Hope for spinal cord injury treatment

Summary: AZD1236, an existing drug primarily used to treat COPD, reduces damage after spinal cord injury by inhibiting the inflammatory response in the spinal cord.

Source: University of Birmingham

Scientists from the University of Birmingham have shown that an existing drug can reduce damage after spinal cord injury by blocking the inflammatory response in the spinal cord.

Their research, published today in Clinical and Translational Medicineshows that AZD1236, a drug developed by AstraZeneca, can significantly reduce “secondary damage” caused by the body’s response to spinal cord injury (SCI).

Researchers led by Professor Zubair Ahmed, professor of neuroscience and head of the Neuroscience and Ophthalmology Section at the university’s Institute of Inflammation and Aging, used animal models to show that AZD1236 can promote significant nerve regeneration, with dramatic 80% retention. of nerve function after spinal cord compression injury.

Crucially, this translated into an 85% improvement in movement and feeling. These dramatic effects were seen after only three days of treatment with AZD1236, starting within 24 hours of injury. Within three weeks, the AZD1236-treated animals showed an unprecedented recovery, while the controls still showed significant deficits six weeks after injury.

One of the major causes of secondary SCI damage is the breakdown of the blood spinal cord barrier (BSCB). This results in edema (accumulation of excess fluid 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 involved in the inflammatory process.

The researchers showed that AZD1236 stops spinal cord edema and reduces BSCB breakdown and scarring at the injury site. They also examined the effect of AZD1236 dosing on MMP-9 and MMP-12 activity in both the bloodstream and the 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 cerebrospinal fluid. Not surprisingly, intrathecal injection produced higher levels (88-90%) of suppression in the cerebrospinal fluid.

Further studies showed that the AZD1236 suppressed the formation of pro-inflammatory cytokines (molecules known to contribute to the development of long-term neuropathic pain, which often follows SCI) by 85-95%. AZD1236 was also found to be 82% more effective in relieving SCI-induced neuropathic pain sensitivity to cold, heat, and touch compared to currently used analgesics such as pregabalin (Lyrica) and gabapentin.

Professor Ahmed noted that “there is currently no restorative drug available for spinal cord injury patients, treatments only provide symptomatic relief and do not address the underlying molecular mechanisms that cause or contribute to edema and breakdown of the blood-spinal cord barrier.

One of the major causes of secondary SCI damage is the breakdown of the blood spinal cord barrier (BSCB). Image is in the public domain

“This drug has the potential to be a first-class treatment against some of the major pathological causes of spinal cord injury and could revolutionize the outlook for spinal cord injury recovery.”

Hitesh Sanganee, Executive Director, Discovery Sciences, AstraZeneca says that “The work of Professor Ahmed and his team has been supported by our Open Innovation Program and represents a highly successful collaboration between academia and industry to explore the possibility of real benefits for affected patients.” by SCI, an area of ​​high medical need.

“Exploring the potential of AZD1236 in this new indication is a great outcome for our Open Innovations program and aligns with our ethos of sharing ideas and enabling scientific innovation to push the boundaries between academia and industry.” will help translate innovative ideas into scientific breakthroughs and potential new medicines faster.”

About this spinal cord injury research news

Writer: press office
Source: University of Birmingham
Contact: Press Office – University of Birmingham
Image: The image is in the public domain

Original research: Open access.
“Clinical-ready inhibitor of MMP-9/-12 reverses sensory and functional impairment in rodent models of spinal cord injury” by Zubair Ahmed et al. Clinical and Translational Medicine


Abstract

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Clinical-ready inhibitor of MMP-9/-12 reverses sensory and functional decline in rodent models of spinal cord injury

This study demonstrated that short-term inhibition of matrix metalloprotease (MMP)-9 and MMP-12 in both mouse and rat models of spinal cord injury (SCI) using the clinically useful, orally bioavailable and specific inhibitor, AZD1236, reversed the damage. diminished. induced edema, pro-inflammatory pain markers, pain sensation, and blood spinal cord barrier (BSCB) breakdown.

Inhibition of MMP-9 and MMP-12 also protected against SCI-induced sensory and locomotor impairment.

By demonstrating these unprecedented improvements with a clinic-ready MMP inhibitor, using a dosing regimen that is expected to be safe and well tolerated in SCI patients, we are now well positioned to rapidly transition to a phase 2a trial in patients.

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