Anticonvulsant treatment of sarin-induced seizures with nasal midazolam: an electrographic, behavioral, and histological study in freely moving rats.
Centrally mediated seizures and convulsions are common consequences of exposure to organophosphates (OPs). These seizures rapidly progress to status epilepticus (SE) and contribute to profound brain injury. Effective management of these seizures is critical for minimization of brain damage. Nasal application of midazolam (1.5 mg/kg) after 5 min of sarin-induced electrographic seizure activity (EGSA) ameliorated EGSA and convulsive behavior (238 +/- 90 s). Identical treatment after 30 min was not sufficient to ameliorate ECoG paradoxical activity and convulsive behavior. Nasal midazolam (1.5 mg/kg), together with scopolamine (1 mg/kg, im) after 5 min of EGSA, exerted a powerful and rapid anticonvulsant effect (53 +/- 10 s). Delaying the same treatment to 30 min of EGSA leads to attenuation of paroxysmal ECoG activity in all cases but total cessation of paroxysmal activity was not observed in most animals tested. Cognitive tests utilizing the Morris Water Maze demonstrated that nasal midazolam alone or together with scopolamine (im), administered after 5 min of convulsions, abolished the effect of sarin on learning. Both these treatments, when given after 30 min of convulsions, only decreased the sarin-induced learning impairments. Whereas rats which were not subject to the anticonvulsant agents did not show any memory for the platform location, both treatments (at 5 min as well as at 30 min) completely abolished the memory deficits. Both treatments equally blocked the impairment of reversal learning when given at 5 min. However, when administered after 30 min, midazolam alone reversed the impairments in reversal learning, while midazolam with scopolamine did not. Rats exposed to sarin and treated with the therapeutic regimen with the exclusion of midazolam exhibited severe brain lesions that encountered the hippocampus, pyriform cortex, and thalamus. Nasal midazolam at 5 min prevented brain damage, while delaying the midazolam treatment to 30 min of EGSA resulted in brain damage. The addition of scopolamine to midazolam did not alter the above observation. In summary, nasal midazolam treatment briefly after initiation of OP-induced seizure leads to cessation of EGSA and prevented brain lesions and behavioral deficiencies in the rat model.
Gilat
E
E
Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona, 74100 Israel. gilat@iibr.gov.il
Kadar
T
T
Levy
A
A
Rabinovitz
I
I
Cohen
G
G
Kapon
Y
Y
Sahar
R
R
Brandeis
R
R
D000281:Administration, Intranasal; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000473:pathology*; D002800:Cholinesterase Inhibitors; D004567:Electrodes, Implanted; D004569:Electroencephalography / Q000187:drug effects*; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008874:Midazolam / Q000008:administration & dosage / Q000627:therapeutic use*; D018727:Muscarinic Antagonists / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D012524:Sarin; D012601:Scopolamine / Q000627:therapeutic use; D012640:Seizures / Q000139:chemically induced* / Q000188:drug therapy* / Q000523:psychology; D014163:Transfer, Psychology / Q000187:drug effects
D000927:Anticonvulsants; D002800:Cholinesterase Inhibitors; D006993:Hypnotics and Sedatives; D018727:Muscarinic Antagonists; D012524:Sarin; D012601:Scopolamine; D008874:Midazolam