Valproic Acid Inhibits Chronic Toxoplasma Infection and Associated Brain Inflammation in Mice

Individuals infected with Toxoplasma gondii are prone to psychobehavioral disorders, most notably schizophrenia and bipolar disorder. Valproic acid reportedly inhibits the proliferation of T. gondii tachyzoites in vitro. However, animals treated with the drug neither lived longer during acute infection nor had fewer brain cysts upon chronic infection. In this study, a quantitative real-time PCR (qPCR) method was applied to quantify copy numbers of BAG1 (a bradyzoite-specific protein), REP529 DNA (a repetitive DNA fragment of the parasite), and SAG1 (a highly expressed tachyzoite-specific surface protein) in the brains of chronically infected mice treated with valproic acid. The treatment inhibited the infection and decreased BAG1, SAG1, and REP529 copy numbers in mice brains (P < 0.0001), comparable to the effects of trimethoprim-sulfamethoxazole (TMP-SMZ), the common medication for toxoplasmosis treatment. Moreover, valproic acid decreased brain tumor necrosis factor alpha (TNF-alpha) expression (P < 0.0001) comparably to TMP-SMZ. Histological examination of mouse brains showed marked reductions in cyst establishment, perivascular infiltration of lymphocytes, and glial nodules to the same levels as those in the TMP-SMZ group. Our results provide direct evidence for the efficacy of valproic acid, a mood-stabilizing and antipsychotic drug, against chronic Toxoplasma infection. These results might help modulate therapeutic regimens for neuropsychiatric patients and aid in the design of more effective anti-Toxoplasma drugs.