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Additional Phase I and Phase II Clinical Trials for Neuroprotective Pharmaceutical Agents during Acute SCI

Cethrin®

The release of pro-inflammatory cytokines and growth inhibitory proteins after a SCI results in enhanced signaling of the protein Rho. When Rho is activated, axon regrowth is inhibited. Cethrin®specifically inactivates Rho and therefore enables axons to regrow. In addition, Cethrin®has been shown to reduce inflammation by decreasing hematogenous monocytes, reducing glial scar formation and augmenting neuron remyelination (McKerracher & Guertin, 2013). Unlike most acute spinal cord drugs reviewed so far that have been delivered intravenously, Cethrin®is applied topically to the spinal cord during the time of surgery.

Minocycline

Another emerging neuroprotective drug is minocycline, a broad spectrum antibiotic. Minocycline is able to cross the blood-brain barrier and exhibits anti-inflammatory and anti-excitatory properties (Baptiste & Fehlings, 2006). Studies investigating SCI in animal models have suggested that this drug inhibits microglial proliferation, reduces cellular apoptosis and neutralizes free radicals (Yong et al. 2004). These properties have made it a promising candidate for neurological disorders such as Parkinson’s disease, stroke, and multiple sclerosis in addition to SCI (Casha et al. 2012).

Riluzole

During secondary injury, an influx of sodium enters nerve cells and instigates an osmotic response where the neurons begin to swell to dangerous levels. In response, calcium rushes into the cell and triggers an amplified sodium excretion from the cell. Subsequently, the high intracellular concentration of calcium results in glutamate release and therefore excitotoxicity (Wilson & Fehlings, 2014). Riluzole acts to block these sodium channels, thus preventing excitotoxicity. Animal studies have found spinal cord injured rats that received riluzole to have improved motor function, more brain stem neurons and a smaller lesion size after 6 weeks compared to rats that received different sodium channel blockers or a placebo (Schwartz & Fehlings, 2001). Earlier human trials with riluzole have led to its approval by the Food and Drug Administrationin the US for the treatment of amyotrophic lateral sclerosis (Wilson & Fehlings, 2014).

Pharmaceutical Agents for Neuroprotection in Acute SCI in Phase I and II Clinical Trials

Discussion

Despite the small sample sizes and open label protocols, Cethrin®, Minocycline and Riluzole show initial promise in terms of effectiveness for treating acute SCI and safe administration in humans; further trials are recommended.

Conclusion

There is level 2 evidence (from one prospective controlled trial; Fehlings et al. 2011) that Cethrin® is a safe and tolerable drug, and may promote neurological recovery in acute SCI individuals.

There is level 1b evidence (from one RCT; Casha et al. 2012) that minocycline is not effective in promoting motor or sensory recovery in acute SCI individuals.

There is level 2 evidence (from one cohort study; Grossman et al.  2014) that riluzole may be effective in promoting long term motor or sensory recovery in acute SCI individuals.

  • Cethrin® is a safe and tolerable drug, but its effect on neurological recovery remains unknown during the acute phase post SCI.

    Minocycline is not effective for neurological recovery during the acute phase post SCI.

    Riluzole may be effective for neurological recovery during the acute phase post SCI.