Voluntary running wheel activity reduces seizure burden and affords neuroprotection in a mouse model of acquired epilepsy.

Abstract

Objective: Physical exercise may improve neurological deficits and neuronal damage after acute brain injuries and decrease established seizures. We investigated whether voluntary running wheel (RW) activity affects epileptogenesis in a mouse model of acquired epilepsy compared to sedentary mice.

Methods: Epilepsy was induced by intra-amygdala kainate causing status epilepticus (SE) in adult male mice. Sham mice were implanted with electrodes and injected with saline, and matched to experimental mice. In the RW-1 protocol, SE mice were trained to run for 5 weeks before SE induction and for 6 weeks thereafter. In the RW-2 protocol, mice began using RWs 24 h post-SE for 10 weeks. At the end of each protocol, electrocorticography (ECoG) was recorded for 2 weeks (24/7) in the absence of RWs. Matched sedentary mice were kept in home cages without RWs, subjected to SE, and had ECoG monitored. At the end of experiment, all mice were processed for assessing hippocampal neuronal cell loss (Nissl staining), hilar mossy cells (GLUR2/3 staining), and blood-brain barrier (BBB) damage (serum matrix metalloproteinase-9 [MMP-9] by enzyme-linked immunosorbent assay). Neuroinflammation (reverse-transcriptase quantitative polymerase chain reaction) and albumin level (western blot) were also measured in the hippocampus of RW1 mice 72 h post-SE, together with serum MMP-9.

Results: RW activity in SE mice reduced the incidence of epilepsy (RW-1 by 38%; RW-2 by 54%, p < .05) and the total time spent in seizures (RW-1, p < .05; RW-2, p < .01) compared to sedentary mice. RW-1 SE mice showed reduced average seizure duration (p < .01), whereas RW-2 SE mice showed reduced number of seizures (p < .01). Reduction in seizure duration was associated with prevention of GluR2/3-positive mossy cell loss, which occurs in sedentary SE mice (p < .01 vs sham mice). Seizure duration in epileptic mice was negatively correlated with the number of hilar mossy cells (p < .01). Preventive RW-1 activity reduced SE duration and severity (p < .05) vs sedentary mice. Aberrant neurogenesis was reduced in the dentate gyrus of SE mice subjected to RWs (p < .01) vs sedentary mice. Serum MMP-9 and brain albumin levels were reduced in SE mice exposed to running activity (p < .05) compared to sedentary mice.

Significance: Physical exercise reduced seizure burden and neuropathology in mice, offering a strategy to improve disease outcomes after acute brain injury.