Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Eur J Neurosci. 2010 Dec;32(11):1912-20. doi: 10.1111/j.1460-9568.2010.07467.x. Epub 2010 Oct 29.
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.
创伤性脑损伤 (TBI) 是随后发生癫痫的主要危险因素。目前，脑损伤后的慢性癫痫发作往往难以用现有的抗癫痫药物控制。低温治疗，即适度降低脑温，可以减轻炎症、激活生存促进信号通路，并改善 TBI 后的认知结果。鉴于治疗性低温对 TBI 后大脑病理性变化的明显改善作用，我们假设低温治疗可能会减轻创伤后癫痫的发展以及一些导致癫痫形成的病理机制。为了验证这一假设，成年雄性 Sprague Dawley 大鼠接受中度旁矢状缝液压脑损伤，然后在正常体温或中度低温下维持 4 小时。在恢复后 12 周，通过戊四氮（GABA(A) 受体拮抗剂）挑战动物来评估癫痫易感性。与假手术动物相比，TBI 常温动物的戊四氮诱发癫痫发作的频率显著增加，而 TBI 低温动物的这种增加则显著减少。早期低温治疗不能挽救慢性齿状回颗粒神经元丢失，也不能改善癫痫发作后齿状回双皮质素标记细胞的丢失。然而，苔藓纤维发芽显著被低温治疗所抑制。这些发现表明，TBI 后癫痫易感性的降低可以通过创伤后低温来改善，并为创伤后癫痫的治疗提供了新的治疗途径。
