Amyotrophic Lateral Sclerosis, AMPK, Bioenergetics, Pre-Conditioning, Spinal Cord, Motoneuron Degeneration, SOD1
This study was supported through a grant from the Science Foundation Ireland (08/IN.1/B1949) and the Irish Health Research Boards (HRA_POR/2011/108) to J.H.M.P. The authors thank Dr Hans Georg Koenig for all discussions and support and Dr Heiko Duessman, Dr Tytus Bernas, and Sinéad Kinsella for excellent technical assistance. Karen S. Coughlan and Jochen H. Prehn designed the research. Karen S. Coughlan and Mollie R. Mitchem performed the research. Karen S. Coughlan, Marion C. Hogg, and Jochen H. Prehn analyzed data. Karen S. Coughlan, Marion C. Hogg, and Jochen H. Prehn wrote the article.
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.
Physics | Physiology
Coughlan KS, Mitchem MR, Hogg MC, Prehn JHM. "Preconditioning" with latrepirdine, an adenosine 5'-monophosphate-activated protein kinase activator, delays amyotrophic lateral sclerosis progression in SOD1(G93A) mice. Neurobiology of Aging. 2015;36(2):1140-50.