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.