The progressive dementia and deterioration of cognitive functions have been characterised as Alzheimer’s disease (AD). The most common causes of Alzheimer’s disease include aging, nutrition, and toxins. It has been reported to be an unsolved sociomedical problem because of their lack of proper treatment in present scenario. The plant based principles and phytochemicals from traditional herbs might delay the onset or/ and progression of Alzheimer’s disease. The phytochemicals may help recovery from Alzheimer’s disease because of their antioxidative, anti-inflammatory, and antiamyloidogenic properties by regulating mitochondrial stress, apoptotic factors, free radical scavenging system, and neurotrophic factors. Neurotrophins (BDNF, NT4/5, NT3, and NGF) play important roles (neuronal and non-neuronal responses) in Alzheimer’s disease and their depletion accelerates the progression of the disease. Therefore, neurotrophins targeted treatment may act as better strategy to treat Alzheimer’s disease. This review presents an updated account of the information available on the phytochemicals mediated signaling pathways (neurotrophin mediated activation of Trk receptors) involved in neuroprotection. The currently available literature suggests that enough attention should be paid towards their clinical trials which still remain to be established. It is necessary to prove the neuroprotective efficacy of such phytochemicals in different preclinical models including humans.

Keywords: neurotrophins, alzheimer’s disease, antioxidative, stress, signalling pathways,phytochemicals

AD, alzheimer’s disease; AChE, acetylcholinesterase; Nrf2, nuclear factor (erythroid-derived 2)-like 2; FOXO, fork head box o; NGF, nerve growth factor; BDNF, brain-derived neurotrophic factor; NT, neurotrophin; Trk, tropomyosin-related kinase; SOD, superoxide dismutase; CAT, catalase; ROS, reactive oxygen species; NO, nitric oxide; TNF-tumor necrosis factor; NF-𝜅B, nuclear factor kappa b; IL, interleukin; iNOS, intrinsic nitric oxide synthase; PG, prostaglandin; ERK, ras/extracellular signal-regulated kinases; and PI3K-phosphatidylinositol 3-kinase

Alzheimer’s disease (AD) is recognized as one of the most complicated neurodegenerative diseases. It is a chronic neurodegenerative disorder characterized by progressive dementia and deterioration of cognitive function.¹ As a result of aging, the number of people with dementia has been growing rapidly worldwide.² According to a consensus the prevalence of neurodegenerative diseases is on the rise worldwide.³ The main physiological symptoms of neurodegenerative diseases are elevation in the level of oxidative stress, misfolding of protein, aberration in mitochondrial function, loss of synapse and decreased survival of neurons which makes the way easier to apoptosis.^4,5 Neurodegenerative diseases are affected by several factors such as stimulating nuclear factor (erythroid-derived 2)-like 2 (Nrf2), Sirtuin genes, fork head box O (FOXO) transcription factors, chaperones, neurotrophic factors and by acetylcholinesterase (AChE) inhibition.⁶

Neurotrophins play important roles in the survival, maintenance, and regeneration of neuronal population.⁷ The neurotrophins that were identified as neuronal survival-promoting proteins in mammals include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4/5.^8,9 A decrease in neurotrophins has been associated with the pathology of several neurodegenerative diseases and their physiological symptoms.¹⁰ Among the neurotrophins, NGF has been studied extensively as a drug target owing to its strong association to neurodegenerative diseases. The next common targets are antioxidants, anti-inflammatory, inhibitors of acetylcholinesterase (AChE) and anti-stress factors.¹¹ Neurotrophins are considered to be promising targets for neuroprotective agents against degenerative diseases.¹² The phytochemicals from natural sources have been shown to have potential of controlling the levels of neurotrophin. In particular, a modulator or enhancer targeting the tropomyosin-related kinase (Trk) receptor could be a valuable candidate to reverse neurotrophin loss.¹³ Additionally, research has led to an increase in the consumption of specific plant ingredients (phytochemicals) to treat neurodegenerative diseases.^14,15 Natural phytochemicals may be less toxic than novel synthetic drugs. However, since these traditional herbal medicines were prepared from crude plant materials, there are so many questions arises concerning their specific medicinal effects, mechanism of action, and the identity of the active ingredients.¹⁶ Therefore, most recent research has focused on specific active components of an herb rather than on the entire herb/ plant. However, a number of active ingredients should be identified and characterized with regard to their potential therapeutic effects in context to their effects on neurodegenerative diseases. The induction of natural compounds and their effects on neurotrophin have already been reported³ and were shown to directly or indirectly function as NGF mimetics or inducers.^9,12,17 Overall, phytochemicals can be able to provide an effective way of halting or delaying the progression of neurodegenerative diseases. Phytochemicals and their derivatives induce neuronal cell differentiation and upregulate neurotrophic factors such as NGF and BDNF.^12,18 These compounds may have the potential to prevent and arrest neurodegeneration by inducing neurotrophins and boosting the activity of the antioxidant system, such as superoxide dismutase (SOD) and catalase (CAT).¹⁹ They may also inhibit the production of reactive oxygen species (ROS), nitric oxide (NO), tumor necrosis factor alpha (TNF-𝛼), nuclear factor kappa B (NF-𝜅B), interleukin (IL)-1𝛽, intrinsic nitric oxide synthase (iNOS), and prostaglandin (PG) E2. NGF triggers the Trk A signaling pathway ^12,18 by inhibiting caspase protein expression²⁰ and via degradation of beta amyloid oligomers in the brain.²¹ This review focuses the phytochemicals that have the potential to treat neurodegenerative diseases or arrest the degeneration and/or loss of neurons by targeting neurotrophins.

Neurodegenerative diseases might be treated by regulating neuron proliferation, differentiation, and survival. Phytochemicals that inhibits acetylcholinesterase (AChE) can regulate intracellular signaling and prevent damage to cognitive function of patients with Alzheimer’s disease by up regulating neurotransmitter (ACh).²² The discharged neurotransmitter targets receptors on pre/postsynaptic cells. Once activated, these receptors facilitate various intracellular signaling mechanisms, which promote both various cellular responses in developing and mature neurons.²³ Similarly, the cells respond to external stimuli via extracellular receptors and neurotrophins individually activate members of the Trk receptor family (TrkA, TrkB, and TrkC show high affinity towards NGF, BDNF, and NT 4/5 and NT-3, respectively).²⁴ Many neurotrophic factors such as NGF, BDNF, NT-3, NT 4/5, erythropoietin and basic fibroblast growth factor-2 protect neurons. Therefore, they are able to reverse the degeneration of neurons by interacting with Trk receptor and promoting the survival, growth, differentiation and maintenance of neurons.²⁵ Among the neurotrophins, NGF was the first growth factor to be identified and has been found to promote the survival of neurons and neurite ganglia outgrowth in terrestrial birds by using mouse sarcoma tissue.²⁶ The binding of neurotrophins to their receptors facilitates different intracellular signaling pathwaws including the Ras/extracellular signal-regulated kinases (ERK), phospholipase C𝛾 and phosphatidylinositol 3-kinase (PI3K)/AKT pathways.²⁷ Neurotrophins also activate downstream signaling pathways to regulate cell survival and promotes recovery from neurodegeneration.²⁸ Neurotrophins promote transcriptional expression of the Trk receptor via Kruppel-like factor 7, Brn3a, cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein, c-Jun, and NeuroD.²⁹ An absence of neurotrophins suppresses Trk receptor expression and may cause cognitive neuronal defects. Neurotrophins also show weak affinity towards the p75 neurotrophin receptor (p75NTR) owing to structural similarities with the Trk family receptors.³⁰ Interestingly, p75NTR mediates the cell-death-promoting tumor necrosis factor (TNF) receptor super family. Tumor necrosis factor (TNF) plays an important role in modulating neuronal and immune interactions.⁷ Dimeric neurotrophins interact with p75NTR monomers by forming a disulfide bond with cysteine-rich intracellular repeating domains and inducing a conformational change in the receptor. This change then causes enzymatic activation of an adaptor protein via NF-𝜅B and c-Jun N-terminal kinase (JNK), which facilitates proliferation and survival via Bcl-2, or cell death through caspases.³¹ Neurotrophin binding triggers the activation of the Trk receptor, causing oligomerization and transautophosphorylation in intracellular domain, which leads to the activation of an intracellular signaling pathway with activation of Ras/mitogen activated protein kinase (MAPK), which results in CREB-dependent neurotrophin secretion and Bcl-2 expression, promoting survival, proliferation and differentiation of the cell.³² Therefore, the study of phytochemicals that can be able to potentiate neurotrophins is necessary to find out new natural agents to combat effectively with neurodegenerative diseases.

The brain uses a major proportion of the nutrients consumed by a person. Therefore, certain diets might improve brain function.³³ Consuming dietary macro and micronutrients derived from different traditional medicinal plants has been shown to enhance cognitive function³⁴ and can partly penetrate the Blood Brain Barrier. The properties of these phytochemicals can effectively reverse the age-related decline in cognitive function by inducing the expression of neurotrophins via the Trk signaling pathway in the hippocampus.³⁴ In addition to their special biological activities, phytochemicals mainly act as antioxidants, scavenging free radicals in the brain and thus induces neuronal regeneration, and neuroprotection activities that lead to improved neuronal survival, differentiation, LTP, and memory enhancement.³⁵ The phytochemicals which have reported to be used as neuroprotectant are listed in Table 1.

A variety of dietary phytochemicals may serve as promising candidates for the treatment of neurodegenerative diseases. Several evidences suggesting that the naturally occurring phytochemicals that affect neurotrophins should be a first-line treatment of neurodegenerative disease. Phytochemicals offer a safe approach towards the protection against neuronal damage and loss caused by neurotrophin deficits in patients with neurodegenerative disease. In particular, the importance of the role of neurotrophins and the value of phytochemicals in regulating neurodegenerative disease has been reported similar activities for phytochemicals through (i) reducing oxidative-stress induced by free radicals, (ii) boosting the phagocytic properties of immunological cells, (iii) increasing the concentration of neurotransmitter by inhibiting neurotransmitter cleaving enzymes and (iv) adapting to the prevailing stress conditions by affecting the differentiation properties of neurons. As nerve growth factor are just responsible for the growth and survival of developing neurons. Phytochemicals may not be the absolute cure, but they may serve to delay or prevent the onset of neurodegenerative diseases. Furthermore, phytochemicals do not appear to be cytotoxic, they may provide the maintenance of mature neurons and allow them to regenerate. As a result, phytochemicals that induces the neurotrophins expression or mimic neurotrophins like functions and activate Trk receptors can potentially prevent neurodegenerative diseases. Hence, phytochemicals that regulate neurodegenerative disease by targeting neurotrophins might be a promising future. Even the prevailing gap exists between pharmacognosy and pharmacological approaches to the treatment and cure of the disease the phytochemicals that regulate neurodegenerative diseases are still needs to be more attention in preclinical and clinical studies. Particularly, in-depth study is needed towards the phytochemicals which regulates neurodegenerative diseases by regulating NGF-Trk A signaling.

VKG would like to thank UGC-New Delhi for financial support in the form of research fellowship.

Author declares there are no conflicts of interest.

None.

1. Mattson MP. Lifelong brain health is a lifelong challenge: from evolutionary principles to empirical evidence. Ageing Res Rev. 2015;20:37‒45.
2. Brookmeyer R, Johnson E, Ziegler-Graham K, et al. Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement. 2007;3(3):186‒191.
3. Venkatesan R, Ji E, Kim SY. Phytochemicals That Regulate Neurodegenerative Disease by Targeting Neurotrophins: A Comprehensive Review. Biomed Res Int. 2015;2015:814068.
4. Winner B, Kohl Z, Gage FH. Neurodegenerative disease and adult neurogenesis. Eur J Neurosci. 2011;33(6):1139‒1151.
5. Finkel T. Signal transduction by reactive oxygen species. J Cell Bio. 2011;194(1):7‒15.
6. Mattson MP, Son TG, Camandola S. Viewpoint: mechanisms of action and therapeutic potential of neurohormetic phytochemicals. Dose-Response. 2007;5(3):174‒186.
7. Gupta VK, Sharma B. Modulations of Mammalian Brain Functions by Antidepressant Drugs: Role of Some Phytochemicals as Prospective Antidepressants. Evidence Based Medicine and Practice. 2016;2:003.
8. Kim KH, Kim MA, Moon E, et al. Furostanol saponinsfrom the rhizomes of Dioscorea japonica and their effects on NGF induction. Bioorg Med Chem Lett. 2011;21(7):2075‒2078.
9. Konar A, Shah N, Singh R, et al. Protective role of Ashwagandha leaf extract and its component with anoneonscopolamine-induced changes in the brain and brain-derived cells. PLoS One. 2011;6(11):e27265.
10. Fitzsimons CP, van Bodegraven E, Schouten M, et al. Epigenetic regulation of adult neural stem cells: implications for Alzheimer's disease. Mol Neurodegener. 2014;9:25.
11. Gupta VK, Sharma B. Alleviation of Acute Poisoning of Organophosphates in Humans. Anat Physiol Biochem Int J. 2016;1(2):555558.
12. Woo KW, Kwon OW, Kim SY, et al. Phenolic derivatives from the rhizomes of Dioscorea nipponica and their anti-neuroinflammatory and neuroprotective activities. J Ethnopharmacol. 2014;155(2):1164‒1170.
13. Reichardt LF. Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B Biol Sci. 2006;361(1473):1545‒1564.
14. Essa MM, Vijayan RK, Castellano-Gonzalez G, et al. Neuroprotective effect of natural products against Alzheimer’s disease. Neurochem Res. 2012;37(9):1829‒1842.
15. Howes MJR, Houghton PJ. Ethnobotanical treatment strategies against alzheimer’s disease. Curr Alzh Res. 2012;9(1):67‒85.
16. Kim J, Lee HJ, Lee KW. Naturally occurring phytochemicals for the prevention of Alzheimer’s disease. J Neurochem. 2010;122(6):1415‒1430.
17. Moon M, Kim HG, Choi JG, et al. 6-Shogaol, an active constituent of ginger, attenuates neuro inflammation and cognitive deficits in animal models of dementia. Biochem Biophys Res Commun. 2014;449(1):8‒13.
18. Kwon G, Lee HE, Lee DH, et al. Spicatoside A enhances memory consolidation through the brain-derived neurotrophic factor in mice. Neurosci Lett. 2014;572:58‒62.
19. Hur JY, Lee P, Kim H, et al. (−)-3,5-Dicaffeoyl-muco-quinic acid isolated from Aster scaber contributes to the differentiation of PC12 cells: through tyrosine kinase cascade signaling. Biochem Biophy Res Comm. 2004;133(4):948‒953.
20. Wang ZJ, Nie BM, Chen HZ, et al.Panaxynol induces neurite outgrowth in PC12D cells via cAMP- and MAP kinase-dependent mechanisms. Chemico-Biol Inter. 2006;159(1):58‒64.
21. Karpagam V, Sathishkumar N, Sathiyamoorthy S, et al. Identification of BACE1 inhibitors from Panax ginseng saponins-An Insilco approach. Comput Biol Med. 2013;43(8):1037‒1044.
22. AliHassan SH, Fry JR, Abu Bakar MF. Phytochemicals content, antioxidant activity and acetylcholinesterase inhibition properties of indigenous Garcinia parvifolia fruit. Biomed Res Int. 2013;2013:138950.
23. Lovinger DM. Neurotransmitter roles in synaptic modulation, plasticity and learning in the dorsal striatum. Neuropharmacology. 2010;58(7):951‒961.
24. Barbacid M. The Trk family of neurotrophin receptors. J Neurobiol. 1994;25(11):1386‒1403.
25. Levi-Montalcini R. The nerve growth factor: thirty-five years later. Biosci Rep. 1987;7(9):681‒699.
26. Soh Y, Kim JA, Sohn NW, et al. Protective effects of quinic acid derivatives on tetrahydropapaveroline- induced cell death in C6 glioma cells. Biol Pharm Bull. 2003;26(6):803‒807.
27. Reichardt LF. Neurotrophin-regulated signalling pathways. Phil. Transac. Philos Trans R Soc Lond B Biol Sci. 2006;361(1473):1545‒1564.
28. Nibuya M, Morinobu S, Duman RS. Regulation of BDNFand trkBmRNAin rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci. 1995;15(11):7539‒7547.
29. Lei L, Parada LF. Transcriptional regulation of Trk family neurotrophin receptors. Cell Mol Life Sci. 2007;64(5):522‒532.
30. Gupta VK, You Y, Gupta VB, et al. TrkB receptor signaling: implications in neurodegenerative, psychiatric and proliferative disorders. Int J Mol Sci. 2013;14(5):10122‒10142.
31. Baud V, Karin M. Is NF-𝜅B a good target for cancer therapy? Hopes and pitfalls. Nature RevDrug Disc. 2009;8(1):33‒40.
32. Descamps S, Toillon RA, Adriaenssens E, et al. Nerve growth factor stimulates proliferation and survival of human breast cancer cells through two distinct signaling pathways. J Biol Chem. 2001;276(21):17864‒17870.
33. Adibhatla RM, Hatcher JF. Role of lipids in brain injury and diseases. Fut Lipid. 2007;2(4):403‒422.
34. Spencer JPE, Vauzour D, Rendeiro C. Flavonoids and cognition: the molecular mechanisms underlying their behavioural effects. Arc Biochem Biophy. 2009;492(1-2):1‒9.
35. Spencer JPE. Flavonoids: modulators of brain function? Brit J Nut. 2008;99(1):ES60‒ES77.
36. Tang W, Hioki H, Harada K, et al. Clerodane diterpenoids with NGF-potentiating activity from Ptychopetalum olacoides. J Nat Prod. 2008;71(10):1760‒1763.
37. Yuan XX, Yang LP, Yang ZL, et al. Effect of nigranoic acid on Ca²⁺ influx and its downstream signal mechanism in NGF-differentiated PC12 cells. J Ethnopharmacol. 2014;153(3):725‒731.
38. Palatty PL, Haniadka R, Valder B, et al. Ginger in the prevention of nausea and vomiting: a review. Crit Rev Food Sci Nut. 2013;53(7):659‒669.
39. Xu F, Wang C, Yang L, et al. C-dideoxyhexosyl flavones from the stems and leaves of Passiflora edulis Sims. Food Chem. 2013;136(1):94‒99.
40. Hsu YY, Tseng YT, Lo YC. Berberine, a natural antidiabetes drug, attenuates glucose neurotoxicity and promotes Nrf2-related neurite outgrowth. Toxicol App Pharmacol. 2013;272(3):787‒796.
41. Liao KK, Wu MJ, Chen PY, et al. Curcuminoids promote neurite outgrowth in PC12 cells through MAPK/ERK- and PKC-dependent pathways. J Agric Food Chem. 2012;60(1):433‒443.
42. Liu M, Chen F, Sha L, et al. (-)-Epigallocatechin-3-gallate ameliorates learning and memory deficits by adjusting the balance of TrkA/p75NTR signaling in APP/PS1 transgenic mice. Mol Neurobiol. 2014;49(3):1350‒1363.
43. Joo SS, Yoo YM, Ahn BW, et al. Prevention of inflammation-mediated neurotoxicity by Rg3 and its role in microglial activation. Biol Pharm Bull. 2008;31(7):1392‒1396.
44. Kwon SH, Kim MJ, Ma SX, et al. Eucommia ulmoides Oliv. Bark protects against hydrogen peroxide-induced neuronal cell death in SH-SY5Y cells. J Ethnopharmacol. 2012;142(2):337‒345.
45. Zhang C, Tian X, Luo Y, Meng X. Ginkgolide B attenuates ethanol-induced neurotoxicity through regulating NADPH oxidases. Toxicol. 2011;287(1-3):124‒130.
46. Hoi CP, Ho YP, Baum L, et al.Neuroprotective effect of honokiol and magnolol, compounds from Magnolia officinalis, on beta-amyloid-induced toxicity in PC12 cells. PhytothRes. 2010;24(10):1538‒1542.
47. Zhang HY, Tang XC. Neuroprotective effects of huperzine A: new therapeutic targets for neurodegenerative disease. Trends Pharmacol Sci . 2006;27(12):619‒625.
48. Roy A, Saraf S. Limonoids: overview of significant bioactive triterpenes distributed in plants kingdom. Biol Pharm Bull. 2006;29(2):191‒201.
49. Xia JH, Zhang SD, Li YL, et al. Sesquiterpenoids and triterpenoids from Abies holophylla and their bioactivities. Phytochem. 2012;74:178‒184.
50. Carito V, Venditti A, Bianco A, et al. Effects of olive leaf polyphenols on male mouse brain NGF, BDNF and their receptors TrkA, TrkB and p75. Nat Prod Res. 2014;28(22):1970‒1984.
51. Peng CH, Liu LK, Chuang CM, et al. Mulberry water extracts possess an anti-obesity effect and ability to inhibit hepatic lipogenesis and promote lipolysis. J Agric Food Chem. 2011;59(6):2663‒2671.
52. Anastácio JR, Netto CA, Castro CC, , et al. Resveratrol treatment has neuroprotective effects and prevents cognitive impairment after chronic cerebral hypoperfusion. Neurol Res. 2014;36(7):627‒633.
53. Yoo DY, Choi JH, Kim W, et al. Effects of Melissa officinalis L. (lemon balm) extract on neurogenesis associated with serum corticosterone and GABA in the mouse dentate gyrus. Neurochem Res. 2011; 36(2):250‒257.