title: Combination treatment with progesterone and vitamin D hormone is more effective than monotherapy in ischemic stroke: the role of BDNF/TrkB/Erk1/2 signaling in neuroprotection.
abstract: We investigated whether combinatorial post-injury treatment with progesterone (P4) and vitamin D hormone (VDH) would reduce ischemic injury more effectively than P4 alone in an oxygen glucose deprivation (OGD) model in primary cortical neurons and in a transient middle cerebral artery occlusion (tMCAO) model in rats. In the OGD model, P4 and VDH each showed neuroprotection individually, but combination of the "best" doses did not show substantial efficacy; instead, the lower dose of VDH in combination with P4 was the most effective. In the tMCAO model, P4 and VDH were given alone or in combination at different times post-occlusion for 7 days. In vivo data confirmed the in vitro findings and showed better infarct reduction at day 7 and functional outcomes (at 3, 5 and 7 days post-occlusion) after combinatorial treatment than when either agent was given alone. VDH, but not P4, upregulated heme oxygenase-1, suggesting a pathway for the neuroprotective effects of VDH differing from that of P4. The combination of P4 and VDH activated brain-derived neurotrophic factor and its specific receptor, tyrosine kinase receptor-B. Under specific conditions VDH potentiates P4's neuroprotective efficacy and should be considered as a potential partner of P4 in a low-cost, safe and effective combinatorial treatment for stroke.
authors.affiliation: Department of Emergency Medicine, Brain Research Laboratory, 1365B Clifton Road NE, Suite 5100, Emory University, Atlanta, GA 30322, USA.
authors.forename: Fahim
authors.initials: F
authors.lastname: Atif
authors.forename: Seema
authors.initials: S
authors.lastname: Yousuf
authors.forename: Iqbal
authors.initials: I
authors.lastname: Sayeed
authors.forename: Tauheed
authors.initials: T
authors.lastname: Ishrat
authors.forename: Fang
authors.initials: F
authors.lastname: Hua
authors.forename: Donald G
authors.initials: DG
authors.lastname: Stein
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000517:prevention & control*; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D002478:Cells, Cultured; D004359:Drug Therapy, Combination; D048370:MAP Kinase Kinase 2 / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D018696:Neuroprotective Agents / Q000008:administration & dosage; D011374:Progesterone / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020521:Stroke / Q000517:prevention & control*; D016896:Treatment Outcome; D014807:Vitamin D / Q000008:administration & dosage*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D014807:Vitamin D; D011374:Progesterone; D020813:Receptor, trkB; D048052:Mitogen-Activated Protein Kinase 3; D048370:MAP Kinase Kinase 2