Growth factors in the nervous system bind to receptor tyrosine kinases that activate intracellular signaling pathways, e.g., those coupled to phosphoinositide 3-kinase (PI3K) or extracellular-regulated kinase (ERK) which promotes the outgrowth of neuronal processes after injury (see section 1.3.7.1 in my new book on Neuroregeneration).
To understand the differential effects of neurotrophic factors on axonal regeneration, it is important to know which signaling pathways are preferentially "driven" by the kinases. For example, PI3K-dependent processes are significant for axonal regeneration in the mature (adult) nervous system and for axonal branch formation, whereas the ERK pathway is particularly important during neurodevelopment and in the formation of axonal growth cones after lesion.
Pharmacological research is investigating potentially beneficial effects of signaling pathway activation through the development of kinase activators. To date, however, mainly inhibitors are on the market for treatment of diseases with PI3K or ERK overactivation, such as cancer or immunological syndromes.
A recent paper in Nature reports the discovery of UCL-TRO-1938 (1938 for short), a small molecule activator of the PI3Kα isoform. The new compound 1938 allosterically activates PI3Kα via a mechanism that enhances several steps of the PI3Kα catalytic cycle and causes conformational changes in the molecular structure.
Interestingly, the compound is apparently selective for PI3Kα over other PI3K isoforms and several protein and lipid kinases. Thus, it specifically and transiently activates PI3 kinase in all animal and human cells tested, promoting cellular proliferation and neurite outgrowth in the nervous system. In this regard, acute treatment with 1938 leads to protection of the heart from ischemia-reperfusion injury (infarct complications). Furthermore, peripheral nerve regeneration after a nerve lesion is stimulated.
First, Bart Vanhaesebroeck's team at University College London showed that 1938 significantly increased axon growth in dissociated cultures of adult rat dorsal root ganglia (DRG). Next, the authors tested the compound in a nerve regeneration model after direct injection of 1938 into the injured nerve or after continuous application via a mini-osmotic pump.
Three weeks after injury, electrophysiological studies were performed and showed clear evidence of faster recovery of nerve and muscle function compared with control animals. The number of motor units, i.e., nerve fibers regenerated into muscle, and the level of muscle action potential were significantly increased. This correlated with histological analyses showing an increase in the number of choline acetyltransferase (ChAT)-positive motor axons reaching the distal branch of the sciatic nerve in animals treated with 1938.
Because microscopic examination of nerve segments closer to the site of injury showed an equal number of neurofilament-positive and ChAT-positive axons in the treatment and control groups, the authors hypothesize that the improved functional reinnervation of muscle associated with 1938 treatment is due to an acceleration of axonal regeneration. Thus, although the total number of regenerated axons was not increased, there may well have been increased axonal sprouting in the distal nerve branch, which would be typical with activation of PI3K and is usually associated with faster but limited recovery of directed movements due to double and false innervation (see chap. 1.3.6 in my new book on neuroregeneration).
Reference:
Gong GQ, Bilanges B, Allsop B, ..., Vanhaesebroeck B (2023) A small-molecule PI3Kα activator for cardioprotection and neuroregeneration. Nature 618:159
Image credit: Structure of compound '1938' (Fig. 1a from Gong et al., 2023, Nature 618:159)