Ryanodex Reduces Persistent Hippocampal Effects of Single Mild Traumatic Brain Injury in Rats

Traumatic brain injury (TBI) affects millions of individuals annually, with a 53% increase in emergency visits since 2006. Despite its prevalence, no FDA-approved treatments exist to mitigate brain damage or promote recovery. While repeated TBI is widely studied, even a single impact can cause persistent neurological changes, likely mediated by Ca²⁺ dysregulation via effects on ryanodine receptors. In a rat model of mild TBI, using a single closed-head controlled cortical impact, we observed no changes in the levels of hippocampal glial fibrillary acidic protein and phosphorylated tau-both markers of cellular damage. However, mild TBI (mTBI) significantly enhanced synaptic transmission at hippocampal CA3-CA1 synapses and increased CA1 pyramidal cell excitability for at least 30 days-effects that were significantly attenuated by acute and subacute injection of Ryanodex, a concentrated nanocrystalline formulation of the ryanodine receptor allosteric modulator dantrolene. Ryanodex may, therefore, offer a promising intervention to reduce persistent hippocampal dysfunction following mTBI, with potential clinical applications for acute TBI treatment.