Research identifies molecule that stimulates nerve regeneration after injury and protects against cardiac damage after heart attacks.
Research led by UCL, in partnership with the MRC Laboratory of Molecular Biology (MRC LMB) and AstraZeneca, has identified a new compound that can stimulate nerve regeneration after injury, as well as protect cardiac tissue from the sort of damage seen in heart attacks [1].
Publishing in Nature, researchers identify a chemical compound called 1938 that demonstrates the potential to activate the phosphoinositide 3-kinase (PI3K) signaling pathway, known for its role in cell growth. This research offers promising prospects for both cardiac and neural regeneration; the compound was found to stimulate neuron growth in nerve cells and, in animal models, it showed the ability to reduce heart tissue damage following major trauma while also promoting the restoration of lost motor function in a model of nerve injury.
Although further research is needed to translate these findings into clinical applications, the discovery of 1938 signals hope for therapeutic interventions to prevent cell damage and promote regeneration in critical conditions.
Longevity.Technology: Cardiovascular disease remains the leading cause of mortality worldwide. During a heart attack, the blood vessels that supply oxygen and nutrients to the heart become blocked, resulting in damage to the heart muscle cells. This damage can eventually lead to cell death and severe consequences for cardiac function. Similarly, nerve cells can sustain damage after trauma, which can lead to the loss of function in the affected limbs. Many cell types, including neurons and heart muscle cells, have limited regenerative abilities – this means that finding ways to prevent damage from occurring and promoting regeneration after injury is crucial. This research is significant because not only are there currently no approved drugs available to boost nerve regeneration, but there is also a scarcity of compounds under development in this area.
Phosphoinositide 3-kinase (PI3K) is an enzyme that plays a crucial role in controlling cell growth. It is involved in various physiological processes, such as wound healing initiation, but cancer cells can exploit this pathway to enhance their proliferation, leading to the development of PI3K inhibitors as cancer drugs to restrict tumor growth. Despite this, the clinical potential of activating the PI3K pathway has remained largely unexplored.
Dr Roger Williams, a senior author of the study from the MRC Laboratory of Molecular Biology, explained: “Kinases are ‘molecular machines’ that are key to controlling the activities of our cells, and they are targets for a wide range of drugs. Our aim was to find activators of one of these molecular machines, with the goal of making the machine work better. 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 [2].”
In collaboration with researchers from AstraZeneca, scientists from UCL and MRC LMB screened thousands of molecules from a chemical compound library to identify a compound capable of activating the PI3K signaling pathway. They successfully identified 1938, which reliably activated PI3K. To assess its biological effects, experiments were conducted on cardiac tissue and nerve cells.
Researchers at UCL’s Hatter Cardiovascular Institute administered 1938 during the restoration of blood flow within the first 15 minutes following a heart attack. The results in a preclinical model demonstrated substantial tissue protection, potentially preventing the formation of dead tissue areas that could lead to heart problems later in life. In nerve cells grown in the laboratory, the addition of 1938 significantly increased neuron growth. Moreover, when 1938 was delivered to an injured sciatic nerve in a rat model, it resulted in enhanced recovery in the hind leg muscle, indicating nerve regeneration [1].
Professor James Phillips from UCL School of Pharmacy, highlighting the significant unmet need for nerve regeneration treatments, said: “Our results 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 [2].”
With these positive findings, the research group aims to develop new therapies for peripheral nerve damage, particularly injuries sustained in the hands and arms. Furthermore, they are exploring the potential of PI3K activators in treating damage within the central nervous system caused by conditions such as spinal cord injury, stroke or neurodegenerative diseases.
Professor Bart Vanhaesebroeck of the UCL Cancer Institute, a senior author of the study, said: “This is a prime example of interdisciplinary research, in which people with expertise ranging from basic science, drug development and clinical studies join forces around an innovative idea, whilst also crossing boundaries between academia and industry. ‘Blue sky’ research of this kind is difficult to get funding for in a world of increasing specialisation, but hopefully this project can provide something of a model for future ambitious research [2].”
The identification of 1938 as a compound capable of activating the PI3K signaling pathway could transpire to be a significant breakthrough in the fields of cardioprotection and neuroregeneration. This interdisciplinary research, conducted in collaboration between academia and industry, highlights the importance of combining expertise from various fields to drive ambitious longevity research forward. While further investigations are required to translate these findings into clinical applications, this study offers hope for developing therapies that can protect against cell damage and stimulate regeneration, addressing a critical unmet need in cardiovascular and neurological health.
[1] https://www.nature.com/articles/s41586-023-05972-2
[2] https://bit.ly/3qdWRTc
