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Post-status epilepticus treatment with the cannabinoid agonist WIN 55,212-2 prevents chronic epileptic hippocampal damage in rats.
Neurobiol Dis 2015; 73:356-65ND

Abstract

Repeated seizures are often associated with development of refractory chronic epilepsy, the most common form of which is temporal lobe epilepsy. G-protein-coupled cannabinoid receptors (CB1 and CB2 receptors) regulate neuronal excitability and have been shown to mediate acute anticonvulsant effects of cannabinoids in animal models. However, the potential of cannabinoids to prevent chronic neuronal damage and development of epilepsy remains unexplored. We hypothesized that treatment with a CB receptor agonist after an episode of status epilepticus--but before development of spontaneous recurrent seizures--might prevent the development of functional changes that lead to chronic epilepsy. Using the rat pilocarpine model, a therapeutic approach was simulated by administering the CB agonist, WIN 55,212-2 after an episode of status epilepticus. Epileptic behavior was monitored during development of spontaneous recurrent seizures for up to 6 months. Histology, neurochemistry, redox status and NMDA receptor subunit expression were assessed at 6 months after pilocarpine-induced seizures. Sub-acute treatment with WIN 55,212-2 (for 15 days starting 24h after PILO injection) dramatically attenuated the severity, duration and frequency of spontaneous recurrent seizures. Further, in contrast to vehicle-treated animals, hippocampi from WIN 55,212-2-treated animals showed: normal thiol redox state, normal NR2A and NR2B subunit expression, preservation of GABAergic neurons and prevention of abnormal proliferation of GABAergic progenitors. This study shows for the first time that, after a known inciting event, treatment with a compound targeting CB receptors has the potential to prevent the epileptogenic events that result in chronic epileptic damage.

Authors+Show Affiliations

Pittsburgh Institute for Neurodegenerative Diseases and Department of Neurology, University of Pittsburgh, USA; RiMED Foundation, Palermo, Italy. Electronic address: rdimaio@hs.pitt.edu.School of Health Sciences, Purdue University, 550 Stadium Mall Drive, West Lafayette, IN 47907, USA.Pittsburgh Institute for Neurodegenerative Diseases and Department of Neurology, University of Pittsburgh, USA.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25447228

Citation

Di Maio, Roberto, et al. "Post-status Epilepticus Treatment With the Cannabinoid Agonist WIN 55,212-2 Prevents Chronic Epileptic Hippocampal Damage in Rats." Neurobiology of Disease, vol. 73, 2015, pp. 356-65.
Di Maio R, Cannon JR, Greenamyre JT. Post-status epilepticus treatment with the cannabinoid agonist WIN 55,212-2 prevents chronic epileptic hippocampal damage in rats. Neurobiol Dis. 2015;73:356-65.
Di Maio, R., Cannon, J. R., & Greenamyre, J. T. (2015). Post-status epilepticus treatment with the cannabinoid agonist WIN 55,212-2 prevents chronic epileptic hippocampal damage in rats. Neurobiology of Disease, 73, pp. 356-65. doi:10.1016/j.nbd.2014.10.018.
Di Maio R, Cannon JR, Greenamyre JT. Post-status Epilepticus Treatment With the Cannabinoid Agonist WIN 55,212-2 Prevents Chronic Epileptic Hippocampal Damage in Rats. Neurobiol Dis. 2015;73:356-65. PubMed PMID: 25447228.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Post-status epilepticus treatment with the cannabinoid agonist WIN 55,212-2 prevents chronic epileptic hippocampal damage in rats. AU - Di Maio,Roberto, AU - Cannon,Jason R, AU - Greenamyre,J Timothy, Y1 - 2014/10/30/ PY - 2014/05/19/received PY - 2014/10/13/revised PY - 2014/10/17/accepted PY - 2014/12/3/entrez PY - 2014/12/3/pubmed PY - 2016/8/30/medline KW - Cannabinoid system KW - Chronic epilepsy KW - Epileptogenesis KW - Oxidative damage KW - Prevention of epilepsy SP - 356 EP - 65 JF - Neurobiology of disease JO - Neurobiol. Dis. VL - 73 N2 - Repeated seizures are often associated with development of refractory chronic epilepsy, the most common form of which is temporal lobe epilepsy. G-protein-coupled cannabinoid receptors (CB1 and CB2 receptors) regulate neuronal excitability and have been shown to mediate acute anticonvulsant effects of cannabinoids in animal models. However, the potential of cannabinoids to prevent chronic neuronal damage and development of epilepsy remains unexplored. We hypothesized that treatment with a CB receptor agonist after an episode of status epilepticus--but before development of spontaneous recurrent seizures--might prevent the development of functional changes that lead to chronic epilepsy. Using the rat pilocarpine model, a therapeutic approach was simulated by administering the CB agonist, WIN 55,212-2 after an episode of status epilepticus. Epileptic behavior was monitored during development of spontaneous recurrent seizures for up to 6 months. Histology, neurochemistry, redox status and NMDA receptor subunit expression were assessed at 6 months after pilocarpine-induced seizures. Sub-acute treatment with WIN 55,212-2 (for 15 days starting 24h after PILO injection) dramatically attenuated the severity, duration and frequency of spontaneous recurrent seizures. Further, in contrast to vehicle-treated animals, hippocampi from WIN 55,212-2-treated animals showed: normal thiol redox state, normal NR2A and NR2B subunit expression, preservation of GABAergic neurons and prevention of abnormal proliferation of GABAergic progenitors. This study shows for the first time that, after a known inciting event, treatment with a compound targeting CB receptors has the potential to prevent the epileptogenic events that result in chronic epileptic damage. SN - 1095-953X UR - https://www.unboundmedicine.com/medline/citation/25447228/Post_status_epilepticus_treatment_with_the_cannabinoid_agonist_WIN_55212_2_prevents_chronic_epileptic_hippocampal_damage_in_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-9961(14)00331-3 DB - PRIME DP - Unbound Medicine ER -