title: 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.
authors.affiliation: Molecular and Cellular Biology Graduate School Program, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. tetsade@yahoo.com.br.
authors.forename: Tetsade
authors.initials: T
authors.lastname: Piermartiri
authors.affiliation: Department of Neurology and Program in Neuroscience, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. hongna.pan@usuhs.edu.
authors.forename: Hongna
authors.initials: H
authors.lastname: Pan
authors.affiliation: Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. taiza.figueiredo.ctr@usuhs.edu.
authors.forename: Taiza H
authors.initials: TH
authors.lastname: Figueiredo
authors.affiliation: Department of Neurology and Program in Neuroscience, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA. ann.marini@usuhs.edu.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Marini
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D019587:Dietary Supplements; D006801:Humans; D023421:Models, Animal; D000067397:Nerve Agents / Q000009:adverse effects*; D009422:Nervous System Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D000069338:Neuropathology; D000066829:Neuroprotection / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010755:Organophosphates / Q000009:adverse effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D017962:alpha-Linolenic Acid / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000928:Antidepressive Agents; D000067397:Nerve Agents; D018696:Neuroprotective Agents; D010755:Organophosphates; D016194:Receptors, N-Methyl-D-Aspartate; D017962:alpha-Linolenic Acid
keywords: BDNF; mTOR; natural product; neuroprotection; neurorestoration; nutraceutical; pleiotropic; rat; soman; α-linolenic acid