Oral administration of a tri-therapy for central pattern generator activation in paraplegic mice: proof-of-concept of efficacy.
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.
Guertin
Pierre A
PA
Laval University Medical Centre (CHUQ/CHUL), Quebec City, Canada. Pierre.Guertin@crchul.ulaval.ca
Ung
Roth-Visal
RV
Rouleau
Pascal
P
D000284:Administration, Oral; D000818:Animals; D001683:Biological Clocks / Q000187:drug effects*; D002065:Buspirone / Q000008:administration & dosage*; D002230:Carbidopa / Q000008:administration & dosage*; D015259:Dopamine Agents / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D005240:Feasibility Studies; D020233:Gait Disorders, Neurologic / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D007980:Levodopa / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D010264:Paraplegia / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage; D013116:Spinal Cord / Q000503:physiopathology*
D015259:Dopamine Agents; D004338:Drug Combinations; D017366:Serotonin Receptor Agonists; D007980:Levodopa; D002230:Carbidopa; D002065:Buspirone