Novel Brain-Penetrating Oxime Acetylcholinesterase Reactivators Attenuate Organophosphate-Induced Neuropathology in the Rat Hippocampus

Abstract

Organophosphate (OP) anticholinesterases cause excess acetylcholine leading to seizures which, if prolonged, result in neuronal damage in the rodent brain. Novel substituted phenoxyalkyl pyridinium oximes have previously shown evidence of penetrating the rat blood-brain barrier (BBB) in in vivo tests with a sarin surrogate (nitrophenyl isopropyl methylphosphonate, NIMP) or the active metabolite of the insecticide parathion, paraoxon (PXN), by reducing the time to cessation of seizure-like behaviors and accumulation of glial fibrillary acidic protein, whereas 2-PAM did not. The neuroprotective ability of our lead oximes (15, 20, and 55) was tested using NeuN, Nissl, and Fluoro-Jade B staining in the rat hippocampus. Following lethal-level subcutaneous challenge with NIMP or PXN, rats were intramuscularly administered a novel oxime or 2-PAM plus atropine and euthanized at 4 days. There were statistically significant increases in the median damage scores of the NeuN-stained NIMP, NIMP/2-PAM, and NIMP/Oxime 15 groups compared with the control whereas the scores of the NIMP/Oxime 20 and NIMP/ Oxime 55 were not significantly different from the control. The same pattern of statistical significance was observed with PXN. Nissl staining provided a similar pattern, but without statistical differences. Fluoro-Jade B indicated neuroprotection from PXN with novel oximes but not with 2-PAM. The longer blood residence times of Oximes 20 and 55 compared with Oxime 15 might have contributed to their greater efficacy. These results suggest that novel oximes 20 and 55 were able to penetrate the BBB and attenuate neuronal damage after NIMP and PXN exposure, indicating potential broad-spectrum usefulness.

Central neuroprotection demonstrated by novel oxime countermeasures to nerve agent surrogates

“…Rats were challenged with a lethal dosage of either NIMP or paraoxon and then provided atropine plus one of the three downselected novel oximes, oximes 15, 20, and 55. 45 Similar to the earlier GFAP results, damage scores for animals treated with oximes 20 and 55 were not statistically different from vehicle controls, while damage scores for 2-PAM and oxime 15 were not statistically different from those for NIMP with only atropine. While this was somewhat surprising, in that, oxime 15 had shown some efficacy earlier in attenuating seizure-like behavior as had oxime 20, but not oxime 55, the results here showed oximes 20 and 55 to be effective.…”

“…The next study was a quantification of undamaged neurons in the CA1 region of the hippocampus through the neuronal marker NeuN. Rats were challenged with a lethal dosage of either NIMP or paraoxon and then provided atropine plus one of the three downselected novel oximes, oximes 15, 20, and 55 45 . Similar to the earlier GFAP results, damage scores for animals treated with oximes 20 and 55 were not statistically different from vehicle controls, while damage scores for 2‐PAM and oxime 15 were not statistically different from those for NIMP with only atropine.…”

“… Note : Data represent mean (SD) of three rats; taken from Ref. 45. Only two rats were included in the oxime 15 group.…”

Сучасні Аспекти Розробки Засобів Базової Терапії Та Профілактики Гострих Отруєнь Фосфорорганічними Сполуками (Огляд Літератури)

“…Останнім часом було синтезовано ряд сполук на базі феноксіалкілпіридинових оксимів (US Patent 9,277,937) [50]. Повідомляється, що окремі представники цього ряду здатні відновлювати активність АХЕ головного мозку щурів до 35% протягом 2 годин після отруєння нітрофенолізопропілметилфосфонатом (сурогатом зарину) та параоксоном [51].…”

Development of a CNS-permeable reactivator for nerve agent exposure: An iterative, multi-disciplinary approach

“…In addition, e cacy needs to be increased and toxicity needs to be reduced by respectively enhancing the antidote-nerve agent complex off rates in adducted AChE and abating off-target binding. Satisfying these requirements is a daunting endeavor and the subject of many efforts; several of which show promise [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] .…”