Alpha-Linolenic Acid-Induced Increase in Neurogenesis is a Key Factor in the Improvement in the Passive Avoidance Task After Soman Exposure

Abstract

Exposure to organophosphorous (OP) nerve agents such as soman inhibits the critical enzyme acetylcholinesterase (AChE) leading to excessive acetylcholine accumulation in synapses, resulting in cholinergic crisis, status epilepticus and brain damage in survivors. The hippocampus is profoundly damaged after soman exposure leading to long-term memory deficits. We have previously shown that treatment with three sequential doses of alpha-linolenic acid, an essential omega-3 polyunsaturated fatty acid, increases brain plasticity in naïve animals. However, the effects of this dosing schedule administered after a brain insult and the underlying molecular mechanisms in the hippocampus are unknown. We now show that injection of three sequential doses of alpha-linolenic acid after soman exposure increases the endogenous expression of mature BDNF, activates Akt and the mammalian target of rapamycin complex 1 (mTORC1), increases neurogenesis in the subgranular zone of the dentate gyrus, increases retention latency in the passive avoidance task and increases animal survival. In sharp contrast, while soman exposure also increases mature BDNF, this increase did not activate downstream signaling pathways or neurogenesis. Administration of the inhibitor of mTORC1, rapamycin, blocked the alpha-linolenic acid-induced neurogenesis and the enhanced retention latency but did not affect animal survival. Our results suggest that alpha-linolenic acid induces a long-lasting neurorestorative effect that involves activation of mTORC1 possibly via a BDNF-TrkB-mediated mechanism.

α-Linolenic Acid, A Nutraceutical with Pleiotropic Properties That Targets Endogenous Neuroprotective Pathways to Protect against Organophosphate Nerve Agent-Induced Neuropathology

“…ALA is an 18 carbon polyunsaturated fatty acid containing three double bonds at the 9, 12 and 15 positions. ALA plays an important role in brain function and protection as well as exhibiting anti-inflammatory and neuroplastic properties [2,3,4] and has a very wide safety margin [5,6]. ALA is a precursor of the long-chain PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).…”

“…Administration of the oxime, atropine and diazepam increases animal survival and are based upon the current drug use developed for personnel entering areas of nerve agent contamination. These drugs are also given to control animals in order to compare results across all groups ([4,21,41,51,76,82,83,84,90] and references therein). Over the course of the first two to four days after soman exposure, animals lose approximately 20% of their body weight.…”

“…The brain regions damaged by soman exposure are the piriform cortex, amygdala, prefrontal/cingulate cortex, hippocampus, caudate/putamen, and thalamus [21,40,41,51,82]. The amygdala and hippocampus are profoundly damaged by soman [4,21,41,76]. The neuronal degeneration induced by OP agents occurs mainly by necrosis, but apoptosis and hybrid forms have been reported in one study [91].…”

Acute and long‐term consequences of exposure to organophosphate nerve agents in humans

“…63,64 Neuronal damage continues for days and weeks after OP exposure in rodents despite lifesaving treatment with an oxime, atropine, and diazepam. [65][66][67] Learning and memory deficits and depressive-like behavior are also associated with soman-induced brain damage. [64][65][66][67][68][69] In summary, long-term neuropsychiatric deficits have been reported in humans exposed to either low or intoxicating levels of OP nerve agents.…”

“…[65][66][67] Learning and memory deficits and depressive-like behavior are also associated with soman-induced brain damage. [64][65][66][67][68][69] In summary, long-term neuropsychiatric deficits have been reported in humans exposed to either low or intoxicating levels of OP nerve agents. A recent report in children exposed to chemical warfare agents suggests that they develop more severe and long-lasting deficits compared with adults.…”