Effects of 9-t-butyl doxycycline on the innate immune response to CNS ischemia-reperfusion injury
- Exp Mol Pathol. 2021 Feb:118:104601. doi: 10.1016/j.yexmp.2020.104601.
- 1. Department of Neuroscience, University of Rochester Medical Center, Rochester, NY 14642, USA; The Center for Neurotherapeutics Discovery, University of Rochester Medical Center, Rochester, NY 14642, USA.
- 2. Department of Neurology, University of Rochester Medical Center, Rochester, NY 14642, USA; The Center for Neurotherapeutics Discovery, University of Rochester Medical Center, Rochester, NY 14642, USA.
- 3. Echelon Biosciences, Salt Lake City, UT 84108, USA.
- 4. Department of Neurology, SUNY Stony Brook, Stony Brook, NY, USA. Electronic address: [email protected].
Cerebral ischemia triggers a cascade of neuroinflammatory and peripheral immune responses that contribute to post-ischemic reperfusion injury. Prior work conducted in CNS ischemia models underscore the potential to harness non-antibiotic properties of Tetracycline antibiotics for therapeutic benefit. In the present study, we explored the immunomodulatory effects of the Tetracycline derivative 9-tert-butyl doxycycline (9-TB) in a mouse model of transient global ischemia that mimics immunologic aspects of the post-cardiac arrest syndrome. Pharmacokinetic studies performed in C57BL/6 mice demonstrate that within four hours after delivery, levels of 9-TB in the brain were 1.6 and 9.5-fold higher than those obtained using minocycline and doxycycline, respectively. Minocycline and 9-TB also dampened inflammation, measured by reduced TNFα-inducible, NF-κβ-dependent luciferase activity in a microglial reporter line. Notably, daily 9-TB treatment following ischemia-reperfusion injury in vivo induced the retention of polymorphonuclear neutrophils (PMNs) within the spleen while simultaneously biasing CNS PMNs towards an anti-inflammatory (CD11bLowYm1+) phenotype. These studies indicate that aside from exhibiting enhanced CNS delivery, 9-TB alters both the trafficking and polarization of PMNs in the context of CNS ischemia-reperfusion injury.