Campbell John N, Gandhi Anandh, Singh Baljinderjit, Churn Severn B
Anatomy and Neurobiology, Virginia Common Wealth University, Richmond, VA.
Neurology, Virginia Commonwealth University, Richmond, VA.
Int J Neurol Brain Disord. 2014;1(1):1-11. doi: 10.15436/2377-1348.14.002.
Epilepsy is a significant but potentially preventable complication of traumatic brain injury (TBI). Previous research in animal models of acquired epilepsy has implicated the calcium-sensitive phosphatase, calcineurin. In addition, our lab recently found that calcineurin activity in the rat hippocampus increases acutely after lateral TBI. Here we use a calcineurin inhibitor test whether an acute increase in calcineurin activity is necessary for the development of late post-traumatic seizures. Adult rats were administered the calcineurin inhibitor Tacrolimus (5mg/kg; i.p.) 1 hour after lateral fluid percussion TBI and then monitored by video-electrocorticography (video-ECoG) for spontaneous seizure activity 5 weeks or 33 weeks later. At 5 weeks post-TBI, we observed epileptiform activity on the video-ECoG of brain injured rats but no seizures. By 33 weeks post-TBI though, nearly all injured rats exhibited spontaneous seizures, including convulsive seizures which were infrequent but lasted minutes (18% of injured rats), and non-convulsive seizures which were frequent but lasted tens of seconds (94% of injured rats). We also identified non-convulsive seizures in a smaller subset of control and sham TBI rats (56%), reminiscent of idiopathic seizures described in other rats strains. Non-convulsive seizures in the brain injured rats, however, were four-times more frequent and two-times longer lasting than in their uninjured littermates. Interestingly, rats administered Tacrolimus acutely after TBI showed significantly fewer non-convulsive seizures than untreated rats, but a similar degree of cortical atrophy. The data thus indicate that administration of Tacrolimus acutely after TBI suppressed non-convulsive seizures months later.
癫痫是创伤性脑损伤（TBI）的一种严重但可能可预防的并发症。先前在获得性癫痫动物模型中的研究表明钙敏感性磷酸酶钙调神经磷酸酶与之有关。此外，我们实验室最近发现大鼠海马体中的钙调神经磷酸酶活性在侧方TBI后会急性增加。在此，我们使用一种钙调神经磷酸酶抑制剂来测试钙调神经磷酸酶活性的急性增加对于创伤后晚期癫痫发作的发展是否必要。成年大鼠在侧方液体冲击性TBI后1小时给予钙调神经磷酸酶抑制剂他克莫司（5mg/kg；腹腔注射），然后在5周或33周后通过视频脑电图（video-ECoG）监测自发癫痫活动。在TBI后5周，我们在脑损伤大鼠的video-ECoG上观察到癫痫样活动，但没有癫痫发作。然而，到TBI后33周时，几乎所有受伤大鼠都出现了自发癫痫发作，包括不常发生但持续数分钟的惊厥性癫痫发作（18%的受伤大鼠）和频繁发生但持续数十秒的非惊厥性癫痫发作（94%的受伤大鼠）。我们还在一小部分对照和假手术TBI大鼠（56%）中发现了非惊厥性癫痫发作，这让人联想到其他大鼠品系中描述的特发性癫痫发作。然而，脑损伤大鼠中的非惊厥性癫痫发作比未受伤的同窝大鼠频繁四倍且持续时间长两倍。有趣的是，TBI后急性给予他克莫司的大鼠比未治疗的大鼠出现的非惊厥性癫痫发作明显更少，但皮质萎缩程度相似。因此，数据表明TBI后急性给予他克莫司可在数月后抑制非惊厥性癫痫发作。
