Leukotriene and prostaglandin production in rat brain synaptosomes treated with phospholipase A2 neurotoxins and enzymes.
beta-Bungarotoxin (beta-BuTX) and notexin cause an irreversible blockade of neurotransmitter release through specific and potent effects at the presynaptic nerve terminal, however, the mechanism of action is uncertain. We examined the effects of beta-BuTX and notexin on LT and PG production in rat cerebrocortical synaptosomes in order to determine if eicosanoid production might mediate or regulate the pharmacological actions of these phospholipase A2 (PLA2) neurotoxins. The effects of the PLA2 enzymes isolated from Naja naja atra and Naja nigricollis snake venoms (which are not presynaptic selective) on LT and PG production were compared with the effects of beta-BuTX and notexin. N. n. atra PLA2, beta-BuTX, and notexin (all 50 nM) produced a time dependent rise in free fatty acids as measured in synaptic plasma membranes isolated from treated synaptosomes. Both the PLA2 neurotoxins and enzymes stimulated LTC4, LTB4, and PGE2 production, as measured by radioimmunoassay. In all cases, the PLA2 enzymes were more potent than the PLA2 neurotoxins. This observation correlates with their relative enzymatic potencies, as measured by free fatty acid generation. EDTA and BSA antagonized PLA2 induced LTB4 production and BSA also antagonized PLA2 induced PGE2 production. These results suggest that stimulation of eicosanoid production does not mediate the potent and specific presynaptic actions of beta-BuTX and notexin.
Yates
S L
SL
Section of Pharmacology & Toxicology, The University of Connecticut, School of Pharmacy, Storrs 06269.
Levine
L
L
Rosenberg
P
P
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D002038:Bungarotoxins / Q000494:pharmacology*; D004546:Elapid Venoms / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000096:biosynthesis; D015289:Leukotrienes / Q000096:biosynthesis*; D008297:Male; D010740:Phospholipases / Q000494:pharmacology*; D010741:Phospholipases A / Q000494:pharmacology*; D054467:Phospholipases A2; D011453:Prostaglandins / Q000096:biosynthesis*; D051381:Rats; D011919:Rats, Inbred Strains; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D002038:Bungarotoxins; D004546:Elapid Venoms; D005230:Fatty Acids, Nonesterified; D015289:Leukotrienes; D011453:Prostaglandins; C005082:notexin; D010740:Phospholipases; D010741:Phospholipases A; D054467:Phospholipases A2