Characterizing a Preclinical Model for Evaluating the Efficacy of a CGRP Monoclonal Antibody Treatment for Post-Traumatic Headaches Following Repeated Blast Neurotrauma

Abstract

Blast-induced traumatic brain injury (bTBI) is a common consequence of combat exposure among active-duty military personnel and Veterans. Repeated blast exposures can lead to a range of persistent and debilitating symptoms, including post-traumatic headaches (PTH), depression, and anxiety, which may endure for months or even years post-injury. With the increasing number of women serving in the military, emerging evidence suggests that sex differences influence both the physical and psychological outcomes following bTBI. Notably, female service members and Veterans are more likely than males to report headache pain, depressive symptoms, and non-PTSD anxiety disorders following head trauma. Despite the high prevalence of PTH, its underlying pathophysiological mechanisms, particularly in females, remain poorly understood. Several mechanistic pathways have been implicated in PTH development, many of which overlap with established migraine neurobiology, including dysregulation of the trigeminovascular system, neuropeptide signaling, and neuroinflammatory responses. Furthermore, there is a critical gap in knowledge regarding the efficacy of targeted therapeutics for treating PTH in the TBI population. However, a more comprehensive and sex-inclusive understanding of these pathways is essential to inform effective treatment strategies for individuals affected by blast-related head trauma.

The objective of this work was to characterize a preclinical model of repeated blast TBI (rbTBI) that results in pain-related behaviors and neurobiological changes at chronic time points in both sexes. Using a rodent model of rbTBI, repeated blast exposure produced long-lasting facial mechanical hypersensitivity and persistent anxiety- and depression-like behaviors in males. These outcomes were paralleled by time-dependent elevations in glial reactivity, and region-specific up- or down-regulation of calcitonin gene-related peptide (CGRP) and substance P (SP). Female blast-exposed rats developed comparable chronic hypersensitivity and depression-like behavior but did not present with an anxiety-like phenotype. Injured females exhibited robust glial activation in the absence of any significant chronic up-regulation of CGRP or SP, suggesting a sex-specific divergence in neuropeptide signaling. Currently, there are no specific treatments 3targeting the underlying mechanisms of TBI and PTH due to the lack of understanding of the underlying pathology of the conditions. This work also evaluated the therapeutic efficacy of a calcitonin gene-related peptide monoclonal antibody (CGRP mAb) for the prevention of PTH.CGRP mAb administration successfully targeted the CGRP signaling pathway. However, it failed to ameliorate pain hypersensitivity, affective disturbances, or glial activation. Collectively, these findings establish a sex-inclusive, chronic bTBI model of PTH and demonstrate that isolated CGRP blockade is insufficient to reverse PTH-like phenotypes, despite effective target suppression. This data highlights the necessity of multi-modal therapeutic approaches that concurrently address neuroimmune activation and nociceptive signaling in blast-induced PTH. While much remains to be understood about the development of PTH following bTBI, this work advances our knowledge of the underlying pathology and provides valuable insight that may inform more effective treatment strategies for this condition.