Cannabidiol reverses myeloperoxidase hyperactivity in the prefrontal cortex and striatum, and reduces protein carbonyls in the hippocampus in a ketamine-induced schizophrenia rat model.

In a rat model of schizophrenia induced by ketamine, cannabidiol (CBD) restored rearing behavior (a measure of exploratory activity) without causing anhedonia-like behavior, whereas risperidone further reduced rearing and induced anhedonia-like effects in control rats. CBD reversed ketamine-induced increases in myeloperoxidase activity in the prefrontal cortex and striatum and protein carbonyls in the hippocampus, while risperidone reduced protein carbonyls in the prefrontal cortex and lowered the nitrite/nitrate ratio in the hypothalamus. Both compounds reduced oxidative stress and neuroinflammation in the striatum, hippocampus, and prefrontal cortex, but CBD did so more broadly and without the side effects seen with risperidone. These findings suggest CBD's antipsychotic effects may stem from its antioxidant and anti-inflammatory properties.

Study at a glance

Abstract

Schizophrenia (SCZ) has limited treatment options, often with significant side effects. Cannabidiol (CBD), a non-euphoric phytocannabinoid, has shown potential as a novel therapeutic option in SCZ due to antipsychotic-like, anti-inflammatory, and antioxidant properties. We compared the therapeutic effects of CBD and risperidone (RISP) in a rat model of SCZ induced by sub-chronic ketamine (KET), focusing on inflammatory and oxidative stress, and behavioral phenotypes. Rats were pre-treated with KET or saline (SAL) for 10 days followed by CBD or RISP for 8 days. Locomotion, anxiety- and anhedonia-like behavior, and recognition memory were assessed. Oxidative damage as measured by protein carbonyls, thiobarbituric acid reactive substances, and catalase activity, and the inflammation markers myeloperoxidase (MPO) activity and nitrite/nitrate (N/N) concentration ratio were assessed in the prefrontal cortex (PFC), hypothalamus (HYP), hippocampus (HPC), and striatum, brain areas relevant to SCZ. CBD restored the KET-induced decreased rearing behavior in the OFT, while RISP further decreased rearing. RISP treatment in control rats decreased rearing and elicited an anhedonic-like phenotype, while CBD did not. CBD, but not RISP restored the KET-induced increased levels of MPO activity in the PFC and the striatum, and protein carbonyls in the HPC. Post-KET treatment with RISP but not CBD decreased protein carbonyls in the PFC, and decreased the N/N concentration ratio in the HYP. CBD restored the KET-induced decrease in rearing behavior without inducing an anhedonic-like phenotype as observed with RISP. CBD, and to a lesser extent RISP restored the oxidative stress and neuroinflammation elicited by KET in the striatum, HPC, and PFC. These findings support the possibility that the antipsychotic effects of CBD might be mediated by its antioxidant and anti-inflammatory effects.