Pharmacological modulation of macrophage phenotype as a novel neuroprotective strategy following TBI.

Given the magnitude and scope of long-term difficulties faced by patients that suffer a TBI, the lack of reliable therapeutics represents a tremendous clinical need. Since the majority of brain injuries occur in adolescents or young adults, the severity of the problem is magnified. Moreover the recent failure of several Phase III clinical trials in neurotrauma underscores the need for improved therapeutic modalities. The acute and chronic molecular, cellular, biochemical and pathophysiological events that follow TBI are complex and multi-factorial. The overall arching hypothesis of this research is that pharmacological treatments that induce macrophage polarization to the M2 phenotype can cause neuroprotection and enhancement of behavioral recovery following brain injury. In the first Specific Aim of this proposal will evaluate the neuroprotective effects of partial agonists of the alpha 7 nicotinic cholinergic receptor. The second Aim will perform similar experiments with the antibiotic azithromycin. The current studies will use 2 independent, but complementary approaches to control brain inflammation: alpha 7 nAChR modulation and AZM treatment. These novel studies will employ the unique expertise of three investigators. Dr. Pauly is a neuropharmacologist with several years of relevant experience in rat and mouse TBI models, alpha 7 nAChR pharmacology and behavioral analyses following trauma. Dr. Gensel is a new faculty member at UK, but not new to neurotrauma research. His previous experience in the area of macrophage phenotype quantitative PCR, immunohistochemistry and neuroprotection in spinal cord injury is a major asset to the present studies. Most of Dr. Feola’s previous research experience is in the area of infectious disease. In a mouse model of cystic fibrosis, Dr. Feola has shown the AZM treatment causes alternative activation of macrophages, which results in improved symptomology in infected mice. Thus his knowledge of AZM dosing schemes and macrophage polarization in rodent models bring added expertise to the research team. Dr. Feola also has previous experience with flow cytometry will be used to measure macrophage alpha 7 nAChRs. Controlling inflammation following TBI is an essential component of the recovery process. The proposed studies will use 2 distinct pharmacological approaches to accomplish the same goal. Macrophages directed to the M2 phenotype are thought to provide anti-inflammatory actions in a number of diverse models. Alpha 7 partial agonists and azithromycin are each easily translatable to clinical scenarios, and may be novel approaches to improve TBI patient recovery and rehabilitation.