Rao Muddanna S, Hattiangady Bharathi, Reddy Doodipala S, Shetty Ashok K
Department of Surgery (Neurosurgery), Duke University Medical Center, Durham, North Carolina 27710, USA.
J Neurosci Res. 2006 May 1;83(6):1088-105. doi: 10.1002/jnr.20802.
The links among the extent of hippocampal neurodegeneration, the frequency of spontaneous recurrent motor seizures (SRMS), and the degree of aberrant mossy fiber sprouting (MFS) in temporal lobe epilepsy (TLE) are a subject of contention because of variable findings in different animal models and human studies. To understand these issues further, we quantified these parameters at 3-5 months after graded injections of low doses of kainic acid (KA) in adult F344 rats. KA was administered every 1 hr for 4 hr, for a cumulative dose of 10.5 mg/kg bw, to induce continuous stages III-V motor seizures for >3 hr. At 4 days post-KA, the majority of rats (77%) exhibited moderate bilateral neurodegeneration in different regions of the hippocampus; however, 23% of rats exhibited massive neurodegeneration in all hippocampal regions. All KA-treated rats displayed robust SRMS at 3 months post-KA, and the severity of SRMS increased over time. Analyses of surviving neurons at 5 months post-KA revealed two subgroups of rats, one with moderate hippocampal injury (HI; 55% of rats) and another with widespread HI (45%). Rats with widespread HI exhibited greater loss of CA3 pyramidal neurons and robust aberrant MFS than rats with moderate HI. However, the frequency of SRMS (approximately 3/hr) was comparable between rats with moderate and widespread HI. Thus, in comparison with TLE model using Sprague-Dawley rats (Hellier et al. [1998] Epilepsy Res. 31:73-84), a much lower cumulative dose of KA leads to robust chronic epilepsy in F344 rats. Furthermore, the occurrence of SRMS in this model is always associated with considerable bilateral hippocampal neurodegeneration and aberrant MFS. However, more extensive hippocampal CA3 cell loss and aberrant MFS do not appear to increase the frequency of SRMS. Because most of the features are consistent with mesial TLE in humans, the F344 model appears ideal for testing the efficacy of potential treatment strategies for mesial TLE.
在颞叶癫痫（TLE）中，海马神经变性程度、自发性反复运动性癫痫发作（SRMS）频率和异常苔藓纤维发芽（MFS）程度之间的联系一直存在争议，因为在不同动物模型和人体研究中结果各异。为了进一步了解这些问题，我们在成年F344大鼠中，于低剂量海藻酸（KA）分级注射后3至5个月对这些参数进行了量化。每隔1小时给予KA，持续4小时，累积剂量为10.5 mg/kg体重，以诱导持续III - V期运动性癫痫发作超过3小时。在KA注射后4天，大多数大鼠（77%）在海马不同区域表现出中度双侧神经变性；然而，23%的大鼠在所有海马区域表现出大量神经变性。所有KA处理的大鼠在KA注射后3个月均出现强烈的SRMS，且SRMS的严重程度随时间增加。对KA注射后5个月存活神经元的分析揭示了两个大鼠亚组，一个是海马中度损伤（HI；55%的大鼠），另一个是广泛HI（45%）。与中度HI的大鼠相比，广泛HI的大鼠CA3锥体神经元损失更大，且有强烈的异常MFS。然而，中度和广泛HI的大鼠之间SRMS频率（约3次/小时）相当。因此，与使用Sprague - Dawley大鼠的TLE模型相比（Hellier等人，[1998]《癫痫研究》31:73 - 84），更低的KA累积剂量可导致F344大鼠出现强烈的慢性癫痫。此外，该模型中SRMS的发生总是与相当程度的双侧海马神经变性和异常MFS相关。然而，更广泛的海马CA3细胞损失和异常MFS似乎并未增加SRMS的频率。由于大多数特征与人类内侧TLE一致，F344模型似乎是测试内侧TLE潜在治疗策略疗效的理想模型。
