disabling mental disorders. Lumateperone is a recent FDA-approved atypical antipsychotic drug for the treatment of schizophrenia. However, the internal FDA pathologist raised concerns regarding pigment deposition associated with degeneration in different tissue in animal studies with lumateperone treatment. The adrenal gland may be implicated in lumateperone side effects, and quercetin may have the ability to fulfill this treatment gap. To prove this hypothesis, 40 male guinea pigs were used and divided into four groups; control, quercetin-treated, lumateperone-treated, and quercetin/lumateperone cotreated orally for 28 consecutive days. Behavioral forced swim (FST) and open field (OF) tests were done at the end of treatment. Retro-orbital blood samples were taken to assess hormones: adrenocorticotropic hormone (ACTH), cortisol, dehydroepiandrosterone acetate (DHEA), and aldosterone, along with an assessment of oxidative stress parameters: malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD). Adrenal glands were extracted for histopathological assessment with H&E, Mallory trichome staining, immunostaining, and electron microscopy studies. Lumateperone-treated group showed a significant reduction in the activity in FST and OF with histopathological deterioration in adrenal secretory function and structure and increased expression of interleukin-6 (IL-6), CASPASE-3, collagen deposition, and decreased proliferating cell nuclear antigen (PCNA). Cytoplasmic vacuolation, pyknosis of the nuclei, increase in the lysosome, lipofuscin pigment, and cellular infiltration with diminishing in the number of secretory granules could all be observed in lumateperone-treated group. Coadministration of quercetin and lumateperone showed improvement of the previously deteriorated parameters. Quercetin had a prophylactic effect against lumateperone depressive-like effect on animal behavior and its possible adrenal damage.Graphical Conceptual framework for the proposed mechanism of action of coadministration of quercetin and lumateperone.
Highlights
Schizophrenia (SCZ) is a serious psychiatric condition associated with hallucinations or delusions coupled with disorganized speech, disorganized thinking, or negative symptoms present for at least 6 months (Andreasen and Olsen, 1982; OrricoSánchez et al, 2020)
Electron Microscopic Results Transmission electron microscopic finding of the adrenal gland of control group appeared ordinary cells in Zona Glomerulosa (ZG) of suprarenal cortex with plenteous lipid beads, rounded nucleus encompassed by a nuclear envelope with conspicuous nucleolus with peripheral heterochromatin
The current study aimed to identify the effects of administering an atypical antipsychotic drug, lumateperone alone or with quercetin, on animal behavior and adrenal gland functions
Summary
Schizophrenia (SCZ) is a serious psychiatric condition associated with hallucinations or delusions coupled with disorganized speech, disorganized thinking, or negative symptoms present for at least 6 months (Andreasen and Olsen, 1982; OrricoSánchez et al, 2020). Negative symptoms include lack of expression, significant reduction in speech/communication, lack of motivation, and decreased social drive (American Psychiatric Association, 1994; Leo and Regno, 2000). Second-generation antipsychotics target more specific dopamine and often serotonin receptors with fewer dystonic side effects; they come with additional concern with the development of metabolic syndrome (Meltzer and McGurk, 1999; Harvey et al, 2016; Remington et al, 2016)
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