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

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.

Coapplication of noisy patterned electrical stimuli and NMDA plus serotonin facilitates fictive locomotion in the rat spinal cord

“…Nevertheless, the discovery of new drug combinations that can selectively act on the CPG (Guertin et al 2010), along with the development of innovative systems for a more localized drug delivery (Kang et al 2009) or with new substrates for the controlled release of neuroactive chemicals directly at the level of the spinal subarachnoid space (Cobacho et al 2009), may help targeting pharmacological agents to modulate the activity of spinal circuits. Hence, the present study suggests that conjoint electrical stimulation using weak noisy waves with even subthreshold concentrations of neurochemicals may actually be a desirable process to pharmacologically manipulate CPG excitability to restore functional benefits to persons with a spinal cord injury.…”

Whats Needed for Approval of Fixed-Dose Combination Products?

“…It has recently completed phase I/II trials (https:// clinicaltrials.gov/ct2/show/NCT01484184). For sleeping disorders, new CNS-mediated actions were found to be induced by THN102 -a FDC comprising an old drug modafinil (in low doses) and a new molecular entity THN02 (currently in phase II clinical development) [6]. Buprenorphine, originally approved as an anesthetic agent (opioid agonist), was recently approved (2014) in combination with naloxone (opioid antagonist) as a novel FDC called Suboxone ® against opioid dependence [7].…”

Could overmedication associated with spinal injuries be treated with one more CNS drug?

“…It is an oral tritherapy composed of buspirone/levodopa/ carbidopa shown first in paraplegic mice to induce, within a few minutes post-administration, 30-45 min episodes of self-weight bearing walking on a treadmill [11]. It has recently undergone successfully, at the Montreal General Hospital/McGill University Health Center, a randomized double-blind study in 45 subjects suffering a SCI (https:// clinicaltrials.gov/ct2/show/NCT01484184).…”