Peripheral Infection after Traumatic Brain Injury Augments Excitability in the Perilesional Cortex and Dentate Gyrus

Abstract

Peripheral infections occur in up to 28% of patients with traumatic brain injury (TBI), which is a major etiology for structural epilepsies. We hypothesized that infection occurring after TBI acts as a “second hit” and facilitates post-traumatic epileptogenesis. Adult male Sprague–Dawley rats were subjected to lateral fluid-percussion injury or sham-operation. At 8 weeks post-injury, rats were treated with lipopolysaccharide (LPS, 5 mg/kg) to mimic Gram-negative peripheral infection. T2-weighted magnetic resonance imaging was used to detect the cortical lesion type (small focal inflammatory [TBIFI] vs. large cavity-forming [TBICF]). Spontaneous seizures were detected with video-electroencephalography, and seizure susceptibility was determined by the pentylenetetrazole (PTZ) test. Post-PTZ neuronal activation was assessed using c-Fos immunohistochemistry. LPS treatment increased the percentage of rats with PTZ-induced seizures among animals with TBIFI lesions (p < 0.05). It also increased the cumulative duration of PTZ-induced seizures (p < 0.01), particularly in the TBIFI group (p < 0.05). The number of c-Fos immunopositive cells was higher in the perilesional cortex of injured animals compared with sham-operated animals (p < 0.05), particularly in the TBI-LPS group (p < 0.05). LPS treatment increased the percentage of injured rats with bilateral c-Fos staining in the dentate gyrus (p < 0.05), particularly in the TBIFI group (p < 0.05). Our findings demonstrate that peripheral infection after TBI increases PTZ-induced seizure susceptibility and neuronal activation in the perilesional cortex and bilaterally in the dentate gyrus, particularly in animals with prolonged perilesional T2 enhancement. Our data suggest that treatment of infections and reduction of post-injury neuro-inflammation are important components of the treatment regimen aiming at preventing epileptogenesis after TBI.

Pre-existing Toxoplasma gondii infection increases susceptibility to pentylenetetrazol-induced seizures independent of traumatic brain injury in mice

“…In addition, pre-clinical studies indicate that peripheral inflammation and cerebral infection can alter susceptibility to seizures via either a primed immune environment or changes to brain pathophysiology ( Ho et al, 2015 ; Grauncke et al, 2016 ; Ssentongo et al, 2017 ; Huang et al, 2018 , 2022 ). However, in the context of PTE, infection has only been considered as a “second-hit” on the back of the neuroinflammatory processes of TBI, rather than as a pre-existing insult or concurrent factor that can modify the neuroinflammatory environment, neural connectivity, and gross anatomy ( Sharma et al, 2021 ; Wang et al, 2021 ).…”

Pathogenesis and Targeted Therapy of Epilepsy

“…Similarly, dysregulation of PP2B-ERK1/2-SGK1-NEDD4-2-mediated GRIA1 ubiquitination may also contribute to AMPA receptor antagonists’ refractory seizures [ 7 ]. In a model of traumatic brain injury (TBI), Wang et al [ 6 ] report that peripheral infection after TBI increases neuronal excitability and facilitates post-traumatic epileptogenesis in the pentylenetetrazole model of seizures [ 8 ]. Furthermore, Ndoke-Ekane et al [ 9 ] provide evidence that magnetic resonance imaging (MRI) improves the placement accuracy of intracerebral electrode implantation and that chronically implanted electrodes do not increase cortical and hippocampal atrophy in a rat model of post-traumatic epilepsy.…”