Substance P Blockers May Prevent Brain Damage Leading to CTE After Head Injuries

NK1 receptor antagonists attenuated tau hyperphosphorylation after blast and concussive TBI by modulating Akt, ERK1/2, and JNK kinases, with the mechanism initiated by TRPV1 mechanoreceptor-mediated substance P release.

Mouse models of single moderate TBI, repeated concussive TBI, and blast-induced mild TBI. Post-injury NK1 antagonist or pre-injury TRPV1 inhibitor treatment. Tau phosphorylation analysis, kinase activity assessment, and neurological outcome testing.

CTE is a devastating neurodegenerative disease affecting athletes and military personnel with no prevention or treatment. Identifying that substance P mediates the initial tau pathology opens a potentially practicable therapeutic window for preventing CTE after known head injuries.

CTE has gained enormous attention as a cause of cognitive decline and behavioral changes in athletes and veterans, but no preventive treatment exists. This study identifies a druggable pathway — substance P/NK1R — and suggests that existing NK1 antagonists (already FDA-approved for other uses) could potentially be repurposed to prevent CTE after head injuries.

Mouse study — TBI models may not perfectly replicate human concussions or blast exposure. Post-injury treatment timing and duration for optimal effect not fully established. Long-term CTE prevention not demonstrated (only acute tau phosphorylation).