Coughlan, Karen S. Mitchem, Mollie R. Hogg, Marion C. Prehn, Jochen HM "Preconditioning" with latrepirdine, an adenosine 5'-monophosphate-activated protein kinase activator, delays amyotrophic lateral sclerosis progression in SOD1(G93A) mice. <p>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.</p> Amyotrophic Lateral Sclerosis;AMPK;Bioenergetics;Pre-Conditioning;Spinal Cord;Motoneuron Degeneration;SOD1;Physiology;Medical Physics 2019-11-22
    https://repository.rcsi.com/articles/journal_contribution/_Preconditioning_with_latrepirdine_an_adenosine_5_-monophosphate-activated_protein_kinase_activator_delays_amyotrophic_lateral_sclerosis_progression_in_SOD1_G93A_mice_/10792373