PROTECTIVE EFFICACY OF C381 IN COCAINE-INDUCED MICROGLIAL ACTIVATION AND NEUROINFLAMMATION

Study Overview: Cocaine use disorder (CUD) remains a significant public health challenge in the United States, with rising prevalence and cocaine-related mortality in Nebraska highlighting an urgent unmet need for effective preventive strategies. Cocaine exposure induces persistent microglial activation, lysosomal-mitochondrial dysfunction, and neuroinflammatory signaling that collectively drive neuronal injury and behavioral impairments. Despite growing recognition of these mechanisms, no targeted interventions currently exist to prevent cocaine-induced neuroimmune and organelle-specific pathology in the brain. This pilot project seeks to evaluate the preventive efficacy of C381, a novel lysosome-targeting small molecule, in an in vivo mouse model of cocaine administration. We hypothesize that C381 administration will mitigate cocaine-induced lysosomal-mitochondrial dysfunction, suppress microglial activation, and attenuate neuroinflammatory signaling. In parallel, this study will determine whether C381 prevents cocaine-associated behavioral deficits, thereby linking molecular protection to functional outcomes. Successful completion of this proof-of-concept study will provide the first in vivo evidence supporting C381 as a preventive strategy against cocaine-induced neurotoxicity.

Biography: My research focuses on elucidating the molecular mechanisms by which microglial dysfunction drives neuroinflammation and neuronal injury in substance use disorders. I investigate how drugs of abuse alter microglial signaling through lysosomal dysfunction, inflammasome activation, oxidative stress, and extracellular vesicle-mediated communication, leading to aberrant neuron-microglia interactions. My research also emphasizes the discovery and preclinical evaluation of small molecule therapeutics that restore microglial homeostasis, attenuate neuroinflammatory signaling, and preserve neuronal function. By integrating molecular neuroscience and translational approaches, my goal is to develop innovative therapies for substance use disorders and related neuroinflammatory diseases.