Natural Withanolides in the Treatment of Chronic Diseases

  • Peter T. White
  • Chitra Subramanian
  • Hashim F. Motiwala
  • Mark S. CohenEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 928)


Withanolides, and in particular extracts from Withania somnifera, have been used for over 3,000 years in traditional Ayurvedic and Unani Indian medical systems as well as within several other Asian countries. Traditionally, the extracts were ascribed a wide range of pharmacologic properties with corresponding medical uses, including adaptogenic, diuretic, anti-inflammatory, sedative/anxiolytic, cytotoxic, antitussive, and immunomodulatory. Since the discovery of the archetype withaferin A in 1965, approximately 900 of these naturally occurring, polyoxygenated steroidal lactones with 28-carbon ergostane skeletons have been discovered across 24 diverse structural types. Subsequently, extensive pharmacologic research has identified multiple mechanisms of action across key inflammatory pathways. In this chapter we identify and describe the major withanolides with anti-inflammatory properties, illustrate their role within essential and supportive inflammatory pathways (including NF-κB, JAK/STAT, AP-1, PPARγ, Hsp90 Nrf2, and HIF-1), and then discuss the clinical application of these withanolides in inflammation-mediated chronic diseases (including arthritis, autoimmune, cancer, neurodegenerative, and neurobehavioral). These naturally derived compounds exhibit remarkable biologic activity across these complex disease processes, while showing minimal adverse effects. As novel compounds and analogs continue to be discovered, characterized, and clinically evaluated, the interest in withanolides as a novel therapeutic only continues to grow.


Autoimmune Cancer Inflammation Neurodegenerative NF-κB Withaferin A Withanolide 



5 FAD mutations carried on APP and PS1 transgenes




Alzheimer’s disease


Adisintegrin and metalloproteinase domain-containing protein 10, or α-secretase


Activator protein 1


Amyloid precursor protein


APP cleaving enzyme 1 or β-secretase




Bcl-2-related protein A1


CCAAT/enhancer-binding proteinα


Chemokine (C–C motif) receptor 7


C-FADD-like IL-1β-converting enzyme–inhibitory proteins


Central nervous system




Cancer stem cell


Epidermal growth factor


EGF receptor


Extracellular signal-regulated kinase


Food and Drug Administration


Gamma-aminobutyric acid


Good manufacturing process


Huntington’s disease


Hypoxia inducible factor-1


High mobility group box 1


Heterogeneous nuclear ribonucleoprotein




Heat shock protein


Mutant Huntingtin


Inhibitor of apoptosis protein-1


Inflammatory bowel disease


Intercellular adhesion molecule




I kappa B kinase




Inducible nitric oxide synthase


Janus kinase


c-Jun N-terminal protein kinase


Kelch like ECH-associated protein-1




Leukotriene B4


Mitogen-activated protein kinase


Mitotic clonal expansion,


Monocyte chemoattractant protein-1


Matrix metalloproteinases


Mouse mammary tumor virus-neu




Mass spectrometry


Mechanistic target of rapamycin


Mucin 1


Nuclear factor kappa B


Nitric oxide


Nuclear factor erythroid 2-related factor 2


Obsessive-compulsive disorder


Peripheral blood mononuclear cells


Parkinson’s disease


Platelet-derived growth factor


Prostaglandin E2




Peroxisome proliferator-activated receptors


Quinone reductase


Rheumatoid arthritis


Reactive oxygen species


Receptor tyrosine kinases


Structural–activity relationship


Synovial fluid mononuclear cells


Super oxide dismutase


Signal transducer and activator of transcription


Transforming growth factor-β-activating kinase


Transforming growth factor beta




Toll-like receptors


Trinitrobenzyl sulfonic acid


Tumor necrosis factor


Tumor necrosis factor-related apoptosis-inducing ligand


Twist family BHLH transcription factor


Ultra-performance liquid chromatography


Vascular endothelial growth factor


Withaferin A


Withania somnifera


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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Peter T. White
    • 1
  • Chitra Subramanian
    • 1
  • Hashim F. Motiwala
    • 1
  • Mark S. Cohen
    • 1
    Email author
  1. 1.Department of SurgeryUniversity of Michigan Hospital and Health SystemsAnn ArborUSA

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