title: Fast and long acting neoflavonoids dalbergin isolated from Dalbergia sissoo heartwood is osteoprotective in ovariectomized model of osteoporosis: Osteoprotective effect of Dalbergin.
abstract: OBJECTIVE
  This study aims to evaluate the skeletal effects of dalbergin (DBN), isolated from Dalbergia sissoo heartwood, in ovariectomized (OVx) BALB/c mice, a postmenopausal osteoporosis model of bone loss.
  
  
  METHODS
  Adult BALB/c mice were used and randomly assigned in to six groups with 6 animals (n=6) in each group: sham (surgery operated without ovariectomy) with vehicle, ovariectomy with vehicle, ovariectomy (OVx) with estradiol (E2 5.0μgkg-1day-1), or ovariectomy with dalbergin at three different doses of DBN (1.0, 5.0 and10mgkg-1day-1). Daily oral administration of the vehicle, estradiol, or DBN was started 8 weeks post-surgery and continued for 8 weeks. At the end of experiment, mice were sacrificed and assessed for trabecular bone structure of tibia, lumbar vertebra (L5) and alterations in biochemical and uterine parameters, pharmacokinetic profile and gene expression were monitored for each group.
  
  
  RESULTS
  Treatment with DBN prevented trabecular bone loss in cancellous bone in the tibial metaphysis and lumbar vertebra region of the ovariectomized mice. Micro-CT data showed that mice treated with DBN at 1.0mgkg-1day-1exhibited improved bone micro-architecture that was sustained with decreased expression of bone resorption markers like TRAP and RANK and caused an increase in osteogenic markers like RUNX2, BMP2 and OPG/RANKL ratio compared with OVx+vehicle treated mice. Moreover, DBN treatment induced no uterine estrogenicity and significantly lowered the osteocalcin amount in serum when compared with OVx+V group. DBN reached its maximum concentration (Cmax) 238.49±21.37ngml-1in serum as early as 1h of administration. Overall, DBN (1.0mgkg-1day-1) treatment exhibited similar bone conserving effect against bone-loss as estradiol treatment.
  
  
  CONCLUSIONS
  Daily oral administration of DBN for 8 weeks showed significant anabolic effects on bone micro-architectural parameters along with down regulation of bone resorptive markers without compromising safety at uterine level. Therefore, our study provides basis for DBN as a therapeutic candidate against postmenopausal osteoporosis.
authors: Division of Endocrinology, CSIR-Central Drug Research Institute,Lucknow, 226031, India.
authors: Dharmendra
authors: D
authors: Choudhary
authors: Division of Endocrinology, CSIR-Central Drug Research Institute,Lucknow, 226031, India.
authors: Priyanka
authors: P
authors: Kushwaha
authors: Division of Endocrinology, CSIR-Central Drug Research Institute,Lucknow, 226031, India.
authors: Jyoti
authors: J
authors: Gautam
authors: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors: Padam
authors: P
authors: Kumar
authors: Division of Pharmaceutics, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors: Ashwani
authors: A
authors: Verma
authors: Division of Endocrinology, CSIR-Central Drug Research Institute,Lucknow, 226031, India.
authors: Avinash
authors: A
authors: Kumar
authors: Department of Chemistry, University of Allahabad, Allahabad, 211002, India.
authors: Saransh Wales
authors: SW
authors: Maurya
authors: Department of Chemistry, University of Allahabad, Allahabad, 211002, India.
authors: Ibadur Rahman
authors: IR
authors: Siddiqui
authors: Division of Pharmaceutics, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors: Prabhat Ranjan
authors: PR
authors: Mishra
authors: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, 226031, India.
authors: Rakesh
authors: R
authors: Maurya
authors: Division of Endocrinology, CSIR-Central Drug Research Institute,Lucknow, 226031, India. Electronic address: ritu_trivedi@cdri.res.in.
authors: Ritu
authors: R
authors: Trivedi
mesh_terms: D000284:Administration, Oral; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D001696:Biomechanical Phenomena / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D016723:Bone Remodeling / Q000187:drug effects; D002113:Calcification, Physiologic / Q000187:drug effects; D000071556:Cancellous Bone / Q000187:drug effects / Q000473:pathology; D003374:Coumarins / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D035782:Dalbergia / Q000737:chemistry*; D004195:Disease Models, Animal; D005260:Female; D005269:Femur / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D005419:Flavonoids / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008807:Mice, Inbred BALB C; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015675:Osteocalcin / Q000097:blood; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010024:Osteoporosis / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010052:Ovariectomy; D020011:Protective Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014599:Uterus / Q000187:drug effects / Q000473:pathology; D055114:X-Ray Microtomography
chemical_list: D015415:Biomarkers; D003374:Coumarins; D005419:Flavonoids; D020011:Protective Agents; C000613895:dalbergin; D015675:Osteocalcin; D000469:Alkaline Phosphatase
keywords: Neo-flavonoids DBN (dalbergin); Ovariectomy; Postmenopausal osteoporosis; Trabecular micro-architecture