Cleavage of [Na.sup.+] channels by calpain increases persistent [Na.sup.+] current and promotes spasticity after spinal cord injury

Upregulation of the persistent sodium current ([I.sub.NaP]) in motoneurons contributes to the development of spasticity after spinal cord injury (SCI). We investigated the mechanisms that regulate [I.sub.NaP] and observed elevated expression of voltage-gated sodium (Nav) 1.6 channels in spinal lumbar motoneurons of adult rats with SCI. Furthermore, immunoblots revealed a proteolysis of Nav channels, and biochemical assays identified calpain as the main proteolytic factor. Calpain-dependent cleavage of Nav channels after neonatal SCI was associated with an upregulation of [I.sub.NaP] in motoneurons. Similarly, the calpain-dependent cleavage of Nav1.6 channels expressed in human embryonic kidney (HEK) 293 cells caused the upregulation of [I.sub.NaP]. The pharmacological inhibition of calpain activity by MDL28170 reduced the cleavage of Nav channels, [I.sub.NaP] in motoneurons and spasticity in rats with SCI. Similarly, the blockade of [I.sub.NaP] by riluzole alleviated spasticity. This study demonstrates that Nav channel expression in lumbar motoneurons is altered after SCI, and it shows a tight relationship between the calpain-dependent proteolysis of Nav1.6 channels, the upregulation of [I.sub.NaP] and spasticity.
Spasticity, a common debilitating complication in people with spinal cord injury (SCI), is characterized by a velocity-dependent increase in the tonic stretch reflex and spasms (1). It is primarily attributed [...]