Scientists have figured out how to stimulate nerve regeneration after injury, as well as protect cardiac tissue from the sort of damage seen in heart attacks.
A groundbreaking study conducted by UCL in collaboration with the MRC Laboratory of Molecular Biology (MRC LMB) and AstraZeneca has unearthed a promising new compound capable of stimulating nerve regeneration following injuries, while also safeguarding cardiac tissue against damage typically associated with heart attacks.
The findings, published in the prestigious journal Nature, shed light on a chemical compound referred to as ‘1938’, which effectively activates the PI3K signaling pathway—a crucial mechanism involved in cell growth. Preliminary investigations demonstrate that this compound facilitates the growth of neurons in nerve cells. Moreover, animal models exhibited reduced heart tissue damage after significant trauma, and a remarkable restoration of lost motor function in simulated nerve injury scenarios.
Although further research is necessary to translate these findings into practical clinical applications, ‘1938’ stands out among a limited number of compounds currently in development that exhibit the potential to promote nerve regeneration. Remarkably, there are presently no approved medicines available for this purpose.
Phosphoinositide 3-kinase (PI3K), an enzyme responsible for regulating cell growth, plays a vital role in various processes, such as initiating wound healing. However, cancer cells can exploit its functions to enable uncontrolled proliferation. Consequently, cancer treatments have been developed to inhibit PI3K, curbing tumor growth. Nonetheless, the clinical prospects of activating the PI3K pathway remain largely unexplored.
“Kinases are ‘molecular machines’ that are key to controlling the activities of our cells, and they are targets for a wide range of drugs,” explains senior author Dr. Roger Williams.
Their “aim was to find activators of one of these molecular machines, with the goal of making the machine work better.”
And they found that they “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.”
New Compound Discovered to Boost Nerve Regeneration and Protect Cardiac Tissue
In this research study, scientists from UCL (University College London) and MRC LMB (Medical Research Council Laboratory of Molecular Biology) collaborated with researchers from AstraZeneca to conduct an extensive screening of numerous molecules from AstraZeneca’s chemical compound library. Their goal was to identify a compound capable of activating the PI3K signalling pathway. Through their investigation, they discovered a compound named 1938 that consistently activated PI3K. To assess its biological effects, experiments were conducted using cardiac tissue and nerve cells.
At UCL’s Hatter Cardiovascular Institute, researchers found that administering compound 1938 within the first 15 minutes of restoring blood flow after a heart attack demonstrated significant tissue protection in a preclinical model. Typically, when blood flow is restored, areas of tissue death can form, which may contribute to future heart problems.
Moreover, when compound 1938 was introduced to cultured nerve cells in the laboratory, it resulted in a substantial increase in neuron growth. The researchers also tested this compound on a rat model with a sciatic nerve injury. Administering 1938 to the injured nerve led to enhanced recovery in the hind leg muscle, indicating nerve regeneration.
The findings of the study “show that there’s potential for drugs that activate PI3K to accelerate nerve regeneration and, crucially, localised delivery methods could avoid issues with off-target effects that have seen other compounds fail,” adds senior author Professor James Phillips.
In light of the promising results, the team is currently engaged in the development of novel treatments for peripheral nerve damage, particularly in cases of severe hand and arm injuries. Additionally, they are investigating the potential of PI3K activators in the management of central nervous system impairments, such as those arising from spinal cord injury, stroke, or neurodegenerative disorders. These endeavors aim to pave the way for advanced therapeutic options and enhance the prospects of recovery in individuals affected by these conditions.
Source: 10.1038/s41586-023-05972-2
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