This project will explore calcium-release-activated calcium channels (CRAC) as a potential therapeutic target in a laboratory model of traumatic brain injury (TBI). TBI is a common problem in the Veteran and civilian populations but definitive treatments are few. Microglia are the brain’s resident immune cell, and many studies have now shown that when activated, they contribute negatively to neurological outcome. Thus, strategies to inhibit microglial functions could prove therapeutic. Recent work has focused on the role of CRAC channels in inflammatory cells such as T cells, mast cells and neutrophils, and other inflammatory conditions such as autoimmune disease and acute pancreatitis; however, very little work has been published on CRAC channels as they pertain to microglia or inflammation in the brain. Past work has focused on calcineurin inhibitors such as cyclosporine A and FK 506 which act downstream of the CRAC channel, but have many off target effects and clinical toxicities which limit their use. These CRAC channel inhibitors are already being studied at the clinical level for other indications, and do not appear to have the same toxicities as the CNIs. In fact, a similar inhibitor produced by the same company was recently shown to improve outcome from severe COVID-19 pneumonia following infection with the SARS-CoV-2 virus, and was well tolerated in this patient population. Prior work in our lab showed that these specific CRAC channel inhibitors block microglial activation and that at least one of these inhibitors protects the brain from experimental TBI. This project will study CRAC channel inhibitors in a model of TBI to further define the conditions where neuroprotection may be observed. The first Aim will determine the more protective of two such novel CRAC channel inhibitors, and determine the optimal dosing required for maximum neurological benefit. This aim will also validate the specificity of the inhibitors and the expected mechanism of action of downstream calcium and inflammatory signaling. The second aim will then determine whether treatment can be delayed by hours and still show improvement in neurological outcomes. The third aim will then use the optimal dose and dosing regimen determined from the first two aims to see if any benefit is long lasting. In vivo experiments will include studies in female animals as well as comparing these novel, specific inhibitors to currently available, but less specific inhibitors.