May 24, 2023 -- Researchers have identified a compound that can stimulate nerve regeneration after injury, as well as protect cardiac tissue from the type of damage seen in heart attacks. The study, published Wednesday in Nature, identified a chemical compound called 1938, which activates the signaling pathway of phosphoinositide 3-kinase (PI3K), an enzyme that helps control cell growth.
PI3K is active in initiating wound healing, but its functions can be hijacked by cancer cells, allowing them to proliferate. As a result, some cancer drugs inhibit PI3K to restrict tumor growth. But the clinical potential of activating the PI3K pathway has remained underexplored.
Researchers from University College London (UCL), the Medical Research Council Laboratory of Molecular Biology (MRC LMB), and AstraZeneca worked collaboratively to screen thousands of molecules from the chemical compound library to create one that could activate the PI3K signaling pathway. They found that the compound 1938 reliably activated PI3K. Its biological effects were then assessed through experiments on cardiac tissue and nerve cells.
Ordinarily, areas of dead tissue form when blood flow is restored following a heart attack; this can lead to heart problems later in life. However, researchers found that administering 1938 during the first 15 minutes of blood flow restoration following a heart attack provided substantial tissue protection in preclinical experiments.
Neuron growth was also significantly increased when 1938 was added to lab-grown nerve cells. A rat with an inflicted sciatic nerve injury was also tested; delivery of 1938 to the injured nerve resulted in increased recovery in the hind leg muscle, indicative of nerve regeneration.
The results indicate that 1938 may increase neuron growth in nerve cells. In animals, it may reduce heart tissue damage after major trauma and regenerate lost motor function after nerve injury. Although further research is needed to move these findings forward to clinical trials, 1938 is one of only a few compounds under development that can promote nerve regeneration, for which no approved medicines currently exist.
"We found that we can directly activate a kinase with a small molecule to achieve therapeutic benefits in protecting hearts from injury and stimulating neural regeneration in animal studies," senior author Roger Williams, structural biologist at the MRC LMB, concluded in a statement.
Based on their positive findings, the team is now working to develop new therapies for peripheral nerve damage, such as those sustained in hand and arm injuries. They are also exploring whether PI3K activators could help treat central nervous system damage due to spinal cord injury, stroke, or neurodegenerative disease.
"There are currently no approved medicines to regenerate nerves, which can be damaged as a result of injury or disease, so there's a huge unmet need," senior author James Phillips, UCL School of Pharmacy professor, said in a statement. "Our results show that there's potential for drugs that activate PI3K to accelerate nerve regeneration, and crucially, localized delivery methods could avoid issues with off-target effects that have seen other compounds fail."