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.
Highlights
Work showed that administration of An Essential Nutraceutical α-Linolenic acid (ALA) resulted in an increase of the omega-3 polyunsaturated fatty acid (PUFA) 7,10,1,3,16,19-docosapentaenoic acid and 4,7,10,13,16,19-docosahexaenoic acid in the brain [7]
In weanling rats made deficient in essential fatty acids, administration of ALA resulted in a reduction in omega-6 polyunsaturated fatty acids such as arachidonic acid suggesting that omega-3 PUFAs exert their effect in brain by inhibiting the desaturation of dihomo-γ-linolenic acid to arachidonic acid
We showed that an increase in activated Akt and mammalian target of rapamycin complex 1 (mTORC1) only occurred in those groups of animals intravenously administered ALA500
Summary
Glutamate is the major excitatory neurotransmitter in brain. Paradoxically, the pathophysiology of hypoxic-ischemic neuronal damage in acute and chronic neurodegenerative disorders involves glutamate. The glutamate phase involves glutamate receptors which in turn participate in the propagation and maintenance of nerve agent-induced seizures; the N-methyl-D-aspartate (NMDA) glutamate receptor subtype plays a major role in excitotoxic-mediated neuronal cell death in vulnerable brain regions [49,50,51,52]. The rapid increase of acetylcholine that occurs early in soman poisoning is known as the cholinergic phase During this phase seizures can be blocked with muscarinic receptor antagonists when given immediately after nerve agent exposure. These findings suggested that ALA may be capable of preventing the primary as well as the secondary neuronal damage triggered by soman, which in turn could reduce the attendant cognitive impairment Taken together, this was the first demonstration that the nutraceutical ALA exerted a potent neuroprotective effect against soman-induced neuropathology. The critical issue was to determine whether the reduction in neuronal degeneration improved functional outcome
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