Microglia Potentiate Damage to Blood–Brain Barrier Constituents

Abstract

Background-Blood-brain barrier (BBB) disruption after stroke can worsen ischemic injury by increasing edema and causing hemorrhage. We determined the effect of microglia on the BBB and its primary constituents, endothelial cells (ECs) and astrocytes, after ischemia using in vivo and in vitro models. Methods and Results-Primary astrocytes, ECs, or cocultures were prepared with or without added microglia. Primary ECs were more resistant to oxygen-glucose deprivation/reperfusion than astrocytes. ECs plus astrocytes showed intermediate vulnerability. Microglia added to cocultures nearly doubled cell death. This increase was prevented by minocycline and apocynin. In vivo, minocycline reduced infarct volume and neurological deficits and markedly reduced BBB disruption and hemorrhage in mice after experimental stroke. Conclusions-Inhibition of microglial activation may protect the brain after ischemic stroke by improving BBB viability and integrity. Microglial inhibitors may prove to be an important treatment adjunct to fibrinolysis.

Recombinant Tissue Plasminogen Activator Enhances Microglial Cell Recruitment after Stroke in Mice

“…24 It was reported that microglia could exacerbate endothelial cell death after oxygen and glucose deprivation and that treatment with minocycline, a drug known to reduce microglial activation and proliferation, 8 could attenuate this phenomenon. 25 Recombinant tPA induces a catalyticindependent activation of the extracellular signal-regulated kinase 1/2 and Jun N-terminal kinase leading to microglial activation in culture. 21 Thus, preventing rtPA-related enhancement of microglial cell recruitment and activation after stroke could possibly limit ischemic brain infarction.…”

Microglial Activation in Stroke: Therapeutic Targets

“…25,26 Recent work has shown that microglia can potentiate injury to blood-brain barrier constituents (astrocytes and endothelial cells) via NOX-mediated superoxide in cell culture models of ischemia. 13 In addition, several groups have shown that mice deficient in the gp91 subunit of NOX2 have smaller infarcts than do wild-type mice, [27][28][29] and that outcomes from experimental cerebral ischemiareperfusion are improved with early administration of the pharmacological NOX inhibitors apocynin 29 -33 and honokiol. 34,35 These results identify NOX as a promising target for therapeutic intervention, but it is possible that the efficacy of these treatment strategies may be due largely or in part to inhibition of NOX in cell types other than microglia.…”

“…It is important, however, to place this approach in context. Although there is now strong evidence that the inflammatory response can exacerbate ischemic injury, [13][14][15][16][17][18] there is also evidence that some aspects of the inflammatory response are important for tissue repair. These aspects include phagocytosis of cell debris, remodeling of the extracellular matrix, and the release of cytokines and trophic factors.…”

Treatment Targets in Intracerebral Hemorrhage

“…Ultimately, it is the inflammation (phagocytosis) that leads to the restoration of tissue structure and function [96,97]. Although inflammation is triggered primarily to remove the blood and other debris left by the hemorrhage, the byproducts of this response are cytotoxic and lead to further tissue damage, blood brain barrier disruption, and edema [72,97,98].…”

“…Other Treatment Modalities Additional treatments that are being evaluated for ICH treatment include hypothermia [148,149], stem cells, minocycline [98,150], and rehabilitation interventions [151][152][153]. The latter treatment modalities are currently in the early stages of preclinical development.…”