Prevention and reversal of ketamine-induced schizophrenia related behavior by minocycline in mice: Possible involvement of antioxidant and nitrergic pathways

Abstract

It has been hypothesized that oxidative imbalance and alterations in nitrergic signaling play a role in the neurobiology of schizophrenia. Preliminary evidence suggests that adjunctive minocycline treatment is efficacious for cognitive and negative symptoms of schizophrenia. This study investigated the effects of minocycline in the prevention and reversal of ketamine-induced schizophrenia-like behaviors in mice. In the reversal protocol, animals received ketamine (20 mg/kg per day intraperitoneally or saline for 14 days, and minocycline (25 or 50 mg/kg daily), risperidone or vehicle treatment from days 8 to 14. In the prevention protocol, mice were pretreated with minocycline, risperidone or vehicle prior to ketamine. Behaviors related to positive (locomotor activity and prepulse inhibition of startle), negative (social interaction) and cognitive (Y maze) symptoms of schizophrenia were also assessed. Glutathione (GSH), thiobarbituric acid-reactive substances (TBARS) and nitrite levels were measured in the prefrontal cortex, hippocampus and striatum. Minocycline and risperidone prevented and reversed ketamine-induced alterations in behavioral paradigms, oxidative markers (i.e. ketamine-induced decrease and increase in GSH levels and TBARS content, respectively) as well as nitrite levels in the striatum. These data provide a rationale for evaluating minocycline as a novel psychotropic agent and suggest that its mechanism of action includes antioxidant and nitrergic systems.

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

“…Our study also 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]…”

“…In another study elsewhere, minocycline, a tetracycline congener of doxycycline demonstrated significant increase (preventive and reversal) in antioxidant defense systems, decrease in MDA and nitrite levels [13] [15]. In view of this, our findings confirmed that the schizophrenia-like behaviors induced by ketamine was accompanied by increased oxidative stress, as demonstrated by the decreased antioxidant defense systems and increased levels of MDA, respectively.…”

“…Indeed, besides stimulating the schizophrenic phenotypes, chronic ketamine treatment is also known to induce oxidative aberrations which correlates with those described in postmortem brains of individuals with schizophrenia [47]. Also, based on the construct, aetiologic and predictive validity with respect to both clinical phenomena and responsiveness to antipsychotic drugs [13] [16], it was thus, chosen for the present study to evaluate the possible anti-oxidative effects of DOX in the repeated administration of ketamine-induced oxidative alterations.…”

“…During the last decade, the neurotherapeutic potentials of minocycline and doxycycline in the treatment of mental disorders have reasonably increased [7] [12] [13]. However, there is a lack of preclinical studies investigating the psychotropic effects of doxycycline as a therapeutic agent for schizophrenia.…”

“…However, there is a lack of preclinical studies investigating the psychotropic effects of doxycycline as a therapeutic agent for schizophrenia. Indeed, recent findings from preclinical studies suggest possible beneficial effects of minocycline as adjunctive therapy for the treatment of negative and cognitive symptoms of schizophrenia [13] [14]. In this context, the therapeutic properties of doxycycline relative to that of minocycline, suggests that it may also have clinical application in schizophrenia symptomology, most especially against the negative and cognitive symptoms of the disease [15] [16].…”