Effects of 9-t-butyl doxycycline on the innate immune response to CNS ischemia-reperfusion injury.

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-κß-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.

Lung-Derived SOD3 Attenuates Neurovascular Injury After Transient Global Cerebral Ischemia.

Background Systemic innate immune priming is a recognized sequela of post-ischemic neuroinflammation and contributor to delayed neurodegeneration. Given mounting evidence linking acute stroke with reactive lung inflammation, we asked whether enhanced expression of the endogenous antioxidant extracellular superoxide dismutase 3 (SOD3) produced by alveolar type II pneumocytes would protect the lung from transient global cerebral ischemia and the brain from the delayed effects of ischemia-reperfusion. Methods and Results Following 15 minutes of global cerebral ischemia or sham conditions, transgenic SOD3 and wild-type mice were followed daily for changes in weight, core temperature, and neurological function. Three days after reperfusion, arterial and venous samples were collected for complete blood counts, flow cytometry, and SOD3 protein blotting, and immunohistochemistry was performed on lung and brain tissue to assess tissue injury, blood-brain barrier permeability, and neutrophil transmigration. Relative to ischemic controls, transgenic SOD3 mice performed better on functional testing and exhibited reduced peripheral neutrophil activation, lung inflammation, and blood-brain barrier leak. Once released from the lung, SOD3 was predominantly not cell associated and depleted in the venous phase of circulation. Conclusions In addition to reducing the local inflammatory response to cerebral ischemia, targeted enrichment of SOD3 within the lung confers distal neuroprotection against ischemia-reperfusion injury. These data suggest that therapies geared toward enhancing adaptive lung-neurovascular coupling may improve outcomes following acute stroke and cardiac arrest.

The post-cardiac arrest syndrome: A case for lung-brain coupling and opportunities for neuroprotection.

Systemic inflammation and multi-organ failure represent hallmarks of the post-cardiac arrest syndrome (PCAS) and predict severe neurological injury and often fatal outcomes. Current interventions for cardiac arrest focus on the reversal of precipitating cardiac pathologies and the implementation of supportive measures with the goal of limiting damage to at-risk tissue. Despite the widespread use of targeted temperature management, there remain no proven approaches to manage reperfusion injury in the period following the return of spontaneous circulation. Recent evidence has implicated the lung as a moderator of systemic inflammation following remote somatic injury in part through effects on innate immune priming. In this review, we explore concepts related to lung-dependent innate immune priming and its potential role in PCAS. Specifically, we propose and investigate the conceptual model of lung-brain coupling drawing from the broader literature connecting tissue damage and acute lung injury with cerebral reperfusion injury. Subsequently, we consider the role that interventions designed to short-circuit lung-dependent immune priming might play in improving patient outcomes following cardiac arrest and possibly other acute neurological injuries.