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Hope for spinal cord injury treatment – Neuroscience News

Summary: AZD1236, an existing drug used primarily for the treatment of COPD, reduces damage following 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 medicinedemonstrates 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 Section of Neuroscience and Ophthalmology at the University Institute of Inflammation and Aging, used animal models to demonstrate that AZD1236 can promote significant nerve regeneration, with a dramatic 80% preservation of nerve function after spinal cord compression injury.

Importantly, this resulted in an 85% improvement in movement and sensation. These dramatic effects were observed after just three days of treatment with AZD1236, beginning within 24 hours of injury. Within three weeks, AZD1236-treated animals showed unprecedented recovery, while controls still showed significant deficits six weeks post-injury.

One of the main drivers of secondary SCI damage is the breakdown of the blood-medullary barrier (BSCB). This leads to edema (excess fluid buildup around the spinal cord) and triggers an inflammatory response that can ultimately impede the healing process and lead to nerve cell death.

AZD1236 is a potent and selective inhibitor of two enzymes, MMP-9 and MMP-12, involved in the inflammatory process.

Researchers demonstrated that AZD1236 halts IBS-induced edema and reduces BSCB breakdown and scarring at the site of injury. They also looked at the effect of AZD1236 dosage on the activity of MMP-9 and MMP-12 in the bloodstream and cerebrospinal fluid, which surrounds the spinal cord.

Here they demonstrated significant suppression of enzyme activity after oral and intrathecal (injection into the spinal canal) administration. Oral administration 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 cerebrospinal fluid.

Other studies have shown that AZD1236 suppresses the formation of pro-inflammatory cytokines (molecules known to contribute to the development of long-lasting neuropathic pain, which often follows spinal cord injury) by 85-95%. AZD1236 was also found to be 82% more effective in relieving IBS-induced neuropathic pain sensitivity to cold, heat, and touch compared to currently used analgesics such as pregabalin (Lyrica) and gabapentin.

Professor Ahmed commented that “there are currently no restorative drugs available for patients with LM, treatments only provide symptomatic relief and do not address the underlying molecular mechanisms that cause or contribute to edema and rupture of the blood-medullary barrier.

One of the main drivers of secondary SCI damage is the breakdown of the blood-medullary barrier (BSCB). Image is in public domain

“This drug has the potential to be a first-in-class treatment against some of the main pathological drivers of SCI and could revolutionize the recovery prospects of patients with SCI.”

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

“Exploring the potential of AZD1236 for this new indication represents an excellent outcome for our open innovation program and aligns with our philosophy that sharing ideas and enabling scientific innovation to cross boundaries between academia and industry will help translate innovative ideas into scientific breakthroughs and new potential. drugs faster.

About this Spinal Cord Injury Research News

Author: Press office
Source: University of Birmingham
Contact: Press Office – University of Birmingham
Picture: Image is in public domain

Original research: Free access.
Clinical-Ready MMP-9/-12 Inhibitor Restores Sensory and Functional Decline in Rodent Spinal Cord Injury Modelsby Zubair Ahmed et al. Clinical and translational medicine


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Clinical-Ready MMP-9/-12 Inhibitor Restores Sensory and Functional Decline in Rodent Spinal Cord Injury Models

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

Inhibition of MMP-9 and MMP-12 also protected against IBS-induced sensory and locomotor deficits.

By demonstrating these unprecedented improvements with a clinical-ready MMP inhibitor, using a dosing regimen that is expected to be safe and well-tolerated in patients with SCI, we are now well positioned to rapidly move into a Phase 2a study in the patients.

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