Temporal effects of newly developed oximes (K027, K048) on malathion-induced acetylcholinesterase inhibition and lipid peroxidation in mouse prefrontal cortex.
The potency of newly developed asymmetric bispyridinium oximes (K027, K048) in reactivating acetylcholinesterase and in eliminating oxidative stress induced by acute exposure to malathion was evaluated in mouse prefrontal cortex using in vivo methods. Malathion (1g/kg, dissolved in saline) was administered subcutaneously. The asymmetric bispyridinium oximes K027 or K048 (1/4 of LD(50), dissolved in saline, i.p.) were administered immediately after malathion and atropine sulfate (20mg/kg, dissolved in saline, i.p.). Control group received saline instead of malathion and antidotes. Acetylcholinesterase activity and biochemical parameters related to oxidative stress (glutathione levels, glutathione peroxidase and glutathione reductase activity and lipid peroxidation) were evaluated in mouse prefrontal cortex at two different time points (3 or 24 h after malathion poisoning). Malathion administration markedly inhibited cortical acetylcholinesterase activity (around 55%) at 3h after malathion challenge and such inhibition was maintained till 24 h after poisoning. Although neither atropine sulfate nor oximes were able to eliminate cortical acetylcholinesterase inhibition at 3h after malathion poisoning, K027 (in combination with atropine) completely eliminated the inhibitory effect of malathion exposure on cortical acetylcholinesterase activity at 24 h after malathion administration. K048 (in combination with atropine) significantly decreased acetylcholinesterase inhibition at 24 h after malathion poisoning. Even though glutathione levels and glutathione peroxidase and glutathione reductase activities were not affected, malathion administration markedly increased lipid peroxidation in the prefrontal cortex at 24 h after poisoning and the oxime K027 (in combination with atropine) was able to significantly decrease such phenomenon. Thus, our results clearly demonstrate that the newly developed asymmetric bispyridinium oximes K027 and K048 are able to reverse malathion-induced acetylcholinesterase inhibition in mouse prefrontal cortex. Moreover, the ameliorative effect of the oxime K027 on the increased lipid peroxidation observed at 24 h after malathion poisoning suggests a potential link between the hyperstimulation of cholinergic system and oxidative stress in the mouse prefrontal cortex after malathion exposure.
Departamento de Bioquímica and Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
Aline P
AP
da Silva
Marcelo
M
Farina
Jeferson L
JL
Franco
Alcir L
AL
Dafre
Jiri
J
Kassa
Kamil
K
Kuca
D000110:Acetylcholinesterase / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008294:Malathion / Q000494:pharmacology*; D051379:Mice; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000201:enzymology; D013997:Time Factors
D002800:Cholinesterase Inhibitors; D018727:Muscarinic Antagonists; D010091:Oximes; D001285:Atropine; D005979:Glutathione Peroxidase; D000110:Acetylcholinesterase; D005978:Glutathione; D008294:Malathion