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Review
. 2021 Apr 30;22(9):4771.
doi: 10.3390/ijms22094771.

Nitric Oxide as a Target for Phytochemicals in Anti-Neuroinflammatory Prevention Therapy

Lalita Subedi  1 , Bhakta Prasad Gaire  1 , Amna Parveen  1 , Sun-Yeou Kim  1
Affiliations
Review

Nitric Oxide as a Target for Phytochemicals in Anti-Neuroinflammatory Prevention Therapy

Lalita Subedi et al. Int J Mol Sci. .

Abstract

Nitric oxide (NO) is a neurotransmitter that mediates the activation and inhibition of inflammatory cascades. Even though physiological NO is required for defense against various pathogens, excessive NO can trigger inflammatory signaling and cell death through reactive nitrogen species-induced oxidative stress. Excessive NO production by activated microglial cells is specifically associated with neuroinflammatory and neurodegenerative conditions, such as Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, ischemia, hypoxia, multiple sclerosis, and other afflictions of the central nervous system (CNS). Therefore, controlling excessive NO production is a desirable therapeutic strategy for managing various neuroinflammatory disorders. Recently, phytochemicals have attracted considerable attention because of their potential to counteract excessive NO production in CNS disorders. Moreover, phytochemicals and nutraceuticals are typically safe and effective. In this review, we discuss the mechanisms of NO production and its involvement in various neurological disorders, and we revisit a number of recently identified phytochemicals which may act as NO inhibitors. This review may help identify novel potent anti-inflammatory agents that can downregulate NO, specifically during neuroinflammation and neurodegeneration.

Keywords: medicinal plants; neurodegeneration; neuroinflammation; nitric oxide; phytochemicals; plants derivatives; reactive nitrogen species.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Scheme of nitric oxide (NO) synthesis MAPK activation in myeloid or glial cells can trigger NF-κB transcriptional activation, leading to expression of iNOS. iNOS is subsequently transformed to NOS, which in the presence of NADPH converts L-arginine to L-citrulline and free NO radicals. Stimulants such as bradykinin, acetylcholine, histamine, leukotrienes, and platelet-activating factors from neuronal/endothelial cells or other origins can induce expression of eNOS, and nNOS converts L-arginine to free NO radicals through the same oxidation process.
Figure 2
Figure 2
Biological role of NO in pathophysiological conditions. NO-mediated activation of cGMP, PKG, and VASP can cause platelet inhibition while NO-mediated induction of pro-apoptotic proteins such as PARP, AIF, cytochrome C, and cleaved caspase-3 can induce cell death. NO-mediated activation of cGMP, PKG, Rho A, and Rho kinase can alter smooth muscles relaxation. Inhibition of NAD, NADPH, and GSH by NO increases the probability of cell death. Lipid peroxidation caused by NO induces oxidative stress or damage. S-nitrosylation elicited by NO can cause neurotoxicity or neurodegeneration. NO-mediated induction of PKG and calcium signaling causes exitotoxicity and contraction effects. NO is also involved in neutrophil infiltration and endothelial dysfunctions through effects of mitochondrial respiration, through NK cell toxicity, and through activation of the GAPDH-PARP pathway and its functions.
Figure 3
Figure 3
Structures of phytochemicals that can inhibit nitrite production. 1. Balanophonin_Firmiana simplex; 2. Chaenomiside A_Chaenomeles Sinensis; 3. (7R, 8S)-dehydrodiconferyl alcohol_Clematis armandii; 4. Melongenamide C & 5. cannabisin F_Solanum melongena; 6. (2R, 3S) dihydro-2-(3,5-dimethoxy-4-hydroxyphenyl)-7-methoxy-5-acetyl-benzofuran_Selagginella tamariscina; 7. Sambucuside_Sambucus williamsii; 8. Cudraflavanone A_Cudrania tricuspidata; 9. Daidzein _Glycine Max; 10. Eupatilin_Artemisia asiatica; 11. Genistein _Pimpinella anisum; 12. Orobol 4ʹ-O-β- D- apiofuranosyl-(1→6)-β-D-glucopyranoside_Tilia amurensis; 13. Quercetin_Impatiens balsamina; 14. Sophoraflavanone G_Sophora alopecuroides; 15. Tangeretin_Citrus aurantium.
Figure 4
Figure 4
Structures of phytochemicals that can inhibit nitrite production: 16. Butein_Oxicodendron vernicifluum; 17. (4E, 6E)-1-(3′,4-dihydroxyphenyl)-7-(4″-hydroxyphenyl)-hepta-4,6-dien-3-one & 18. Tsaokarylone_Dioscorea nipponica; 19. Gingerol_Zingiber officinale; 20. Oleuropein_Fraxinus rhynchophylla; 21. Paradol_Zingiber officinale; 22. Salicortin_Salix glandulosa; 23. Shogaol & 24. Zingerone_ Zingiber officinale; 25. Alphitolic acid_Ziziphus jajuba; 26. Betulinic acid & 27. Coussaric acid_ Diospyros Kaki; 28. Corosolic acid & 29. Ambradiolic acid_ Betula schmidtii; 30. 23-hydroxybetulinic acid_Chaenomeles speciose.
Figure 5
Figure 5
Structures of phytochemicals that can inhibit nitrite production. 31. Holophyllane A_Abies holophylla; 32. Ilimaquinone_Smenospongia cerebriformis; 33. Masilinic acid_Olea euroopaea; 34. Saikosaponins_Bupleurum falcatum; 35. Sesquiterpene dimer_Artemisia argyi 36. Spathulenol_Phaeanthus veitnamensis; 37. Coumestrol_Medicago sativa Linn; 38. Omphalocarpin_Toddaliae Asiaticae; 39. Aucuparin & 40. Dihydrometosolic acid_Chaenomeles speciose; 41. ε-Cotonefuran_Chaenomeles Sinensis; 42. Citrusin XI_Citrus unshiu; 43. Koaburaside_Lindera neesiana; 44. Sinapoyl desulfoglucoraphenin_Raphanus sativus; 45. Zanthplanispine_Zanthoxylum schinifolium; 46. (+)-Faurinone_Lindera glauca.
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