Ischemic postconditioning is defined as a protective series of brief episodes of ischemia-reperfusion subsequent to a prolonged ischemic insult. Thus far, the majority of experimental studies have focused on the acute mechanisms of ischemic postconditioning, mostly at 24 hours. However, effects and mechanisms of postconditioning in the brain for longer periods post-stroke remain to be fully elucidated. Our hypothesis states that ischemic postconditioning promotes neurovascular unit recovery after stroke, in part by augmenting the production of BDNF and MMP9 in astrocytes, thus promoting neurogenesis and angiogenesis. These factors may allow postconditioning to amplify neurogenesis and angiogenesis, hence improving stroke recovery. Our preliminary data showed that postconditioning is neuroprotective at 3 days and 2 weeks, increases neurogenesis and angiogenesis and elevates Akt, MMP9 and BDNF protein expression levels especially in reactive astrocytes within the peri-infarct cortex. We will build on these pilot data by pursuing 2 aims.
Aim 1 : Investigate effects of postconditoning on the ability of astrocytes to protect neurons in vitro. We will use primary cell cultures and media transfer experiments to test the hypothesis that postconditioning amplifies the ability of astrocytes to produce BDNF and MMP9, which then protects neurons and promotes their neuroplastic recovery after oxygen-glucose deprivation.
Aim 2 : Investigate the effects of postconditoning on astrocytic production of BDNF and MMP9 during stroke recovery in vivo. We will use rat models of focal cerebral ischemia to verify in vivo, the hypothesis that postconditioning increases astrocytic production of BDNF and MMP9 during stroke recovery. We will assess causality by blocking MMP9 and/or BDNF and tracking the subsequent effects on neurologic recovery. To test the hypothesis that postconditioning augments neurogenesis and angiogenesis via astrocyte-derived BDNF and MMP9, we will suppress astrocytic production of BDNF and MMP9, and then document the subsequent effects on neurogenesis, angiogenesis and correlate this with neurologic outcomes over time. We will also use astrocyte specific BDNF deficient mice to confirm our hypothesis, as suggested by previous reviewers. We expect that in KO mice the neuroprotective effect of ischemic postconditioning is in part prevented. Understanding the mechanisms of postconditioning in long-term stroke recovery is fundamentally required. This R03 allows a new PI to begin this line of investigation to further contribute to the development and translation of postconditioning as a therapeutic approach for stroke.
Postconditioning may be a practically feasible way to promote stroke recovery. But many obstacles prevent clinical translation. First, all existing studies are mostly on acute 24 hr outcomes. Second, the mechanisms of protection and augmented long-term benefits remain unclear. Our goal is to define mechanisms that explain long-term benefits of improved recovery. This step is fundamentally required before one can attempt to design rigorous clinical trials for postconditioining to improve stroke recovery.
| Esposito, Elga; Hayakawa, Kazuhide; Ahn, Bum Ju et al. (2018) Effects of ischemic post-conditioning on neuronal VEGF regulation and microglial polarization in a rat model of focal cerebral ischemia. J Neurochem 146:160-172 |
