TY - JOUR
T1 - A model of chronic temporal lobe epilepsy presenting constantly rhythmic and robust spontaneous seizures, co-morbidities and hippocampal neuropathology
AU - Upadhya, Dinesh
AU - Kodali, Maheedhar
AU - Gitai, Daniel
AU - Castro, Olagide W.
AU - Zanirati, Gabriele
AU - Upadhya, Raghavendra
AU - Attaluri, Sahithi
AU - Mitra, Eeshika
AU - Shuai, Bing
AU - Hattiangady, Bharathi
AU - Shetty, Ashok K.
N1 - Funding Information:
Grants from the Department of Defense (W81XWH-14-1-0558 to A.K.S.), and the State of Texas (Emerging Technology Fund to A.K.S.) supported this study.
Publisher Copyright:
© 2019 Upadhya D et al.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Many animal prototypes illustrating the various attributes of human temporal lobe epilepsy (TLE) are available. These models have been invaluable for comprehending multiple epileptogenic processes, modifications in electrophysiological properties, neuronal hyperexcitability, neurodegeneration, neural plasticity, and chronic neuroinflammation in TLE. Some models have also uncovered the efficacy of new antiepileptic drugs or biologics for alleviating epileptogenesis, cognitive impairments, or spontaneous recurrent seizures (SRS). Nonetheless, the suitability of these models for testing candidate therapeutics in conditions such as chronic TLE is debatable because of a lower frequency of SRS and an inconsistent pattern of SRS activity over days, weeks or months. An ideal prototype of chronic TLE for investigating novel therapeutics would need to display a large number of SRS with a dependable frequency and severity and related co-morbidities. This study presents a new kainic acid (KA) model of chronic TLE generated through induction of status epilepticus (SE) in 6-8 weeks old male F344 rats. A rigorous characterization in the chronic epilepsy period validated that the animal prototype mimicked the most salient features of robust chronic TLE. Animals displayed a constant frequency and intensity of SRS across weeks and months in the 5th and 6th month after SE, as well as cognitive and mood impairments. Moreover, SRS frequency displayed a rhythmic pattern with 24-hour periodicity and a consistently higher number of SRS in the daylight period. Besides, the model showed many neuropathological features of chronic TLE, which include a partial loss of inhibitory interneurons, reduced neurogenesis with persistent aberrant migration of newly born neurons, chronic neuroinflammation typified by hypertrophied astrocytes and rod-shaped microglia, and a significant aberrant mossy fiber sprouting in the hippocampus. This consistent chronic seizure model is ideal for investigating the efficacy of various antiepileptic drugs and biologics as well as understanding multiple pathophysiological mechanisms underlying chronic epilepsy.
AB - Many animal prototypes illustrating the various attributes of human temporal lobe epilepsy (TLE) are available. These models have been invaluable for comprehending multiple epileptogenic processes, modifications in electrophysiological properties, neuronal hyperexcitability, neurodegeneration, neural plasticity, and chronic neuroinflammation in TLE. Some models have also uncovered the efficacy of new antiepileptic drugs or biologics for alleviating epileptogenesis, cognitive impairments, or spontaneous recurrent seizures (SRS). Nonetheless, the suitability of these models for testing candidate therapeutics in conditions such as chronic TLE is debatable because of a lower frequency of SRS and an inconsistent pattern of SRS activity over days, weeks or months. An ideal prototype of chronic TLE for investigating novel therapeutics would need to display a large number of SRS with a dependable frequency and severity and related co-morbidities. This study presents a new kainic acid (KA) model of chronic TLE generated through induction of status epilepticus (SE) in 6-8 weeks old male F344 rats. A rigorous characterization in the chronic epilepsy period validated that the animal prototype mimicked the most salient features of robust chronic TLE. Animals displayed a constant frequency and intensity of SRS across weeks and months in the 5th and 6th month after SE, as well as cognitive and mood impairments. Moreover, SRS frequency displayed a rhythmic pattern with 24-hour periodicity and a consistently higher number of SRS in the daylight period. Besides, the model showed many neuropathological features of chronic TLE, which include a partial loss of inhibitory interneurons, reduced neurogenesis with persistent aberrant migration of newly born neurons, chronic neuroinflammation typified by hypertrophied astrocytes and rod-shaped microglia, and a significant aberrant mossy fiber sprouting in the hippocampus. This consistent chronic seizure model is ideal for investigating the efficacy of various antiepileptic drugs and biologics as well as understanding multiple pathophysiological mechanisms underlying chronic epilepsy.
UR - http://www.scopus.com/inward/record.url?scp=85074573517&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85074573517&partnerID=8YFLogxK
U2 - 10.14336/AD.2019.0720
DO - 10.14336/AD.2019.0720
M3 - Article
AN - SCOPUS:85074573517
SN - 2152-5250
VL - 10
SP - 915
EP - 936
JO - Aging and Disease
JF - Aging and Disease
IS - 5
ER -