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

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.

► Low-dose vitamin D enhanced progesterone (P4) neuroprotection after in vitro stroke. ► P4 + VDH reduced infarct in rats after transient stroke more than P4 alone. ► P4 + VDH showed better functional recovery than P4 alone at post-stroke day 7. ► P4 + VDH modulates neuroinflammation, oxidative damage, and growth factor signaling.