Alpha-Linolenic Acid-Induced Increase in Neurogenesis is a Key Factor in the Improvement in the Passive Avoidance Task After Soman Exposure.
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.
Molecular and Cellular Biology Graduate Student Program, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
Tetsade C B
TC
Piermartiri
Hongna
H
Pan
Jun
J
Chen
John
J
McDonough
Neil
N
Grunberg
James P
JP
Apland
Ann M
AM
Marini
D000818:Animals; D034961:Antigens, Nuclear / Q000096:biosynthesis / Q000235:genetics; D001286:Atropine Derivatives / Q000627:therapeutic use; D001362:Avoidance Learning / Q000187:drug effects* / Q000502:physiology; D001925:Brain Damage, Chronic / Q000209:etiology / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics; D004261:DNA Replication / Q000187:drug effects; D003975:Diazepam / Q000627:therapeutic use; D000089622:Doublecortin Domain Proteins; D004597:Electroshock; D005106:Exploratory Behavior / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D055495:Neurogenesis / Q000187:drug effects*; D009479:Neuropeptides / Q000096:biosynthesis / Q000235:genetics; D018696:Neuroprotective Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D009498:Neurotoxins / Q000378:metabolism; D010091:Oximes / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics; D011726:Pyridinium Compounds / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology; D012999:Soman / Q000633:toxicity*; D013226:Status Epilepticus / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D017962:alpha-Linolenic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000627:therapeutic use
D034961:Antigens, Nuclear; D001286:Atropine Derivatives; D019208:Brain-Derived Neurotrophic Factor; D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010091:Oximes; D011726:Pyridinium Compounds; C546339:Rbfox3 protein, rat; D017962:alpha-Linolenic Acid; C006649:methylatropine; D012999:Soman; D020813:Receptor, trkB; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C022870:asoxime chloride; D003975:Diazepam; D020123:Sirolimus