title: "Preconditioning" with latrepirdine, an adenosine 5'-monophosphate-activated protein kinase activator, delays amyotrophic lateral sclerosis progression in SOD1(G93A) mice.
abstract: Adenosine 5'-monophosphate-activated protein kinase (AMPK) is a master regulator of energy balance. As energy imbalance is documented as a key pathologic feature of amyotrophic lateral sclerosis (ALS), we investigated AMPK as a pharmacologic target in SOD1(G93A) mice. We noted a strong activation of AMPK in lumbar spinal cords of SOD1(G93A) mice. Pharmacologic activation of AMPK has shown protective effects in neuronal "preconditioning" models. We tested the hypothesis that "preconditioning" with a small molecule activator of AMPK, latrepirdine, exerts beneficial effects on disease progression. SOD1(G93A) mice (n = 24 animals per group; sex and litter matched) were treated with latrepirdine (1 μg/kg, intraperitoneal) or vehicle from postnatal day 70 to 120. Treatment with latrepirdine increased AMPK activity in primary mouse motor neuron cultures and in SOD1(G93A) lumbar spinal cords. Mice "preconditioned" with latrepirdine showed a delayed symptom onset and a significant increase in life span (p < 0.01). Our study suggests that "preconditioning" with latrepirdine may represent a possible therapeutic strategy for individuals harboring ALS-associated gene mutations who are at risk for developing ALS.
authors.affiliation: Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Coughlan
authors.affiliation: Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Mollie R
authors.initials: MR
authors.lastname: Mitchem
authors.affiliation: Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin, Ireland.
authors.forename: Marion C
authors.initials: MC
authors.lastname: Hogg
authors.affiliation: Department of Physiology and Medical Physics, Centre for the Study of Neurological Disorders, Royal College of Surgeons in Ireland, Dublin, Ireland. Electronic address: JPrehn@rcsi.ie.
authors.forename: Jochen H M
authors.initials: JH
authors.lastname: Prehn
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics* / Q000517:prevention & control*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018450:Disease Progression; D004734:Energy Metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D007211:Indoles / Q000008:administration & dosage*; D007274:Injections, Intraperitoneal; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000201:enzymology / Q000473:pathology; D009154:Mutation; D012306:Risk; D013116:Spinal Cord / Q000201:enzymology; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: D007211:Indoles; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D055372:AMP-Activated Protein Kinases; C010119:latrepirdine
keywords: AMPK; Amyotrophic lateral sclerosis; Bioenergetics; Motoneuron degeneration; Pre-conditioning; SOD1; Spinal cord