A Combination of Low Doses of Lithium and Valproate Improves Cognitive Outcomes after Mild Traumatic Brain Injury

The prevalence of mild traumatic brain injury (mTBI) is high compared with moderate and severe TBI, comprising almost 80% of all brain injuries. mTBI activates a complex cascade of biochemical, molecular, structural, and pathological changes that can result in neurological and cognitive impairments. These impairments can manifest even in the absence of overt brain damage. Given the complexity of changes triggered by mTBI, a combination of drugs that target multiple TBI-activated cascades may be required to improve mTBI outcomes. It has been previously demonstrated that cotreatment with the U.S. Food and Drug Administration (FDA)-approved drugs lithium plus valproate (Li + VPA) for 3 weeks after a moderate-to-severe controlled cortical impact injury reduced cortical tissue loss and improved motor function. Since both lithium and valproate can exhibit toxicity at high doses, it would be beneficial to determine if this combination treatment is effective when administered at low doses and for a shorter duration, and if it can improve cognitive function, after a mild diffuse TBI. In the present study, we tested if the combination of low doses of lithium (1 mEq/kg or 0.5 mEq/kg) plus valproate (20 mg/kg) administered for 3 days after a mild fluid percussion injury can improve hippocampal-dependent learning and memory. Our data show that the combination of low-dose Li + VPA improved spatial learning and memory, effects not seen when either drug was administered alone. In addition, postinjury Li + VPA treatment improved recognition memory and sociability and reduced fear generalization. Postinjury Li + VPA also reduced the number of anti-ionized calcium binding adaptor molecule 1 (Iba1)-positive microglia counted using a convolutional neural network, indicating a reduction in neuroinflammation. These findings indicate that low-dose Li + VPA administered acutely after mTBI may have translational utility to reduce pathology and improve cognitive function.