Enantiomer (+)physostigmine prevents organophosphate‐induced subjunctional damage at the neuromuscular synapse by a mechanism not related to cholinesterase carbamylation

Abstract

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)

Molecular Targets and Synaptic Effects of Carbamates, Organophosphates, Oximes, and Pyridiniums: Implications for Prophylaxis and Therapy of Organophosphate Toxicity

“…Accordingly, among the carbamaten (+) and (-) physostigmine provided the best protection to animals exposed to lethal doses of OP compounds Kawabuchi et aL, 1988. In vitro experiments carried out for light microsopic and ugtrastructural analyses confirmed these findings.…”

“…Furthermore, these interactions were implicated in the ability of certain carbamates to protect against organophasphate (OP) compounds. Our studies demonstrated that carbamates (Albuquerque et al, , 1988aKawabuchi et aL, 1988Kawabuchi et aL, . 1989) and oximes (Alkondon et al, 1988), chemicals used as antidotes for OP intoxication, alter AChR function by mechanisms not related to AChE inhibition or reactivation.…”

“…Z lines showed some slight irregularities and dislocation. It is obvious that (+) physostigmine offers significant protection against the marked damage induced by irreversible organophosphate poison~ing (Kawabuchi et al, 1987(Kawabuchi et al, , 1988(Kawabuchi et al, , 1989). …”

“…The agents not only prevent ACh hydrolysis but also directly interact with site(s) located on the AChR macromolecule Kawabuchi et al, 1986Kawabuchi et al, , 1988Kawabuchi et al, , 1989Albuquerque et al, 1988a). The morpholoa of the neuromuscular junction and the function of the postsynaptic AChRt were altered differently depending upon the carbasnate used.…”

“…et aL, !987; Albuquerque et al, 1988aj. iii) The pharmacological and toxicolgockal effects differ among the reversible AChE inhibitors. The physostigmine enadmsoers and particularly the (+) isomer induced the least damage to the neuromuscular synaptic elements (Meshail et al, Kawabuchi et al, 1988Kawabuchi et al, , 1989). …”