Doxycycline Ameliorates Schizophrenia-Like Behaviors in Experimental Models in Mice by Targeting Underlying Oxidative Stress

Abstract

Current evidences support the inhibition of oxidative and inflammatory signaling mechanisms in the treatment of schizophrenia; as cure for this disease still remains limited. Doxycycline is a tetracycline antibiotic (a minocycline congener) with strong antioxidant and anti-inflammatory properties, and better pharmacokinetic profiles. Preclinical evidence indicates that minocycline possesses antipsychotic properties. This present study was designed to evaluate the effect of doxycycline on schizophrenialike behaviors, as well as biomarkers of oxidative stress in mice brains. Noveltyinduced rearing (NIR) behavior was used to evaluate the tranquilizing effect of doxycycline (25 -200 mg/kg). The acute antipsychotic effects of doxycycline were assessed using apomorphine-induced stereotypy, ketamine-induced stereotypy, hyperlocomotion and enhanced immobility in forced swim test (FST). Catalepsy test was also employed to evaluate the extrapyramidal adverse effect of doxycycline in mice. The chronic antipsychotic effect of doxycycline was evaluated following oral administration of doxycycline in combination with ketamine (100 mg/kg) intraperitoneally for 10 days. Twenty four hours after the last administration, positive (locomotor activity), cognitive (Y-maze) and negative (FST) symptoms were assessed. Thereafter, levels of biomarkers of oxidative stress were evaluated in mice brains. Doxycycline significantly (P < 0.05) decreased NIR, inhibited stereotypy induced by apomorphine and ketamine. Additionally, doxycycline significantly (P < 0.05) prevented ketamineinduced hyperlocomotion, cognitive deficit and reduced enhanced-immobility by ketamine in mice. Furthermore, doxycycline decreased malondialdehyde concentrations in a dose-related manner. Moreover, doxycycline significantly (P < 0.05) prevented the decrease in glutathione, and increased activities of superoxide dismutase and catalase in brain tissues. The results from this study suggest that doxycycline 540ameliorated schizophrenic-like behaviors via mechanisms related to attenuation of oxidative stress in mouse brain.