title: Preventive effects of withaferin A isolated from the leaves of an Indian medicinal plant Withania somnifera (L.): comparisons with 17-β-estradiol and alendronate.
abstract: OBJECTIVE
  Bone protective effects of withaferin A (WFA) from leaves of Withania somnifera (L.) were evaluated in preventive model of Balb/c mice with 17 β-estradiol (E2) and alendronate (ALD).
  
  
  METHODS
  Adult female Balb/c mice, 7 to 9 wk, were bilaterally ovariectomized (OVx) to mimic the state of E2 deficiency. Immediately after surgery mice were administrated WFA at doses of 1, 5, 10 mg/kg/d while other two OVx groups received ALD or E2 for 2 mo. Sham and OVx groups with vehicle and no treatment served as controls.
  
  
  RESULTS
  WFA administration increased new bone formation, as well as improving microarchitecture and biomechanical strength of the bones. It prevented bone loss by reducing expression of osteoclastic genes tartrate resistant acid phosphatase (TRAP) and receptor activator of nuclear factor κ B (RANK). Increase in bone turnover marker, osteocalcin (OCN) and inflammatory cytokine tumor necrosis factor-alpha (TNF-α) because of ovariectomy were reduced with WFA treatment, with effects comparable to E2 administration. Histomorphometric analysis of uterus shows that WFA was not fraught with estrogenic or antiestrogenic effects. At cellular level, WFA promoted differentiation of bone marrow cells (BMCs) and increased mineralization by inducing expression of osteogenic genes. WFA has bone protective potential as its treatment prevents bone loss that is comparable to ALD and E2.
  
  
  CONCLUSIONS
  It is surmised that WFA in preclinical setting is effective in preserving bone loss by both inhibition of resorption and stimulation of new bone formation before onset of osteoporosis with no uterine hyperplasia.
authors.affiliation: Division of Endocrinology, Central Drug Research Institute, Council of Scientific and Industrial Research-CDRI, Lucknow, India; Jawaharlal Nehru University, New Delhi, India.
authors.forename: Vikram
authors.initials: V
authors.lastname: Khedgikar
authors.affiliation: Division of Endocrinology, Central Drug Research Institute, Council of Scientific and Industrial Research-CDRI, Lucknow, India.
authors.forename: Naseer
authors.initials: N
authors.lastname: Ahmad
authors.affiliation: Division of Endocrinology, Central Drug Research Institute, Council of Scientific and Industrial Research-CDRI, Lucknow, India; Academy of Scientific and Innovation Research, New Delhi, India.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Kushwaha
authors.affiliation: Division of Endocrinology, Central Drug Research Institute, Council of Scientific and Industrial Research-CDRI, Lucknow, India; Jawaharlal Nehru University, New Delhi, India.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Gautam
authors.affiliation: Division of Endocrinology, Central Drug Research Institute, Council of Scientific and Industrial Research-CDRI, Lucknow, India.
authors.forename: Geet K
authors.initials: GK
authors.lastname: Nagar
authors.affiliation: Division of Endocrinology, Central Drug Research Institute, Council of Scientific and Industrial Research-CDRI, Lucknow, India.
authors.forename: Divya
authors.initials: D
authors.lastname: Singh
authors.affiliation: Plant Gene Expression Laboratory, Council of Scientific and Industrial Research-National Botanic Research Institute, Lucknow, India.
authors.forename: Prabodh K
authors.initials: PK
authors.lastname: Trivedi
authors.affiliation: Division of Pharmaceutics Central Drug Research Institute, Council of Scientific and Industrial Research-CDRI, Lucknow, India.
authors.forename: Prabhat R
authors.initials: PR
authors.lastname: Mishra
authors.affiliation: Council of Scientific and Industrial Research-Central Institute of Medicinal and Aromatic Plants, Lucknow, India.
authors.forename: Neelam S
authors.initials: NS
authors.lastname: Sangwan
authors.affiliation: Division of Endocrinology, Central Drug Research Institute, Council of Scientific and Industrial Research-CDRI, Lucknow, India. Electronic address: Ritu_trivedi@cdri.res.in.
authors.forename: Ritu
authors.initials: R
authors.lastname: Trivedi
mesh_terms: D000135:Acid Phosphatase / Q000235:genetics / Q000378:metabolism; D019386:Alendronate / Q000494:pharmacology*; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001842:Bone and Bones / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D015675:Osteocalcin / Q000097:blood; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism; D010024:Osteoporosis / Q000517:prevention & control*; D010052:Ovariectomy; D018515:Plant Leaves / Q000737:chemistry; D010946:Plants, Medicinal / Q000737:chemistry*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D032341:Withania / Q000737:chemistry*; D054358:Withanolides / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D007527:Isoenzymes; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D054358:Withanolides; D015675:Osteocalcin; D004958:Estradiol; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase; C009684:withaferin A; D019386:Alendronate
keywords: Antiresorptive; Microcomputed tomography; Osteogenic; Premenopausal; Trabecular microarchitecture