pridopidine and Amyotrophic-Lateral-Sclerosis

Topics: Amyotrophic Lateral Sclerosis; Animals; Autophagy; C9orf72 Protein; Frontotemporal Dementia; Heat-Shock Proteins; Membrane Proteins; Mice; Nuclear Pore Complex Proteins; Receptors, sigma; Sigma-1 Receptor; Transcription Factors

Amyotrophic lateral sclerosis (ALS) is a lethal and incurable neurodegenerative disease due to the loss of upper and lower motor neurons, which leads to muscle weakness, atrophy, and paralysis. Sigma-1 receptor (σ-1R) is a ligand-operated protein that exhibits pro-survival and anti-apoptotic properties. In addition, mutations in its codifying gene are linked to development of juvenile ALS pointing to an important role in ALS. Here, we investigated the disease-modifying effects of pridopidine, a σ-1R agonist, using a delayed onset SOD1 G93A mouse model of ALS. Mice were administered a continuous release of pridopidine (3.0 mg/kg/day) for 4 weeks starting before the appearance of any sign of muscle weakness. Mice were monitored weekly and several behavioural tests were used to evaluate muscle strength, motor coordination and gait patterns. Pridopidine-treated SOD1 G93A mice showed genotype-specific effects with the prevention of cachexia. In addition, these effects exhibited significant improvement of motor behaviour 5 weeks after treatment ended. However, the survival of the animals was not extended. In summary, these results show that pridopidine can modify the disease phenotype of ALS-associated cachexia and motor deficits in a SOD1 G93A mouse model.

Topics: Amyotrophic Lateral Sclerosis; Animals; Cachexia; Disease Models, Animal; Mice; Mice, Transgenic; Muscle Weakness; Neurodegenerative Diseases; Phenotype; Piperidines; Superoxide Dismutase; Superoxide Dismutase-1

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease affecting both the upper and lower motor neurons (MNs), with no effective treatment currently available. Early pathological events in ALS include perturbations in axonal transport (AT), formation of toxic protein aggregates and Neuromuscular Junction (NMJ) disruption, which all lead to axonal degeneration and motor neuron death. Pridopidine is a small molecule that has been clinically developed for Huntington disease. Here we tested the efficacy of pridopidine for ALS using in vitro and in vivo models. Pridopidine beneficially modulates AT deficits and diminishes NMJ disruption, as well as motor neuron death in SOD1

Topics: Amyotrophic Lateral Sclerosis; Animals; Axonal Transport; Cell Death; Cell Survival; Cells, Cultured; Coculture Techniques; Disease Models, Animal; Female; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Transgenic; Motor Neurons; Muscle Cells; Myoblasts, Smooth Muscle; Neuromuscular Junction; Piperidines; Receptors, sigma; Sigma-1 Receptor; Spinal Cord; Superoxide Dismutase-1