Effect of Physical Exercise on Acute Post-traumatic Hyperexcitability: The Role of Thrombin/PAR1 Signaling

Traumatic brain injury (TBI) is a leading cause of long-term neurological disability worldwide. Among its complications, post-traumatic seizures (PTS) can exacerbate injury outcomes and increase the risk of developing post-traumatic epilepsy (PTE), particularly in severe cases. This study investigated the role of thrombin/PAR1 signaling in early post-traumatic hyperexcitability and evaluated whether prior physical exercise could mitigate excitability-related mechanisms, such as blood-brain barrier (BBB) disruption and ionic imbalance following TBI. The investigation comprised two separate experiments using the lateral fluid-percussion injury (LFPI) model. In the first, male rats underwent LFPI and were assessed via electroencephalographic (EEG) recordings, followed by biochemical analysis of the ipsilateral hippocampus six hours post-injury. In the second, animals were randomly assigned to sedentary or exercise groups. After four weeks of aerobic training, animals received a PAR1 antagonist for one week and then underwent the same injury and evaluation protocols. Our results show that prior physical exercise and PAR1 antagonism significantly reduced LFPI-induced epileptiform activity, as evidenced by lower EEG total power, amplitude, and interictal spike frequency. These interventions also preserved BBB integrity, reduced thrombin extravasation, modulated PAR1 and downstream PKC/P70S6K signaling, and mitigated astrocytic reactivity and Na⁺/K⁺-ATPase dysfunction. Furthermore, both treatments inhibited GABAergic dysregulation and decreased pro-inflammatory cytokine levels, thereby attenuating the neurotoxic post-injury environment. These findings highlight the critical role of thrombin/PAR1 signaling in PTS and support the neuroprotective potential of physical exercise in modulating post-traumatic excitability, offering a promising therapeutic strategy for preventing PTE.