Neuregulin-1 signaling in brain endothelial cells.

Neuregulin-1 (NRG1) signaling has multiple functions in neurons and glia. The data in this study show that NRG1 may also possess significant signaling and cytoprotective properties in human brain microvascular endothelial cells (BMECs). Neuregulin-1 mRNA and protein expression are present in these cells, and NRG1 receptors erbB2 and erbB3 are phosphorylated in response to NRG1. Neuregulin-1 triggers clear biologic responses in BMECs--elevated phospho-Akt levels, increased ring formation in a Matrigel assay, and decreased cell death after oxidative injury with H(2)O(2). These data suggest that NRG1 signaling is functional and cytoprotective in BMECs.

Neuroprotection via matrix-trophic coupling between cerebral endothelial cells and neurons.

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 beta-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.

Beyond NMDA and AMPA glutamate receptors: emerging mechanisms for ionic imbalance and cell death in stroke.

The glutamate receptor was one of the most intensely investigated targets for neuroprotection. However, numerous clinical trials of glutamate receptor antagonists for the treatment of stroke were unsuccessful. These failures have led to pessimism in the field. But recent advances could provide hope for the future. This minireview looks beyond the traditional mechanism of glutamate-receptor-driven excitotoxicity to identify other mechanisms of ionic imbalance. These advances include findings implicating sodium-calcium exchangers, hemichannels, volume-regulated anion channels, acid-sensing channels, transient receptor potential channels, nonselective cation channels and signaling cascades that mediate crosstalk between redundant pathways of cell death. Further in vivo validation of these pathways could ultimately lead us to new therapeutic targets for stroke, trauma and neurodegeneration.

White matter vulnerability to ischemic injury increases with age because of enhanced excitotoxicity.

Stroke incidence increases with age and this has been attributed to vascular factors. We show here that CNS white matter (WM) is intrinsically more vulnerable to ischemic injury in older animals and that the mechanisms of WM injury change as a function of age. The mouse optic nerve was used to study WM function. WM function in older animals (12 months) was not protected from ischemic injury by removal of extracellular Ca2+ or by blockade of reverse Na+/Ca2+ exchange, as is the case with young adults. Ischemic WM injury in older mice is predominately mediated by glutamate release and activation of AMPA/kainate-type glutamate receptors. Glutamate release, attributable to reverse glutamate transport, occurs earlier and is more robust in older mice that show greater expression of the glutamate transporter. The observation that WM vulnerability to ischemic injury is age dependent has possible implications for the pathogenesis of other age-related CNS conditions.