Recovery of Locomotor Function with Combinatory Drug Treatments Designed to Synergistically Activate Specific Neuronal Networks

Pierre   A.   Guertin

Abstract

Spinal cord injury (SCI) is a devastating condition generally leading to a permanent and irreversible loss of sensory and motor functions. We have identified recently a number of serotonergic, adrenergic and dopaminergic receptor agonists or precursors that can acutely elicit some motor and locomotor-like movements in completely spinal cordtransected (thoracic level) animals. However, only partial central network-activating effects were found with single molecules since none administered separately could elicit weight-bearing and functional stepping movements in Tx animals. In turn, a recent breakthrough revealed that full spinal locomotor network-activating effects may be induced with synergistic drug combinations. Indeed, specific cocktails comprising some of these agonists and precursors were found, indeed, to powerfully generate weight-bearing stepping with plantar foot placement in untrained, non-assisted and non-sensorystimulated Tx mice. This significant finding provides clear evidence suggesting that combinatorial approaches based on drug-drug synergistic interactions may constitute innovative solutions for the design and development of novel pharmacological therapies in the field of SCI and related neurological disorders.

Keywords: Spinal cord, SCI, central pattern generator, CPG, locomotion, dopamine, serotonin, L-DOPA, mice