Among the TrkA agonists, the small molecule gambogic amide exerts a potent neurotrophic activity decreasing apoptosis in primary hippocampal neurons. The non-peptidic TrkA agonist MT2 protects neurons from Aβ amyloid-mediated death in NGF-deficient neurons and talaumidin and its derivatives show neuroprotective effects, promoting neurite outgrowth in PC12 cells. Furthermore, the peptidomimetic cerebrolysin is known for its protective role in Alzheimer’s disease (AD). It was shown to improve the activities of daily living and the psychiatric symptoms in patients with mild to severe form of AD, after intravenous administration in a double-blind trial. In addition, the cyclic peptide tavilermide (MIM-D3), acting as a partial TrkA receptor agonist, showed a relevant improvement of cognitive capacities of treated aged rats, leading to a selective survival of the cholinergic neurons.
A phase 3 clinical trial of 5% and 1% tavilermide ophthalmic solutions for the treatment of dry eye was completed in 2020 (NCT03925727), with positive results concerning safety and efficacy. Recent studies demonstrated the neurotrophic activity of carvacrol by inducing neurite outgrowth and phosphorylation of TrkA in cells deprived of NGF. The same research group investigated the neurotrophic effect of the well-known antibiotic doxycycline and they found that it prevents amyloid toxicity in a Drosophila model of AD both in vitro and in vivo and induces neuritogenesis by activation of TrkA.
Additionally, some novel DHEA derivatives were shown to be TrkA agonists. In particular, the C17-spiroepoxy derivative, BNN-27, induces phosphorylation of TrkA in neuronal and glial cells in culture and it exerts antiapoptotic effect without inducing hyperalgesia. Moreover, it improved memorizing abilities in rats after i.p. administration and restored the myelin loss in cuprizone-induced demyelination in vivo. Moreover, the C17-spirocyclopryl DHEA derivatives, ENT-A010 and ENT-A013, were shown to be potent TrkA agonists. In particular, ENT-A010 acts as dual TrkA and TrkB agonist while, ENT-A013 acts as a selective TrkA agonist. Both induce phosphorylation of TrkA and its downstream signaling pathways, and promote cell survival of PC12 cells from serum deprivation. In addition, they exhibit potent neuroprotective effects in dorsal root ganglia and anti-amyloid activity in hippocampal neurons.