Plumbagin Alleviates Mild Traumatic Brain Injury‐Induced Obsessive‐Compulsive Disorder in Mice by Inhibiting <scp>nNOS</scp> and Augmenting Cortico‐Striatal Serotonin Levels

Increased nitric oxide activity in the medial prefrontal cortex (mPFC) and striatum plays a key role in the pathogenesis of obsessive-compulsive disorder (OCD) by lowering serotonin contents and triggering neurodegeneration. Since molecular docking analysis revealed plumbagin as a potent inhibitor of neuronal nitric oxide synthase (nNOS) enzyme, this study aims to investigate the ameliorative potential of plumbagin on mild traumatic brain injury (mTBI)-induced OCD-like behavior in mice. Following mTBI, the mice were administered with plumbagin (1 mg/kg, intraperitoneal) for 6 days. Animals were subjected to rotarod, open field and beam walk tests for studying neuromuscular functions, and marble-burying test for evaluating OCD phenotypes. Subsequently, the brains were processed for Golgi-Cox and crystal violet stainings to examine dendritic arborization and cell viability in the mPFC and striatum. Moreover, the contents of serotonin and nitric oxide in these regions were quantified using high-performance liquid chromatography (HPLC) and enzyme-linked immunosorbent assay (ELISA), respectively. Plumbagin improved neuromuscular functions and reduced marble-burying behavior. Also, dendritic arborization, cell viability, and serotonin levels in the mPFC and striatum were improved. However, concentrations of nitric oxide were significantly decreased in these brain regions. The data of this study suggest that plumbagin by inhibiting nNOS might reverse the mTBI-associated degenerative neuronal changes in the mPFC and striatum. Furthermore, neuronal survival might promote cortico-striatal serotonergic neurotransmission to mitigate OCD-like behavior. Thus, plumbagin seems to be a promising therapeutic candidate for the management of OCD associated with traumatic brain injuries.