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

Abstract

α-Linolenic acid (ALA) is a nutraceutical found in vegetable products such as flax and walnuts. The pleiotropic properties of ALA target endogenous neuroprotective and neurorestorative pathways in brain and involve the transcription factor nuclear factor kappa B (NF-κB), brain-derived neurotrophic factor (BDNF), a major neuroprotective protein in brain, and downstream signaling pathways likely mediated via activation of TrkB, the cognate receptor of BDNF. In this review, we discuss possible mechanisms of ALA efficacy against the highly toxic OP nerve agent soman. Organophosphate (OP) nerve agents are highly toxic chemical warfare agents and a threat to military and civilian populations. Once considered only for battlefield use, these agents are now used by terrorists to inflict mass casualties. OP nerve agents inhibit the critical enzyme acetylcholinesterase (AChE) that rapidly leads to a cholinergic crisis involving multiple organs. Status epilepticus results from the excessive accumulation of synaptic acetylcholine which in turn leads to the overactivation of muscarinic receptors; prolonged seizures cause the neuropathology and long-term consequences in survivors. Current countermeasures mitigate symptoms and signs as well as reduce brain damage, but must be given within minutes after exposure to OP nerve agents supporting interest in newer and more effective therapies. The pleiotropic properties of ALA result in a coordinated molecular and cellular program to restore neuronal networks and improve cognitive function in soman-exposed animals. Collectively, ALA should be brought to the clinic to treat the long-term consequences of nerve agents in survivors. ALA may be an effective therapy for other acute and chronic neurodegenerative disorders.

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

“…[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.…”

The possible role of intravenous lipid emulsion in the treatment of chemical warfare agent poisoning

“…Recently, the ω-3 polyunsaturated fatty acid α-linolenic acid was shown to be neuroprotective in soman-poisoned rats [102] . The neuroprotective action of this fatty acid is pleiotropic in nature and the known anti-inflammatory properties of this and other ω-3 polyunsaturated fatty acids may play part in neuroprotection [110] . Cardioprotective and hemodynamic properties: these may be beneficial in the control of OP-associated pulmonary and cardiac complications [3] , [10] .…”

“…In any case, before we can decide on the role of ILE in the treatment of CWA poisoning, we should direct and conduct a methodical research program aimed at understanding better its mechanism-of-action in OP and sulfur mustard poisonings, study better its PK/PD, routes and timing of administration, and interactions with currently used antidotes in order to design combination therapies. Another important research direction is the effect of different types and compositions of ILE, especially those enriched in ω-3 polyunsaturated fatty acids, shown recently to be superior to standard ILE preparations in the protection of ARDS patients [119] , [120] and in animal models [62] , and, as cited above, may be useful in amelioration of nerve agent neuropathological effects2 [102] , [110] .…”

Monoraphidium sp. HDMA-20 is a new potential source of α-linolenic acid and eicosatetraenoic acid

“…As one of ω-3 fatty acids, ALA has been reported to have nutraceutical/pharmacological benefits and is safe as a food ingredient [5]. ALA exhibits a variety of health benefits, such as endogenous neurorestoration [6], reducing the risk of nonfatal acute myocardial infarction and coronary heart disease [7, 8], and anti-cancer effect [9].…”