A clinical trial has begun enrolling 51 patients with chronic spinal cord injuries in the Canadian Province of Quebec. It’s a double-blinded, placebo controlled trial: Participants will get either a single drug, a two-drug combo, a three-drug blend called Spinalon, or placebo.
Spinalon comprises three drugs already approved for human use: levodopa, cabidopa and busipirone. Discovered by Pierre Guertin at the University of Laval in Quebec City, with key funding acknowledged from a two-year research grant in 2004 from the Reeve Foundation, Spinalon is a potent activator of pattern generation within the spinal locomotor network. It is not being studied or pitched as a cure drug; it is intended as a temporary treatment for secondary complications of chronic paralysis related to lack of activity, including sarcopenia (loss of muscle mass), osteoporosis, cardiovascular issues, high cholesterol, obesity, type II diabetes, anemia, immune system deficiency, deep vein clotting, depression, and so on.
Spinalon acts for 30 minutes to an hour by allowing for increased activity, such as weight bearing and hindlimb stepping.
Background: As we have reported several times, the spinal cord contains circuitry that has memory and can execute function; the cord, if stimulated in the right way, can activate rhythmic patterns of stepping -- without brain input. This is the basis of Locomotor Training (body-weight supported on treadmill), which has been clinically studied in the Reeve NeuroRecovery Network
for several years.
The concept of activity-based therapy and central pattern generation has also been demonstrated, at the University of Louisville in the Susan Harkema lab, in four human subjects who had epidural stimulators surgically implanted over their lumbar spinal cords. While only the results from the first patient (Rob Summers
) have been published, Harkema has stated that all four gained significant stepping while being stimulated. What’s more, all four gained meaningful control of some autonomic functions, including bowel, bladder and sexual function.
The animal work (at the Reggie Edgerton
lab at UCLA, a member of the Reeve International Research Consortium on Spinal Cord Injury) that preceded the human trials used treadmill training and epidural stimulation, but also added a drug, quipizine, to further enhance the response of the spinal cord to sensory input. When the human trials were designed, there was no known drug that humans could tolerate. Guertin, with his Spinalon tri-therapy, hopes to be first-in-class. He has licensed it to a company called Nordic Life Science, in Quebec.
Two of the drugs in Spinalon are commonly used for Parkinson’s disease. Levodopa is the go-to drug for Parkinson’s; it works by being converted to dopamine in the brain. Carbidopa, prevents levodopa from being broken down before it reaches the brain, thus allowing for lower doses, and therefore less nausea and vomiting.
Buspirone is an anti-anxiety drug that affects the neurotransmitter serotonin; it also appears to boost availability of dopamine by blocking certain receptors.
What the three drugs do is a complicated bit of pharmacology, but in simple terms, they allow for improved nerve signal transmission by lowering the threshold for signal strength. The circuitry that controls locomotion is specifically influenced by what are called monoamines – dopamine, serotonin and noradrenalin are examples. Successful locomotion relies heavily on the coordinated release of these monoamines in various spinal regions.
While the exact tuning of neural behavior is quite complex, Spinalon is a cocktail that appears to modulate the monoamines in ways that improve neurological function.
In the clinical trial, patients will receive either placebo capsules (starch) or capsules with buspirone only, levodopa/carbidopa only or buspirone/levodopa/carbidopa (Spinalon).
For more on the clinical trial see this link
• Clinical diagnosis of complete or motor-complete SCI (ASIA-A, ASIA-B)
• Chronically injured (at least 3 months post-injury)
• Paraplegic (within T1-T12) or tetraplegic (within C3-C8)
• In relatively good health condition (no significant bed sore, urinary tract infection)
• 18-65 years of age
• Men and women
• Quebec Province residents only
Proof of concept paper from Guertin, 2010: Oral administration of a tri-therapy for central pattern generator activation in paraplegic mice: proof-of-concept of efficacy
. From the paper:
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.
Here’s an excerpt from a 2011 paper with Guertin as first author, with further support for his drug combination: Effects on locomotion, muscle, bone, and blood induced by a combination therapy eliciting weight-bearing stepping in nonassisted spinal cord-transected mice:
Subcutaneous administration 4 times per week for 1 month of 1.5 mg/kg buspirone, 1.5 mg/kg apomorphine, 12.5 mg/kg benserazide, and 50 mg/kg L-DOPA induced episodes of weight-bearing stepping on a treadmill in nonassisted paraplegic mice for 45-minute sessions. Hindlimb muscle cross-sectional area and fiber area values as well as several blood cell constituent levels assessed at 30 days postinjury were positively affected by the combination therapy, as compared with controls. Episodes of locomotion remained effective on each treatment. Femoral bone mineral density loss was not prevented by triple therapy.....CONCLUSION: Although translation of these findings needs further experimentation, similar pharmacological activation of the CPG offers a novel therapeutic target to provide some health benefits in motor-complete SCI patients.
Guertin is not alone in searching for a drug to enhance CPG activity. From Gregoire Courtine
, then at the University of Zurich in Switzerland, along with Reggie Edgerton, 2011 (Courine was Edgerton’s graduate student until he started his own lab in Europe): Controlling specific locomotor behaviors through multidimensional monoaminergic modulation of spinal circuitries.
Descending monoaminergic inputs markedly influence spinal locomotor circuits, but the functional relationships between specific receptors and the control of walking behavior remain poorly understood. To identify these interactions, we manipulated serotonergic, dopaminergic, and noradrenergic neural pathways pharmacologically during locomotion enabled by electrical spinal cord stimulation in adult spinal rats in vivo.
Capitalizing on these predictive interactions, we elaborated a multidimensional monoaminergic intervention that restored coordinated hindlimb locomotion with normal levels of weight bearing and partial equilibrium maintenance in spinal rats. These findings provide new perspectives on the functions of and interactions between spinal monoaminergic receptor systems in producing stepping, and define a framework to tailor pharmacotherapies for improving neurological functions after CNS disorders.