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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 schizophrenia-like behaviors, as well as biomarkers of oxidative stress in mice brains. Novelty-induced 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 P 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 ameliorated schizophrenic-like behaviors via mechanisms related to attenuation of oxidative stress in mouse brain.
Highlights
Psychosis (e.g., Schizophrenia) is a heterogeneous neuropsychiatric disorder characterized by distorted or non-existent sense of reality [1]
The results of this study revealed that single and repeated administration of doxycycline ameliorated schizophrenia-like behaviors and reduced the increased brain levels of biomarkers of oxidative stress induced by repeated administration of ketamine
Our study showed that risperidone, an atypical antipsychotic agent, demonstrated an increase in the antioxidant defense mechanisms with a significant decrease in MDA levels compared to ketamine treated animals, which is in line with previous findings [13] [38] [48], and further supports the role of oxidative stress in the pathophysiology of schizophrenia
Summary
Psychosis (e.g., Schizophrenia) is a heterogeneous neuropsychiatric disorder characterized by distorted or non-existent sense of reality [1]. First-generation antipsychotics are responsive in reducing the positive symptoms, these agents have been relatively less effective in ameliorating the severity of negative and cognitive deficits, and are limited by their high tendency to produce extrapyramidal side effects, due to excessive blockade of dopaminergic D2 receptors [5]. The need for newer antipsychotic agents with multipronged mechanisms of action that could target various aspects of the pathologies of schizophrenia has become imperative [7] [8] To this end, the second-generation tetracycline antibiotic drugs (e.g., minocycline, doxycycline) have recently been attracting much attention in neuropsychiatric preclinical researches due to their antioxidant and anti-inflammatory/immunomodulatory mechanisms of action [9]
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