Hattiangady Bharathi, Kuruba Ramkumar, Shetty Ashok K
Medical Research and Surgery Services, Veterans Affairs Medical Center, Durham, NC 27705. Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, NC 27710.
Aging Dis. 2011 Feb 1;2(1):1-17.
The aged population displays an enhanced risk for developing acute seizure (AS) activity. However, it is unclear whether AS activity in old age would result in a greater magnitude of hippocampal neurodegeneration and inflammation, and an increased predilection for developing chronic temporal lobe epilepsy (TLE) and cognitive dysfunction. Therefore, we addressed these issues in young-adult (5-months old) and aged (22-months old) F344 rats after three-hours of AS activity, induced through graded intraperitoneal injections of kainic acid (KA), and terminated through a diazepam injection. During the three-hours of AS activity, both young adult and aged groups exhibited similar numbers of stage-V motor seizures but the numbers of stage-IV motor seizures were greater in the aged group. In both age groups, three-hour AS activity induced degeneration of 50-55% of neurons in the dentate hilus, 22-32% of neurons in the granule cell layer and 49-52% neurons in the CA3 pyramidal cell layer without showing any interaction between the age and AS activity. However, degeneration of neurons in the CA1 pyramidal cell layer showed a clear interaction between the age and AS activity (12% in the young adult group and 56% in the aged group), suggesting that an advanced age makes the CA1 pyramidal neurons more susceptible to die with AS activity. The extent of inflammation measured through the numbers of activated microglial cells was similar between the two age groups. Interestingly, the predisposition for developing chronic TLE at 2-3 months after AS activity was 60% for young adult rats but 100% for aged rats. Moreover, both frequency & intensity of spontaneous recurrent seizures in the chronic phase after AS activity were 6-12 folds greater in aged rats than in young adult rats. Furthermore, aged rats lost their ability for spatial learning even in a scrupulous eleven-session water maze learning paradigm after AS activity, in divergence from young adult rats which retained the ability for spatial learning but had memory retrieval dysfunction after AS activity. Thus, AS activity in old age results in a greater loss of hippocampal CA1 pyramidal neurons, an increased propensity for developing robust chronic TLE, and a severe cognitive dysfunction.
老年人群发生急性癫痫发作（AS）活动的风险更高。然而，老年期的AS活动是否会导致更大程度的海马神经变性和炎症，以及增加患慢性颞叶癫痫（TLE）和认知功能障碍的倾向尚不清楚。因此，我们通过腹腔注射不同剂量的海藻酸（KA）诱导年轻成年（5个月大）和老年（22个月大）的F344大鼠进行3小时的AS活动，并通过注射地西泮终止活动，以此来解决这些问题。在3小时的AS活动期间，年轻成年组和老年组的V期运动性癫痫发作次数相似，但老年组的IV期运动性癫痫发作次数更多。在两个年龄组中，3小时的AS活动均导致齿状回门区50 - 55%的神经元、颗粒细胞层22 - 32%的神经元以及CA3锥体细胞层49 - 52%的神经元发生变性，且年龄与AS活动之间未表现出任何相互作用。然而，CA1锥体细胞层的神经元变性在年龄与AS活动之间表现出明显的相互作用（年轻成年组为12%，老年组为56%），这表明老年使CA1锥体细胞神经元在AS活动时更易死亡。通过活化小胶质细胞数量衡量的炎症程度在两个年龄组中相似。有趣的是，AS活动后2 - 3个月，年轻成年大鼠患慢性TLE的倾向为60%，而老年大鼠为100%。此外，AS活动后慢性期自发复发性癫痫发作的频率和强度在老年大鼠中比年轻成年大鼠高6 - 12倍。此外，与AS活动后保留空间学习能力但存在记忆检索功能障碍的年轻成年大鼠不同，老年大鼠在AS活动后即使在严格的11节水迷宫学习范式中也失去了空间学习能力。因此，老年期的AS活动会导致海马CA1锥体细胞神经元更大程度的丧失、患严重慢性TLE的倾向增加以及严重的认知功能障碍。
