No abstract

Although the neurovascular unit was originally developed as a conceptual framework for stroke, it is now recognized that these cell-cell interactions play critical roles in many other CNS disorders as well. In brain trauma, perturbations within the neurovascular unit may be especially important. Changes in neurovascular coupling may disrupt blood flow and metabolic regulation. Disruption of transmitter release-reuptake kinetics in neurons and astrocytes may augment excitotoxicity. Alterations in gliovascular signaling may underlie blood-brain barrier disruptions and traumatic edema. Perturbations in cell-cell signaling between all neuronal, glial, and vascular compartments may increase susceptibility to cell death. Finally, repairing the brain after trauma requires the integrated restoration of all neural, glial, and vascular connectivity for effective functional recovery. Just as in stroke, saving neurons alone may also be insufficient for treating brain trauma. In this minireview, we attempt to briefly highlight some of these pathways to underscore the importance of rescuing the entire neurovascular unit in brain trauma.

The syntheses and characterization of two new tetrathiafulvalene (TTF) derivatives bearing pyridine-based substituents and 1,5'-dimethyl-6-oxoverdazyl radicals are described. The TTF-pyridine and bipyridine aldehydes were prepared via a palladium-catalyzed cross-coupling reaction between mono(tributylstannyl)tetrathiafulvalene (3) and the appropriate formylpyridyl halides (4). The radical precursors, the corresponding 1,2,4,5-tetrazanes, were prepared by condensation of the bis(1-methylhydrazide) of carbonic acid with the TTF bearing pyridyl aldehyde. Oxidation of tetrazanes 8 and 9 with 1,4-benzoquinone afforded the donor radicals 1 and 2 as 1:1 complexes with hydroquinone. Both complexes are stable in the solid state and their electronic properties have been characterized by EPR, cyclic voltammetry, and UV/vis spectroscopy. The TTF core of both compounds was oxidized both chemically and electrochemically to afford the corresponding cation diradical species. The electronic properties of both donor radicals have been probed by cyclic voltammetry, UV-vis spectroscopy, and preliminary EPR measurements.

Apolipoprotein E (apoE) and certain peptides derived from it have been shown to exert neurotoxic effects in vitro, and apoE has been linked to the etiology of Alzheimer's disease. The mechanisms underlying these toxic and pathological effects are, however, not known. To approach this question, we have studied the effects of apoE peptides on the cytoplasmic calcium ([Ca2+]i) homeostasis of cultured cortical neurons. A tandem dimer repeat peptide (apoEdp) derived from the receptor binding domain of apoE was found to have a potent effect on elevation of [Ca2+]i calcium. The pathway by which apoEdp exerted this effect was shown to involve both the mobilization of intracellular calcium and the influx of extracellular calcium, although the effect on influx was more pronounced. Calcium mobilization occurs via a G-protein-linked phospholipase C (PLC) pathway, whereas calcium influx appears to involve a novel Co2+-sensitive channel. Both the mobilization and the influx of calcium require the binding of the apoE peptide to a membrane receptor because both pathways are blocked by antibody to low-density-lipoprotein receptor-related protein. The data suggest that the neurotoxic effects of apoE may be mediated by a persistent elevation of [Ca2+]i.