Post-traumatic seizure susceptibility is attenuated by hypothermia therapy.
Traumatic brain injury (TBI) is a major risk factor for the subsequent development of epilepsy. Currently, chronic seizures after brain injury are often poorly controlled by available antiepileptic drugs. Hypothermia treatment, a modest reduction in brain temperature, reduces inflammation, activates pro-survival signaling pathways, and improves cognitive outcome after TBI. Given the well-known effect of therapeutic hypothermia to ameliorate pathological changes in the brain after TBI, we hypothesized that hypothermia therapy may attenuate the development of post-traumatic epilepsy and some of the pathomechanisms that underlie seizure formation. To test this hypothesis, adult male Sprague Dawley rats received moderate parasagittal fluid-percussion brain injury, and were then maintained at normothermic or moderate hypothermic temperatures for 4 h. At 12 weeks after recovery, seizure susceptibility was assessed by challenging the animals with pentylenetetrazole, a GABA(A) receptor antagonist. Pentylenetetrazole elicited a significant increase in seizure frequency in TBI normothermic animals as compared with sham surgery animals and this was significantly reduced in TBI hypothermic animals. Early hypothermia treatment did not rescue chronic dentate hilar neuronal loss nor did it improve loss of doublecortin-labeled cells in the dentate gyrus post-seizures. However, mossy fiber sprouting was significantly attenuated by hypothermia therapy. These findings demonstrate that reductions in seizure susceptibility after TBI are improved with post-traumatic hypothermia and provide a new therapeutic avenue for the treatment of post-traumatic epilepsy.
Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Coleen M
CM
Atkins
Jessie S
JS
Truettner
George
G
Lotocki
Juliana
J
Sanchez-Molano
Yuan
Y
Kang
Ofelia F
OF
Alonso
Thomas J
TJ
Sick
W Dalton
WD
Dietrich
Helen M
HM
Bramlett
D000818:Animals; D001831:Body Temperature; D001930:Brain Injuries / Q000150:complications*; D000089662:Doublecortin Protein; D004834:Epilepsy, Post-Traumatic / Q000209:etiology* / Q000628:therapy*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D007036:Hypothermia, Induced; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley