A model of chronic temporal lobe epilepsy presenting constantly rhythmic and robust spontaneous seizures, co-morbidities and hippocampal neuropathology

Dinesh Upadhya, Maheedhar Kodali, Daniel Gitai, Olagide W. Castro, Gabriele Zanirati, Raghavendra Upadhya, Sahithi Attaluri, Eeshika Mitra, Bing Shuai, Bharathi Hattiangady, Ashok K. Shetty

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)915-936
Number of pages22
JournalAging and Disease
Volume10
Issue number5
DOIs
Publication statusPublished - 01-01-2019

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Temporal Lobe Epilepsy
Seizures
Morbidity
Status Epilepticus
Biological Products
Anticonvulsants
Epilepsy
Neuronal Plasticity
Neuropathology
Kainic Acid
Neurogenesis
Inbred F344 Rats
Microglia
Interneurons
Periodicity
Astrocytes
Hippocampus
Neurons
Therapeutics

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine
  • Geriatrics and Gerontology
  • Clinical Neurology
  • Cell Biology

Cite this

Upadhya, Dinesh ; Kodali, Maheedhar ; Gitai, Daniel ; Castro, Olagide W. ; Zanirati, Gabriele ; Upadhya, Raghavendra ; Attaluri, Sahithi ; Mitra, Eeshika ; Shuai, Bing ; Hattiangady, Bharathi ; Shetty, Ashok K. / A model of chronic temporal lobe epilepsy presenting constantly rhythmic and robust spontaneous seizures, co-morbidities and hippocampal neuropathology. In: Aging and Disease. 2019 ; Vol. 10, No. 5. pp. 915-936.
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abstract = "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.",
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Upadhya, D, Kodali, M, Gitai, D, Castro, OW, Zanirati, G, Upadhya, R, Attaluri, S, Mitra, E, Shuai, B, Hattiangady, B & Shetty, AK 2019, 'A model of chronic temporal lobe epilepsy presenting constantly rhythmic and robust spontaneous seizures, co-morbidities and hippocampal neuropathology', Aging and Disease, vol. 10, no. 5, pp. 915-936. https://doi.org/10.14336/AD.2019.0720

A model of chronic temporal lobe epilepsy presenting constantly rhythmic and robust spontaneous seizures, co-morbidities and hippocampal neuropathology. / Upadhya, Dinesh; Kodali, Maheedhar; Gitai, Daniel; Castro, Olagide W.; Zanirati, Gabriele; Upadhya, Raghavendra; Attaluri, Sahithi; Mitra, Eeshika; Shuai, Bing; Hattiangady, Bharathi; Shetty, Ashok K.

In: Aging and Disease, Vol. 10, No. 5, 01.01.2019, p. 915-936.

Research output: Contribution to journalArticle

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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.

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