There are a number of natural products with neurotrophic activity, which results from several mechanisms including enhancing BDNF gene transcription, upregulating the expression of BDNF and TrkB, and extracellular signal-regulated kinase (ERK) and CREB signalling.
The first discovered non-protein neurotrophic natural product was lactacystin, isolated from a culture broth of Streptomyces sp. Magnolol and honokiol, the main constituents of Magnolia officinalis and Magnolia obovata stem bark, have been reported to have neurotrophic activity in primary cultured rat cortical by enhancing the BDNF expression. Merrilactone A, jiadifenin, jiadifenolide, (1R,10S)-2-oxo-3,4-dehydroxyneomajucin, jiadifenoxolane A, (2R)-hydroxynorneomajucin, 11-O-debenzoyltashironin,tricycloillicinone, and bicycloillicinone, natural products of the Illicium family have been shown to promote neurite outgrowth in primary cultures of cortical neurons of fetal rats. Neurotrophic properties are also possessed by several members of the Lycopodium alkaloids (huperzine A, lyconadins, complanadine A and B, and nankakurine A and B). Studies have shown that huperazine A can elevate the levels of NGF and BDNF. Synthesis of NGF can be upregulated by administration of cyathanediterpenoids specifically erinacines, scabronines and cyrneines.
Some flavonoids, Isoflavonoids and neoflavonoids were found to have neuroprotective activity. Among the effective flavonoids, luteolin from Lonicera japonica sp., isorhamnetin from Opuntia ficus-indica, genistein from Genista tinctoria, and calycosin from Astragalus membranaceus showed the most promising effects by increasing the mRNA expression and protein secretion of NGF, GDNF, and BDNF. Paecilomycine A and spirotenuipesines A and B, members of the trichothecenes, isolated from the fruiting bodies of Paecilomycestenuipes, have significant neurotrophic profiles especially paecilomycine A which can stimulate the synthesis of neurotrophic factors. Polyprenylatedacylphloroglucinols (PPAPs) represented by hyperforin, hypericin and garsubellin A, have neurotrophic like properties. Hyperforin, isolated from the herb St. Johns wort (Hypericum perforatum'), can stimulate the upregulation of the TrkB receptor.
Beside natural products, there are some small molecules of natural origin that exert neurotrophic activities such as: Panaxytriol (promotes NGF-induced neurite outgrowth in PC-12 cells); 7,8-dihydroxyflavone (TrkB activator); Deoxygedunin (BDNF mimetic); Kansuinin E (promotes neurotrophic activity, most likely through TrkA activation); Tripchlorolide (stimulates expression of BDNF mRNA); Fucoxanthin (increases BDNF production and activates PKA/CREB pathway); Silibinin (Activate hippocampal ROS-BDNF-TrkB patway).