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Apocynin - From the Plant Kutki - Oxidative Stress, Calpains, Intra Cellular Calcium, NMDA Receptor Activation, Aptosis, & Neurodegeneration

This article is not medical advice. Before starting any health related regimen, you should seek the advice of your Primary Care Physician, or an M.D.


The compound Apocynin has been receiving significant research of late - related to its ability to lower calpain activity and NADPH Oxidase activity, although that appears limited to neutrophils. All related to lowering oxidative stress, in particular super oxide. The plant, Kutki, is a source of Apocynin, and has been used medicinally for thousands of years.


Kutki - A Source of Apocynin

"Traditional remedies for the treatment of various ailments are gaining popularity. Traditionally, one of the most valuable therapeutic herbs has been Picrorhiza kurroa Royle ex Benth. Traditional and folk uses of P. kurroa include chronic constipation, skin-related problems, burning sensation, chronic reoccurring fever, jaundice, heart problems, breathing, digestion, allergy, tuberculosis, blood-related problems, prediabetes and obesity, laxative, cholagogue, and liver stimulatory. Phytoconstituents such as glycosides, alkaloids, cucurbitacins, iridoids, phenolics, and terpenes in P. kurroa have shown promising pharmacological potential. In order to uncover novel compounds that may cure chronic illnesses, such as cardiovascular, diabetes, cancer, respiratory, and hepatoprotective diseases, the screening of P. kurroa is essential. This study comprehensively evaluated the ethnopharmacological efficacy, phytochemistry, pharmacological activity, dose, and toxicity of P. kurroa. This review provides comprehensive insights into this traditional medication for future research and therapeutic application. The purpose of this review article was to determine the pharmacological effects of P. kurroa on a variety of disorders. P. kurroa may be a natural alternative to the standard treatment for eradicating newly evolving diseases. This study is intended as a resource for future fundamental and clinical investigations."[1]


Kutki is believed to have the following impact on specific pathways and genes:

  • Downregulates: TNFA, NFKB, COX-2, HO-1, TLR4, IL1-B, IL-6, ERK1/2, HMBG1, ROS, LDH, MPO, MDA, NOX

  • Upregulates: SOD, GSH (Glutathione)


Its used for various immune and mast cell regulation, anti-inflammatory, anti oxidant, anti cancer properties. It is also used for fatty liver, and jaundice, and hepatitis related issues.[1]


Apocynin

"Apocynin is a naturally occurring methoxy-substituted catechol, experimentally used as an inhibitor of NADPH-oxidase. It can decrease the production of superoxide (O2 ) from activated neutrophils and macrophages while the ability of phagocytosis remains unaffected. The anti-inflammatory activity of apocynin has been demonstrated in a variety of cell and animal models of inflammation. Apocynin, after metabolic conversion, inhibits the assembly of NADPH-oxidase that is responsible for reactive oxygen species (ROS) production. It is, therefore, extensively used to reveal the role of this enzyme in cell and experimental models. Although some of the ROS serve as signaling molecules in the cells, excessive production is damaging and has been implicated to play an important role in the progression of many disease processes. This is why in many studies apocynin presents a promising potential treatment for some disorders; however, its utility with inflammatory diseases remains to be determined."[2]


Apocynin Inhibits NADPH Oxidase

"A large body of literature suggest that vascular reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases are important sources of reactive oxygen species. Many studies, however, relied on data obtained with the inhibitor apocynin (4′-hydroxy-3′methoxyacetophenone). Because the mode of action of apocynin, however, is elusive, we determined its mechanism of inhibition on vascular NADPH oxidases. In HEK293 cells overexpressing NADPH oxidase isoforms (Nox1, Nox2, or Nox4), apocynin failed to inhibit superoxide anion generation detected by lucigenin chemiluminescence. In contrast, apocynin interfered with the detection of reactive oxygen species in assay systems selective for hydrogen peroxide or hydroxyl radicals. Importantly, apocynin interfered directly with the detection of peroxides but not superoxide, if generated by xanthine/xanthine oxidase or nonenzymatic systems. In leukocytes, apocynin is a prodrug that is activated by myeloperoxidase, a process that results in the formation of apocynin dimers. Endothelial cells and smooth muscle cells failed to form these dimers and, therefore, are not able to activate apocynin. Dimer formation was, however, observed in Nox-overexpressing HEK293 cells when myeloperoxidase was supplemented. As a consequence, apocynin should only inhibit NADPH oxidase in leukocytes, whereas in vascular cells, the compound could act as an antioxidant. Indeed, in vascular smooth muscle cells, the activation of the redox-sensitive kinases p38-mitogen-activate protein kinase, Akt, and extracellular signal–regulated kinase 1/2 by hydrogen peroxide and by the intracellular radical generator menadione was prevented in the presence of apocynin. These observations indicate that apocynin predominantly acts as an antioxidant in endothelial cells and vascular smooth muscle cells and should not be used as an NADPH oxidase inhibitor in vascular systems."[3]


Apocynin - Neurodegenerative Diseases

"Accumulating evidence suggests that inflammatory mediators secreted by activated resident or infiltrated innate immune cells have a significant impact on the pathogenesis of neurodegenerative diseases. This may imply that patients affected by a neurodegenerative disease may benefit from treatment with selective inhibitors of innate immune activity. Here we review the therapeutic potential of apocynin, an essentially nontoxic phenolic compound isolated from the medicinal plant Jatropha multifida(Coral Plant). Apocynin is a selective inhibitor of the phagocyte NADPH oxidase Nox2 that can be applied orally and is remarkably effective at low dose."[4]


Apocynin - Lowers Calpains - Which Are Implicated In High Intra-Cellular Calcium - Which Activates The NMDA Receptors And Leads To Neuro Degeneration

"Apoptosis, a form of programmed cell death that occurs under physiological as well as pathological conditions, is characterized by morphological and biochemical features. While the importance of caspases in apoptosis is established, several noncaspase proteases (Ca2+-dependent proteases) such as calpain may play a role in the execution of apoptosis. The calpain family consists of two major isoforms, calpain I and calpain II which require µM and mM Ca2+ concentrations to initiate their activity. An increase in intracellular Ca2+ level is thought to trigger a cascade of biochemical processes including calpain activation. Once activated, calpains degrade membrane, cytoplasmic and nuclear substrates, leading to the breakdown of cellular architecture and finally apoptosis. The activation of calpain has been implicated in neuronal apoptosis following spinal cord injuries and neurodegenerative diseases."[5]




References:

  1. Pharmacological and Clinical Efficacy of Picrorhiza kurroa and Its Secondary Metabolites: A Comprehensive Review. By Tahani M. Almeleebia, Abdulrhman Alsayari, and Shadma Wahab. Molecules. 2022 Dec; 27(23): 8316. Published online 2022 Nov 29. doi: 10.3390/molecules27238316 PMCID: PMC9738980 PMID: 36500409

  2. Apocynin: Molecular Aptitudes. By J. Stefanska and R. Pawliczak*Mediators Inflamm. 2008; 2008: 106507. Published online 2008 Dec 2. doi: 10.1155/2008/106507 PMCID: PMC2593395. PMID: 19096513

  3. Apocynin Is Not an Inhibitor of Vascular NADPH Oxidases but an Antioxidant. By Sabine Heumüller,Sven Wind, et. al. 17 Dec 2007. https://doi.org/10.1161/HYPERTENSIONAHA.107.100214Hypertension. 2008;51:211–217

  4. Apocynin, a Low Molecular Oral Treatment for Neurodegenerative Disease Bert A. Hart, Sjef Copray,and Ingrid Philippens. BioMEd Research International. Neurodegeneration: Etiologies and New Therapies. Volume 2014 | Article ID 298020 | https://doi.org/10.1155/2014/298020

  5. Role of Calpain in Apoptosis. By Hamid Reza Momeni, Ph.D. "Cell J. 2011 Summer; 13(2): 65–72. Published online 2011 Aug 24. PMCID: PMC3584455. PMID: 23507938




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