Hippocampal Neural Stem Cell Grafting after Status Epilepticus Alleviates Chronic Epilepsy and Abnormal Plasticity, and Maintains Better Memory and Mood Function

Abstract

Hippocampal damage after status epilepticus (SE) leads to multiple epileptogenic changes, which lead to chronic temporal lobe epilepsy (TLE). Morbidities such as spontaneous recurrent seizures (SRS) and memory and mood impairments are seen in a significant fraction of SE survivors despite the administration of antiepileptic drugs after SE. We examined the efficacy of bilateral intra-hippocampal grafting of neural stem/progenitor cells (NSCs) derived from the embryonic day 19 rat hippocampi, six days after SE for restraining SE-induced SRS, memory, and mood impairments in the chronic phase. Grafting of NSCs curtailed the progression of SRS at 3-5 months post-SE and reduced the frequency and severity of SRS activity when examined at eight months post-SE. Reduced SRS activity was also associated with improved memory function. Graft-derived cells migrated into different hippocampal cell layers, differentiated into GABA-ergic interneurons, astrocytes, and oligodendrocytes. Significant percentages of graft-derived cells also expressed beneficial neurotrophic factors such as the fibroblast growth factor-2, brain-derived neurotrophic factor, insulin-like growth factor-1 and glial cell line-derived neurotrophic factor. NSC grafting protected neuropeptide Y-and parvalbumin-positive host interneurons, diminished the abnormal migration of newly born neurons, and rescued the reelin+ interneurons in the dentate gyrus. Besides, grafting led to the maintenance of a higher level of normal neurogenesis in the chronic phase after SE and diminished aberrant mossy fiber sprouting in the dentate gyrus. Thus, intrahippocampal grafting of hippocampal NSCs shortly after SE considerably curbed the progression of epileptogenic processes and SRS, which eventually resulted in less severe chronic epilepsy devoid of significant cognitive and mood impairments.

Baicalin Rescues Cognitive Dysfunction, Mitigates Neurodegeneration, and Exerts Anti-Epileptic Effects Through Activating TLR4/MYD88/Caspase-3 Pathway in Rats

“…Multiple cognitive domains in these patients could be widely affected, which is becoming a major health threat and bringing a heavy economic burden on society and families. 51,52 In recent years, improving cognitive dysfunction is a crucial factor that must be considered when treating epilepsy. 53 Therefore, to verify whether BA could improve cognitive impairment in the treatment of epilepsy, MWM and NORT are common behavioural paradigms used to evaluate spatial learning and object cognition in rodents, and the order of different tasks will not have an impact particularly if cognitive tasks are involved.…”

Animal Models of Epilepsy: A Phenotype-oriented Review

“…Temporal lobe epilepsy (TLE) is a result of an initial precipitating injury (IPI), such as SE, head trauma, or febrile seizures, with a latent period of weeks, years, or even decades after an IPI [ 89 ]. The process is divided into three main stages: (1) IPI, (2) latent period, and (3) TLE development [ 90 ].…”

The role of adult hippocampal neurogenesis in epilepsy and comorbidities

“…除了认知障碍以外，癫痫后共患焦虑、抑郁的情况也非常普遍，癫痫患者共患焦虑、抑郁 的概率比正常人高 2 倍 [77,104] ，且最近的研究也表明成体海马神经发生与焦虑、抑郁样行为密 切相关。最初的研究结果发现抗抑郁药物的应用可以提高成体海马神经发生的水平，提示成体 海马神经发生可能与抑郁存在直接或间接的联系 [83,84,105] 。而成体海马神经发生水平下降是否 与焦虑和抑郁的发病存在必然联系还有待进一步的研究。随后的研究也给出了一定的证据，使 用转基因动物或者辐射等手段降低成体海马神经发生水平可以诱导抑郁样行为 [32,106,107] ，这些 结果表明成体新生神经元在抑郁中可能承担一定的功能。同样地，近几年的研究表明通过丰富 环境等方式提高成体海马神经发生水平或直接激活成体新生神经元等方式可以直接改善动物 的焦虑、抑郁样行为 [108][109][110][111][112] [115] 。此外，也有报道表示癫痫 SE 后将小鼠暴露于 丰富环境中，可以减少后期癫痫的自发频率且伴随的抑郁症状也有改善 [116] 。而外源性移植神 经干细胞的应用也被发现可以改善大鼠脑内癫痫后引起的新生神经元异常，且可以抑制后续癫 痫的发展并阻止相关抑郁样行为 [117] 。在小鼠 KA 模型中，通过特异性地抑制 BDNF 受体 TrkB 也被报道可以在妨碍癫痫形成的同时改善焦虑样行为和海马神经元的丢失 [118]…”