Inverse relationship of cannabimimetic (R+)WIN 55, 212 on behavior and seizure threshold during the juvenile period.
Cannabinoids have anti-convulsant effects in both in vivo and in vitro models of status epilepticus. Since the development of spontaneous seizures and neuronal vulnerability are age-dependent, we hypothesized that the anti-convulsant effects of cannabimimetics are also age-dependent. We administered a single injection of varied doses of (R+)WIN 55,212 (0.5, 1, 5 mg/kg) to postnatal (P) day 20 rats 90 min prior to induction of kainate (KA)-induced status epilepticus. The highest dose of (R+)WIN 55,212 (5 mg/kg) resulted in rapid onset of behavioral stupor, loss of balance, stiffening and immobility while standing on hind legs or laying flat in prone position; lower doses had minimal or no behavioral effect. After KA administration, seizure scores and electroencephalography (EEG) recordings were inversely related to (R+)WIN 55,212 dosage whereby higher doses were associated with high seizures scores and synchronous epileptiform activity and low doses with low seizure scores and diminished spiking in the EEG. Immunohistochemistry revealed a dose-dependent reduction in CB1 receptor expression with increasing concentrations of (R+)WIN 55,212 in presence or absence of KA seizures. Nissl and NeuN staining showed hippocampal injury was attenuated only when seizures were mild following low doses of WIN 55,212 (0.5, 1 mg/kg), consistent with the level of CB1 expression. Since low doses abolished seizures without psychotropic side-effects further study may facilitate a groundbreaking cannabamimetic therapeutic strategy to treat early-life seizures. Higher doses had adverse effects on behavior and failed to prevent seizures and protect CA1 neurons possibly due to inactivation or loss of CB1 receptors.
New York College of Osteopathic Medicine, Old Westbury, NY 11568, USA.
V
V
Rudenko
A
A
Rafiuddin
J R
JR
Leheste
L K
LK
Friedman
D000375:Aging; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D048588:Benzoxazines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002186:Cannabinoids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007608:Kainic Acid; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D009281:Naphthalenes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020258:Neurotoxicity Syndromes / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists* / Q000378:metabolism; D012640:Seizures / Q000209:etiology / Q000517:prevention & control*; D012720:Severity of Illness Index; D013226:Status Epilepticus / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
D000927:Anticonvulsants; D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D009419:Nerve Tissue Proteins; D043884:Receptor, Cannabinoid, CB1; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D007608:Kainic Acid