Potentiation of neuromuscular transmission by a small molecule calcium channel gating modifier improves motor function in a severe spinal muscular atrophy mouse model

Abstract

Spinal muscular atrophy (SMA) is a monogenic disease that clinically manifests as severe muscle weakness due to neurotransmission defects and motoneuron degeneration. Individuals affected by SMA experience neuromuscular weakness that impacts functional activities of daily living. We have used a mouse model of severe SMA (SMNΔ7) to test whether a calcium channel gating modifier (GV-58), alone or in combination with a potassium channel antagonist (3,4-diaminopyridine; 3,4-DAP), can improve neuromuscular function in this mouse model. Bath application of GV-58 alone or in combination with 3,4-DAP significantly restored neuromuscular transmission to control levels in both a mildly vulnerable forearm muscle and a strongly vulnerable trunk muscle in SMNΔ7 mice at postnatal day 10–12. Similarly, acute subcutaneous administration of GV-58 to postnatal day 10 SMNΔ7 mice, alone or in combination with 3,4-DAP, significantly increased a behavioral measure of muscle strength. These data suggest that GV-58 may be a promising treatment candidate that could address deficits in neuromuscular function and strength, and that the addition of 3,4-DAP to GV-58 treatment could aid in restoring function in SMA.

A cross‐sectional study of ageing at the mouse neuromuscular junction and effects of an experimental therapeutic approach for dynapenia

“…Our data support the therapeutic potential of GV‐58 as a neurotransmitter release enhancer which could strengthening weakened transmission, potentially restoring reduced neuromuscular activity in ageing. Previously, the effect of acute GV‐58 exposure on two mouse neuromuscular disease models (Lambert–Eaton myasthenic syndrome and spinal muscular atrophy) was examined (Ojala et al., 2023; Tarr et al., 2013, 2014). In both cases, the effects of GV‐58 were similar to what we reported here for aged NMJs (∼1.8‐fold increase in the magnitude of transmitter release).…”

“…In both cases, the effects of GV‐58 were similar to what we reported here for aged NMJs (∼1.8‐fold increase in the magnitude of transmitter release). It is also true that GV‐58 will increase the magnitude of transmitter release in healthy synapses to the same degree, but this in not relevant to nerve‐evoked muscle contraction because all neuromuscular synapses are already above threshold after motor action potential activity; as such, increased transmitter release has no impact on nerve‐evoked muscle contraction (Ojala et al., 2023).…”

Nifedipine Ameliorates Cellular Differentiation Defects of Smn-Deficient Motor Neurons and Enhances Neuromuscular Transmission in SMA Mice

“…R-Roscovitine also improves Ca 2+ signaling and development in SMN-deficient motor neurons in culture [20]. GV-58, an R-Roscovitine derivate that also increases the opening time of Cav2.1 and Cav2.2 channels, significantly enhances neuromuscular transmission and muscle strength in SMA mice [23].…”