Oral administration of a tri-therapy for central pattern generator activation in paraplegic mice: proof-of-concept of efficacy

Biotechnol J. 2010 Apr;5(4):421-6. doi: 10.1002/biot.200900278.

Abstract

Spinal cord injury (SCI) is a neurological condition, for which no cure exists, typically leading to an immediate and irreversible loss of sensory and voluntary motor functions accompanied by significant health problems. We conducted proof-of-concept experiments aimed at assessing efficacy upon oral administration of a novel combination therapy for central pattern generator (CPG) activation and corresponding locomotor movement generation in completely paraplegic animals. Co-administration orally (by gavage) of buspirone, levodopa and carbidopa was found to dose-dependently induce episodes of steady weight-bearing stepping in low-thoracic (Th9/10) spinal cord-transected (Tx) mice (with no other form of assistance or training). Robust hindlimb stepping with weight-bearing capabilities was induced with the tri-therapy but not with clinically relevant doses of these compounds administered separately. These results provide evidence suggesting that this drug combination may be ideally suited to constitute a first-in-class therapy (CPG activator) for locomotor activity induction in chronic SCI individuals, given that efficacy was shown using commercially available brain-permeable small molecules, already known as safe for the treatment of various neurological indications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Biological Clocks / drug effects*
  • Buspirone / administration & dosage*
  • Carbidopa / administration & dosage*
  • Dopamine Agents / administration & dosage
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Feasibility Studies
  • Gait Disorders, Neurologic / drug therapy
  • Gait Disorders, Neurologic / etiology
  • Gait Disorders, Neurologic / physiopathology*
  • Levodopa / administration & dosage*
  • Male
  • Mice
  • Paraplegia / complications
  • Paraplegia / drug therapy*
  • Paraplegia / physiopathology
  • Serotonin Receptor Agonists / administration & dosage
  • Spinal Cord / physiopathology*

Substances

  • Dopamine Agents
  • Drug Combinations
  • Serotonin Receptor Agonists
  • Levodopa
  • Carbidopa
  • Buspirone