Existing drug may help treat spinal cord injury
Scientists at the University of Birmingham have shown that an existing drug may reduce damage after spinal cord injury (SCI), by blocking the inflammatory response in the spinal cord. Their research, published in the journal Clinical and Translational Medicine, demonstrates that AstraZeneca’s AZD1236 can significantly reduce ‘secondary damage’ caused by the body’s response to SCI.
One of the key drivers of SCI secondary damage is breakdown of the blood–spinal cord barrier (BSCB). This results in oedema (excess fluid build-up around the spinal cord) and triggers an inflammatory response that can ultimately hinder the healing process and lead to nerve cell death. AZD1236 is a potent and selective inhibitor of two enzymes, MMP-9 and MMP-12, which are implicated in the inflammatory process.
The researchers used animal models to demonstrate that AZD1236 halts SCI-induced oedema, and reduces BSCB breakdown and scarring at the site of the injury. They also examined the effect of AZD1236 dosing on MMP-9 and MMP-12 activity in both the bloodstream and cerebrospinal fluid, which surrounds the spinal cord. Here they demonstrated significant suppression of enzyme activity after both oral dosing and intrathecal dosing (injection into the spinal canal). Oral dosing reduced enzyme activity by 90% in serum and 69–74% in the cerebrospinal fluid. Intrathecal injection delivered higher levels (88–90%) of suppression in the cerebrospinal fluid.
Further studies showed that AZD1236 suppressed the formation of pro-inflammatory cytokines (molecules that are known to contribute to the development of long-lasting neuropathic pain, which often follows SCI) by 85–95%. The drug was also found to be 82% more effective at alleviating SCI-induced neuropathic pain sensitivity to cold, heat and touch when compared to currently used pain medications such as pregabalin (Lyrica) and gabapentin.
The study showed that AZD1236 can promote significant nerve regeneration, with a dramatic 80% preservation in nerve function following spinal cord compression injury — which translated into an 85% improvement in movement and sensation. These effects were observed following only three days of treatment with AZD1236, starting within 24 hours post-injury. Within three weeks, the AZD1236-treated animals were said to be showing unprecedented recovery, while controls still showed significant deficits at six weeks post-injury.
“There is currently no reparative drug available for SCI patients — treatments only provide symptomatic relief and do not tackle the underlying molecular mechanisms that cause or contribute to oedema and blood-spinal cord barrier breakdown,” said research leader Professor Zubair Ahmed. “This drug has the potential to be a first-in-class treatment against some of the key pathological drivers of SCI and could revolutionise the prospects for recovery of SCI patients.”
University of Birmingham Enterprise has filed a patent application covering selective combined inhibition activity or expression of both matrix metalloproteinase MMP-9 (gelatinase B) and MMP-12 (macrophage metalloelastase) after SCI or related injury to neurological tissue. University of Birmingham Enterprise is now seeking investors and partners to take the therapeutic to clinical trials.
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