Background: Amyotrophic Lateral Sclerosis (ALS) in a neurodegenerative disease that results in the progressive deterioration and loss of function of the motor neurons leading to paralysis. Studies indicated that synaptic transmission at neuromuscular junctions (NMJs) is reduced in early stages of the disease – before denervation and motoneuron death. To date, there are no treatments for ALS that target improving neuromuscular transmission, which would improve quality of life for ALS patients by enhancing neuromuscular strength.
Objectives: Our goal was to test the acute and chronic effect of GV-58, a novel Cav2-specific voltage-gated calcium channel gating modifier that we have developed, on neuromuscular function and innervation in SOD1G93A ALS model mice.
Results: First, we show significant denervation in the epitrochleoanconeus (ETA) muscle of SOD1G93A mice (which has not previously been documented as vulnerable) at the early symptomatic stage (P90). Our results also demonstrate impaired magnitude of transmitter release in the ETA muscle of SOD1G93A mice, at the symptomatic stage (P90) (~40% below control levels) and that treating ex vivo nerve muscle preparations from SOD1G93A mice with GV-58, significantly increased quantal content. We hypothesized that a GV-58-mediated increase in synaptic activity may reduce denervation and provide better support for the NMJ. Interestingly, a chronic (20 days) once-daily i.p. injection of GV58 starting at P90 delayed disease progression, significantly enhanced end plate potential amplitude, and maintained synapse innervation (20 days post injection), compared to vehicle-treated mice.
Conclusions: Based on our promising results demonstrating the beneficial effects of GV-58 In ALS mice, we hypothesize that GV-58 could prove to be a new intervention approach to strengthen synaptic transmission, improve neuromuscular function, delay the loss of motor skills, increase the quality of life, and potentially prolong the life-span of ALS patients.