Effects of S-Ethyl Hexahydro-1H-azepine-1-carbothioate (Molinate) on Di-n-butyl Dichlorovinyl Phosphate (DBDCVP) Neuropathy

Abstract

Certain esterase inhibitors protect from organophosphate-induced delayed polyneuropathy (OPIDP) when given before a neuropathic organophosphate by inhibiting neuropathy target esterase (NTE). In contrast, they can exaggerate OPIDP when given afterwards and this effect (promotion) is associated with inhibition of another esterase (M200). In vitro sensitivities of hen, rat, and human NTE and M200 to the active metabolites of molinate, sulfone, and sulfoxide, were similar. NTE and M200 were irreversibly inhibited (> 78%) in brain and peripheral nerve of hens and rats given molinate (100-180 mg/kg, sc). No clinical or morphological signs of neuropathy developed in these animals. Hens and rats were protected from di-n-butyl dichlorovinyl phosphate neuropathy (DBDCVP, 1 and 5 mg/kg, sc, respectively) by molinate (180 or 100 mg/kg, sc, 24 h earlier, respectively) whereas 45 mg/kg, sc molinate causing about 34% NTE inhibition offered partial protection to hens. Hens treated with DBDCVP (0.4 mg/kg, sc) developed a mild OPIDP; molinate (180 mg/kg, 24 h later) increased the severity of clinical effects and of histopathology in spinal cord and in peripheral nerves. Lower doses of molinate (45 mg/kg, sc), causing about 47% M200 inhibition, did not promote OPIDP whereas the effect of 90 mg/kg, sc (corresponding to about 50-60% inhibition) was mild and not statistically significant. OPIDP induced by DBDCVP (5 mg/kg, sc) in rats was promoted by molinate (100 mg/kg, sc). In conclusion, protection from DBDCVP neuropathy by molinate is correlated with inhibition of NTE whereas promotion of DBDCVP neuropathy is associated with > 50% M200 inhibition.

Kinetics of inhibition of soluble peripheral nerve esterases by PMSF: a non-stable compound that potentiates the organophosphorus-induced delayed neurotoxicity

“…However, when ''protective'' NTE inhibitors such as PMSF are dosed after a low non-neuropathic dose of a neuropathic OP (causing[40-50% NTE inhibition), its neurotoxicity is ''potentiated'' (Pope and Padilla 1990) or ''promoted'' (Lotti et al 1991), causing severe neuropathy. Although the target of ''potentiation'' by PMSF remains unknown, it is suspected to be another esterase related to peripheral nerve soluble PVases (Moretto 2000;Moretto et al 2001). However, the global interaction of PMSF with nerve tissue esterases has not been kinetically analyzed in detail, and it is necessary to identify which are the relevant sensitive esterases to PMSF as possible target(s) for promotion/potentiation of organophosphorus-induced delayed polyneuropathy (OPIDP) before isolation and molecular characterization.…”

Late Onset Polyneuropathy due to Organophosphate (DDVP) Intoxication

“…We did not encounter reports of delayed polyneuropathy due to DDVP in humans, nor an experimental study involving DDVP. Moretto and his coworkers [28][29][30] examined experimental animals with a similar compound, di-n-butyl dichlorovinyl phosphate, which they define as a potent organophosphate for causing delayed polyneuropathy. Our case is probably the first reported OPIDP due to DDVP.…”

Neuropathy target esterase (NTE/PNPLA6) and organophosphorus compound-induced delayed neurotoxicity (OPIDN)

“…Accordingly, Veronesi and Padilla (1985) were able to show protection by PMSF against spinal cord lesions produced by mipafox in rats. Likewise, protection was conferred by the thiocarbamate, molinate, against OPIDN induced by di-n-butyl dichlorvos (DBDCV) in rats as well as in hens (Moretto et al, 2001).…”

“…The specific basis for potentiation or promotion of OPIDN has not been elucidated, but in view of the fact that potentiators or promoters delay recovery from nerve crush (Moretto et al, 1993), a plausible general explanation involves the notion of interference with mechanisms of repair of axonal injury (Lotti, 2002). In addition, although the first reports of potentiation/promotion indicated that the effective compounds were NTE inhibitors, subsequent work by Lotti and colleagues strongly suggested that the target for promotion/potentiation is not NTE (Lotti, 2002;Lotti and Moretto, 1993;Moretto et al, 1994Moretto et al, , 2001.…”