Treatment of neuroinflammation for remediation of chemoradiation-induced dysphagia

Chemoradiation (CRT) to the head and neck for cancer treatment exposes normal tissues to radiation, which has many devastating effects and often results in difficulty with speech and swallowing. Acute effect of radiation-induced peripheral neuropathy (RIPN) includes transient electrophysiological and biochemical changes combined with altered vascular permeability followed by demyelination. RIPN of either motor or sensory nerves in the head and neck could cause major disruption to the deglutition process including reduced tongue force and reflexive airway protection. Pharmaceutical interventions such as glibenclamide (GLC) have been shown to reduce inflammatory cytokines such as tumor necrosis factor (TNFα) and interleukin 6 (IL-6), decrease oxidative stress, increased neurotrophic factors, and increase the myelin sheath in response to peripheral nerve injury. However, controlled research examining these putative benefits of GLC for the treatment of RIPN in the oral motor cavity has not been performed and optimal treatment modalities or timelines have not been established. Our hypothesis is CRT delivered to the base of the tongue creates neuroinflammation in the PNS and CNS and that GLC therapy with the early implementation of tongue exercise can mitigate the neurogenic source of dysphagia and improve swallow-related physiologic outcomes. To examine these clinically-relevant issues, we will use a rat model to test tongue exercise and GLC treatment for the remediation of chemoradiation-induced muscle damage. The proposed research has two specific aims: 1): To test the hypothesis that treatment with GLC and tongue exercise will improve functional measures of deglutition in a rat animal model of head and neck CRT. 2): To test the hypothesis that the use of a GLC and tongue exercise will mitigate inflammation of the PNS and CNS following CRT. This work is innovative and significant because the mechanisms by which GLC treatment combined with tongue exercise can prevent or treat the effects of chemoradiation-induced speech and swallowing dysfunction is unexplored. Our animal model and treatment are analogs to treatments used in human patients and follow the Institute of Medicine guidelines for increasing translation. Further, this work is highly significant in providing a basis for understanding the mechanisms underlying the potential of therapeutic interventions for chemoradiation-induced dysphagia. Translation of findings will assist with increasing the effectiveness of treatments for chemoradiation-induced tongue muscle impairments that are so prevalent in patients with head and neck cancer. Project Number: 1R01CA301371-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: John Russell | Institution: UNIVERSITY OF WISCONSIN-MADISON, MADISON, WI | Award Amount: $634,644 | Activity Code: R01 | Study Section: Motor Function, Speech and Rehabilitation Study Section[MFSR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11295624