In a mouse model of ischaemia, mitochondrial particles released from astroctyes are taken up by adjacent neurons, leading to enhanced cell survival signalling; disruption of this release mechanism resulted in worsened neurological outcomes. Emerging results suggest that neurons can transfer damaged mitochondria into adjacent astrocytes for disposal and recycling. Here Eng Lo and colleagues identify a transfer of healthy mitochondria in the opposite direction. In a mouse model of ischaemia, the authors demonstrate the release of mitochondrial particles from astrocytes that are taken up by adjacent neurons, leading to enhanced cell survival signalling. Disrupting this transfer led to worsened neurological outcomes. These findings suggest a previously unknown form of crosstalk between glia and damaged neurons, and suggest pathways that may be potentially targeted for improving stroke recovery in the future. Neurons can release damaged mitochondria and transfer them to astrocytes for disposal and recycling1. This ability to exchange mitochondria may represent a potential mode of cell-to-cell signalling in the central nervous system. Here we show that astrocytes in mice can also release functional mitochondria that enter neurons. Astrocytic release of extracellular mitochondrial particles was mediated by a calcium-dependent mechanism involving CD38 and cyclic ADP ribose signalling. Transient focal cerebral ischaemia in mice induced entry of astrocytic mitochondria into adjacent neurons, and this entry amplified cell survival signals. Suppression of CD38 signalling by short interfering RNA reduced extracellular mitochondria transfer and worsened neurological outcomes. These findings suggest a new mitochondrial mechanism of neuroglial crosstalk that may contribute to endogenous neuroprotective and neurorecovery mechanisms after stroke.

Background and Purpose — Thrombolytic therapy with tissue plasminogen activator (tPA) for acute ischemic stroke remains complicated by risks of hemorrhagic transformation. In this study we used a previously established quantitative rat model of tPA-associated hemorrhage to test the hypothesis that matrix metalloproteinases (MMPs) are involved. Methods — Spontaneously hypertensive rats were subjected to embolic focal ischemia by placing homologous blood clots into the middle cerebral artery. Three groups of rats were studied: (1) untreated controls that received saline at 6 hours after ischemia; (2) rats that received tPA alone (10 mg/kg at 6 hours after ischemia); and (3) rats that received tPA plus the broad-spectrum MMP inhibitor BB-94 (50 mg/kg of BB-94 before ischemia and at 3 and 6 hours after ischemia plus tPA at 6 hours). Gelatin zymography was used to quantify MMP levels. A hemoglobin spectrophotometry method was used to quantify cerebral hemorrhage. Ischemic lesions were measured at 24 hours with tetrazolium staining. Results — At 6, 12, and 24 hours, pro-MMP-9 and cleaved MMP-9 were upregulated in ischemic brain. At 12 hours, tPA-treated rats showed significantly higher levels of pro-MMP-9 and cleaved MMP-9 than untreated controls. By 24 hours, all rats showed evidence of hemorrhagic transformation in the ischemic territory. Rats treated with BB-94 and tPA showed significantly reduced hemorrhage volumes compared with those that received tPA alone. There was no effect on infarct size. Conclusions — These results indicate that (1) tPA treatment increases levels of MMP-9 after embolic focal cerebral ischemia, (2) MMPs are involved in the mechanism of tPA-associated hemorrhage, and (3) combination therapies with MMP inhibitors may be useful for decreasing the risk and severity of this dreaded complication of thrombolytic therapy.

After brain injury, neuroblast cells from the subventricular zone (SVZ) expand and migrate toward damaged tissue. The mechanisms that mediate these neurogenic and migratory responses remain to be fully dissected. Here, we show that bromodeoxyuridine-labeled and doublecortin-positive cells from the SVZ colocalize with the extracellular protease matrix metalloproteinase-9 (MMP-9) during the 2 week recovery period after transient focal cerebral ischemia in mice. Treatment with the broad spectrum MMP inhibitor GM6001 significantly decreases the migration of doublecortin-positive cells that extend from the SVZ into the striatum. These data suggest that MMPs are involved in endogenous mechanisms of neurogenic migration as the brain seeks to heal itself after injury.

The neurovascular unit is an emerging concept that emphasizes homeostatic interactions between endothelium and cerebral parenchyma. Here, we show that cerebral endothelium are not just inert tubes for delivering blood, but they also secrete trophic factors that can be directly neuroprotective. Conditioned media from cerebral endothelial cells broadly protects neurons against oxygen-glucose deprivation, oxidative damage, endoplasmic reticulum stress, hypoxia, and amyloid neurotoxicity. This phenomenon is largely mediated by endothelial-produced brain-derived neurotrophic factor (BDNF) because filtering endothelial-conditioned media with TrkB-Fc eliminates the neuroprotective effect. Endothelial production of BDNF is sustained by β-1 integrin and integrin-linked kinase (ILK) signaling. Noncytotoxic levels of oxidative stress disrupts ILK signaling and reduces endothelial levels of neuroprotective BDNF. These data suggest that cerebral endothelium provides a critical source of homeostatic support for neurons. Targeting these signals of matrix and trophic coupling between endothelium and neurons may provide new therapeutic opportunities for stroke and other CNS disorders.