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.
Highlights
Chronic temporal lobe epilepsy (TLE) is characterized by periodic and unpredictable occurrences of partial complex seizures and variable levels of impairments in learning, memory, and mood [1,2,3,4,5]
Animals were euthanized nine months after status epilepticus (SE) to measure graft cell yield, migration, and differentiation, and long-term effects of grafts on the survival of host interneurons expressing neuropeptide Y (NPY), parvalbumin (PV) and reelin, aberrant migration of newly born neurons, the extent and pattern of ongoing neurogenesis and anomalous mossy fiber sprouting in the dentate gyrus (DG)
To ascertain the effects of early neural stem/progenitor cells (NSCs) grafting on the quantity of abnormal neurogenesis that occurs over 9 months' period after SE, we processed serial sections through the hippocampus for Prox-1 immunostaining using a rabbit Prox-1 antibody (1:1000; Millipore) and quantified the numbers of Prox1+ granule cells in the dentate hilus via stereology
Summary
Chronic temporal lobe epilepsy (TLE) is characterized by periodic and unpredictable occurrences of partial complex seizures and variable levels of impairments in learning, memory, and mood [1,2,3,4,5]. The development of alternative therapies that are efficient for blocking or reducing the progression of IPI-induced epileptogenic changes has considerable significance for positively modulating hippocampal plasticity after injury [18,19,20]. If efficient, such therapies would likely prevent or delay the onset of TLE or at least reduce TLE's intensity after an IPI. If found efficient for restraining epilepsy development in animal models, NSC grafting can be translated to the clinic because such cells can be obtained from multiple sources. Animals were euthanized nine months after SE to measure graft cell yield, migration, and differentiation, and long-term effects of grafts on the survival of host interneurons expressing neuropeptide Y (NPY), parvalbumin (PV) and reelin, aberrant migration of newly born neurons, the extent and pattern of ongoing neurogenesis and anomalous mossy fiber sprouting in the dentate gyrus (DG)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
