Caramiphen and scopolamine prevent soman-induced brain damage and cognitive dysfunction.
Exposure to soman, a toxic organophosphate nerve agent, causes severe adverse effects and long term changes in the peripheral and central nervous systems. The goal of this study was to evaluate the ability of prophylactic treatments to block the deleterious effects associated with soman poisoning. scopolamine, a classical anticholinergic agent, or caramiphen, an anticonvulsant anticholinergic drug with anti-glutamatergic properties, in conjunction with pyridostigmine, a reversible cholinesterase inhibitor, were administered prior to sbman (1 LD50). Both caramiphen and scopolamine dramatically attenuated the process of cell death as assessed by the binding of [3H]RoS-4864 to peripheral benzodiazepine receptors (omega3 sites) on microglia and astrocytes. In addition, caramiphen but not scopolamine, blocked the soman-evoked down-regulation of [3H]AMPA binding to forebrain membrane preparations. Moreover, cognitive tests utilizing the Morris water maze, examining learning and memory processes as well as reversal learning, demonstrated that caramiphen abolished the effects of soman intoxication on learning as early as the first trial day, while scopolamine exerted its effect commencing at the second day of training. Whereas the former drug completely prevented memory deficits, the latter exhibited partial protection. Both agents equally blocked the impairment of reversal learning. In addition, there is a significant correlation between behavioral parameters and [3H]RoS-4864 binding to forebrain membrane preparations of rats, which participated in these tests (r(21) = 0.66, P < 0.001; r(21) = 0.66, P < 0.001, -0.62, P < 0.002). These results demonstrate the beneficial use of drugs exhibiting both anti-cholinergic and anti-glutamatergic properties for the protection against changes in cognitive parameters caused by nerve agent poisoning. Moreover, agents such as caramiphen may eliminate the need for multiple drug therapy in organophosphate intoxications.
Raveh
Lily
L
Department of Pharmacology, Israel Institute for Biological Research, Ness Ziona. lili@iibr.gov.il
Weissman
Ben Avi
BA
Cohen
Giora
G
Alkalay
David
D
Rabinovitz
Ishai
I
Sonego
Hagar
H
Brandeis
Rachel
R
D000818:Animals; D003072:Cognition Disorders / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D003517:Cyclopentanes / Q000494:pharmacology / Q000627:therapeutic use*; D004924:Escape Reaction / Q000187:drug effects / Q000502:physiology; D002534:Hypoxia, Brain / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D012601:Scopolamine / Q000494:pharmacology / Q000627:therapeutic use*; D012999:Soman / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D013550:Swimming / Q000502:physiology; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism
D003517:Cyclopentanes; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D012999:Soman; C004519:caramiphen; D012601:Scopolamine