Chapter 21 - Calpain role in the pathophysiology of spasticity after spinal cord injury

Abstract

Spasticity is a highly impairing condition following spinal cord injury (SCI) that develops in more than 60% of patients as early as one-year postinjury. To date, pharmacological therapy shows limited effectiveness and various systemic side effects. Animal models allow carrying out in-depth investigations on pathophysiological mechanisms of spasticity after SCI to identify innovative and efficacious therapeutic strategies. So far, several maladaptive changes in sublesional motoneurons have been reported, causing an increased excitation (hyperexcitability) and a reduced inhibition (disinhibition) in the spinal cord. We demonstrated that calpains, a family of calcium-dependent proteases, have an upstream role in promoting the excitatory/inhibitory imbalance of spinal motoneurons that leads to spasticity after SCI. On the one hand, calpains cleave voltage-gated sodium channels Nav1.6 up-regulating the sodium persistent inward current(INaP), which evokes huge plateau potentials with self-sustained spiking, lastly causing spinal hyperexcitability contributing to spasticity. On the other hand, calpains down-regulate the potassium-chloride cotransporter KCC2 on motoneuron membranes, depolarizing the chloride equilibrium potential (ECl−) and inducing spinal disinhibition also involved in the onset of spasticity. Therefore, calpain inhibition might represent an effective antispastic therapy targeting the main upstream molecule accounting for multiple mechanisms of spasticity, instead of singularly acting on downstream players. Furthermore, this therapeutic strategy can be adopted not only to prevent spasticity after SCI but also to counteract neurological disorders where calpains have a critical role.