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Natural Withanolides in the Treatment of Chronic Diseases

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

Abstract

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.

Keywords

Autoimmune Cancer Inflammation Neurodegenerative NF-κB Withaferin A Withanolide 

Abbreviations

5XFAD

5 FAD mutations carried on APP and PS1 transgenes

AChE

Acetylcholinesterase

AD

Alzheimer’s disease

ADAM10

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

AP-1

Activator protein 1

APP

Amyloid precursor protein

BACE

APP cleaving enzyme 1 or β-secretase

BChE

Butyrylcholinesterase

Bfl-1/A1

Bcl-2-related protein A1

C/EBPα

CCAAT/enhancer-binding proteinα

CCR7

Chemokine (C–C motif) receptor 7

cFLIP

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

CNS

Central nervous system

COX

Cyclooxygenase

CSC

Cancer stem cell

EGF

Epidermal growth factor

EGFR

EGF receptor

ERK

Extracellular signal-regulated kinase

FDA

Food and Drug Administration

GABA

Gamma-aminobutyric acid

GMP

Good manufacturing process

HD

Huntington’s disease

HIF-1

Hypoxia inducible factor-1

HMGB1

High mobility group box 1

hnRNP-K

Heterogeneous nuclear ribonucleoprotein

KHPA

Hypothalamic–pituitary–adrenal

Hsp

Heat shock protein

HTT

Mutant Huntingtin

IAP1

Inhibitor of apoptosis protein-1

IBD

Inflammatory bowel disease

ICAM

Intercellular adhesion molecule

IFN

Interferon

IKK

I kappa B kinase

IL

Interleukin

iNOS

Inducible nitric oxide synthase

JAK

Janus kinase

JNK1

c-Jun N-terminal protein kinase

Keap1

Kelch like ECH-associated protein-1

LPS

Lipopolysaccharide

LTB4

Leukotriene B4

MAPK

Mitogen-activated protein kinase

MCE

Mitotic clonal expansion,

MCP-1

Monocyte chemoattractant protein-1

MMPs

Matrix metalloproteinases

MMTV-neu

Mouse mammary tumor virus-neu

MPTP

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MS

Mass spectrometry

mTOR

Mechanistic target of rapamycin

MUC-1

Mucin 1

NF-κB

Nuclear factor kappa B

NO

Nitric oxide

Nrf2

Nuclear factor erythroid 2-related factor 2

OCD

Obsessive-compulsive disorder

PBMC

Peripheral blood mononuclear cells

PD

Parkinson’s disease

PDGF

Platelet-derived growth factor

PGE2

Prostaglandin E2

PI3K

Phosphatidylinositol-3-kinase

PPARs

Peroxisome proliferator-activated receptors

QR

Quinone reductase

RA

Rheumatoid arthritis

ROS

Reactive oxygen species

RTKs

Receptor tyrosine kinases

SAR

Structural–activity relationship

SFMC

Synovial fluid mononuclear cells

SOD

Super oxide dismutase

STAT

Signal transducer and activator of transcription

TAK1

Transforming growth factor-β-activating kinase

TGF-β

Transforming growth factor beta

Th

T-helper

TLRs

Toll-like receptors

TNBS

Trinitrobenzyl sulfonic acid

TNF

Tumor necrosis factor

TRAIL

Tumor necrosis factor-related apoptosis-inducing ligand

TWIST

Twist family BHLH transcription factor

UPLC

Ultra-performance liquid chromatography

VEGF

Vascular endothelial growth factor

WA

Withaferin A

WS

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
  1. 1.Department of SurgeryUniversity of Michigan Hospital and Health SystemsAnn ArborUSA

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