Phytochemicals that regulate neurodegenerative disease by targeting neurotrophins: a comprehensive review

Abstract

Alzheimer's disease (AD), characterized by progressive dementia and deterioration of cognitive function, is an unsolved social and medical problem. Age, nutrition, and toxins are the most common causes of AD. However, currently no credible treatment is available for AD. Traditional herbs and phytochemicals may delay its onset and slow its progression and also allow recovery by targeting multiple pathological causes by antioxidative, anti-inflammatory, and antiamyloidogenic properties. They also regulate mitochondrial stress, apoptotic factors, free radical scavenging system, and neurotrophic factors. Neurotrophins such as BDNF, NGF, NT3, and NT4/5 play a vital role in neuronal and nonneuronal responses to AD. Neurotrophins depletion accelerates the progression of AD and therefore, replacing such neurotrophins may be a potential treatment for neurodegenerative disease. Here, we review the phytochemicals that mediate the signaling pathways involved in neuroprotection specifically neurotrophin-mediated activation of Trk receptors and members of p75(NTR) superfamily. We focus on representative phenolic derivatives, iridoid glycosides, terpenoids, alkaloids, and steroidal saponins as regulators of neurotrophin-mediated neuroprotection. Although these phytochemicals have attracted attention owing to their in vitro neurotrophin potentiating activity, their in vivo and clinical efficacy trials has yet to be established. Therefore, further research is necessary to prove the neuroprotective effects in preclinical models and in humans.

Figure 1

Schematic representation of phytochemicals involved with neurotrophins. By binding to the Trk receptor, neurotrophin signaling mediates cell survival, proliferation, and differentiation through the Ras/MAPK, PI3K/AKT, and PL-Cγ pathways. NGF-p75^NTR receptor binding activates bidirectional cell survival and apoptosis via the NF-κB and JNK pathways, as well as external stress stimuli-mediated generation of ROS with suppression of antioxidative enzyme levels. Trk, tropomyosin-related kinase; p75^NTR, p75 neurotrophin receptor; NGF, nerve growth factor; BDNF, brain derived neurotrophic factor; LPS, lipopolysaccharide; NADPH, nicotinamide adenine dinucleotide phosphate; PI3K, phosphatidylinsoitol-3-kinase; mTOR, mammalian target of rapamycin; MEK, mitogen-activated protein kinase; MAPK, mitogen activated protein kinase; ERK, extracellular signal-regulated kinases; PL-Cγ, phospholipase Cγ; PKC, protein kinase C; NF-κB, nuclear factor-kappa B; JNK, c-Jun N-terminal kinase; IκB, inhibitory kappa B; CREB, cyclic adenosine monophosphate response element binding protein; GSK3β, glucose synthase kinase-3β; CaMKII/IV, Ca²⁺-calmodulin kinase II/IV. 1: Diosniposide B, 2: Diosgenin, 3: Cyanidin-3-glucopyranoside, 4: 3,7-dihydroxy-2,4,6-trimethoxy-phenanthrene, 5: Spicatoside A, 6: Quercetin, 7: Apigenin, 8: Ginsenoside Rg3, 9: Rosmarinic acid, 10: Ginkgolide B, 11: Limonoid, 12: 4,6-dimethoxy phenanthrene-2,3,7-triol, 13: Furostanol, 14: Coreajaponins B, 15: Quinic acid, 16: Luteolin-7-O-β-glucopyranoside, 17: Kaempferol, 18: (−)-4,5-dicaffeoyl quinic acid, 19: (−)-3,5-dicaffeoyl mucoquinic acid, 20: (−)-3,4-dicaffeoyl mucoquinic acid, 21: Ginsenosides, 22: Panaxynol, 23: Nigranoic acid, 24: Clerodane diterpenoids, 25: Ligraminol E4-O-β-d-xyloside, 26: Geniposidic acid, 27: Epigallocatechin-3-galate, 28: Curcumin, 29: Resveratrol, 30: Berberine, 31: 6-shogaol, 32: Oleuropein, 33: Honokiol and magnolol, 34: Huperzine A.

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