Enantiomer (+)physostigmine prevents organophosphate-induced subjunctional damage at the neuromuscular synapse by a mechanism not related to cholinesterase carbamylation.
The natural alkaloid (-)PHY is a reversible anticholinesterase carbamate, but in contrast, its optical isomer (+)PHY, is a very weak anticholinesterase. We have shown that treatment of rats with atropine and (-)PHY prior to injections of a lethal dose of the irreversible organophosphate sarin (0.13 mg/kg) not only protected 100% of the animals from lethality but also reduced the size of the subneural lesions of the nicotinic synapses of skeletal muscle. Similar protection against lethality is provided by pretreatment with (+)PHY. At the concentration used (0.3 mg/kg), there was no detectable inhibition of AChE activity. We have examined the protection afforded by (+)PHY or (-)PHY against lethality and myopathy due to organophosphate agents such as sarin. The major alterations in the soleus motor endplates 1 hr after drug treatment were as follows: (1) A single sublethal dose of sarin (0.08 mg/kg) produced enlarged, blistered, and severely disrupted subjunctional regions, with muscle damage extending beyond the endplate to include myofiber necrosis and subsequent phagocytosis; (2) (+)PHY (0.3 mg/kg) produced no obvious damage in the postjunctional region; (3) (-)PHY (0.1 mg/kg) had a selective effect in inducing irregularities of the subjunctional sarcomere band patterns without any gross vacuolization; (4) light microscopic data indicated that the combination of atropine and (+)PHY, or of atropine and (-)PHY (0.1 mg/kg), 30 min prior to a lethal dose of sarin, offered dramatic reduction in the average dimension of lesions. Lesions were detectable in most endplates but recognizable changes were markedly less severe than those seen in sarin myopathy. Few instances of extensive muscle damage and myofiber necrosis were visible.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore 21201.
M
M
Kawabuchi
A F
AF
Boyne
S S
SS
Deshpande
W M
WM
Cintra
A
A
Brossi
E X
EX
Albuquerque
D000818:Animals; D002219:Carbamates / Q000494:pharmacology*; D002802:Cholinesterases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D009469:Neuromuscular Junction / Q000187:drug effects* / Q000648:ultrastructure; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010830:Physostigmine / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012524:Sarin / Q000494:pharmacology*; D013237:Stereoisomerism; D013997:Time Factors
D002219:Carbamates; D009943:Organophosphorus Compounds; D010830:Physostigmine; D012524:Sarin; D002802:Cholinesterases