Faculty Bibliography

Endothelin-1 (ET-1) is synthesized by endothelial cells and astrocytes in stroke and in brains of Alzheimer's disease patients. Our transgenic mice with ET-1 overexpression in the endothelial cells (TET-1) showed more severe blood-brain barrier (BBB) breakdown, neuronal apoptosis, and glial reactivity after 2-hour transient middle cerebral artery occlusion (tMCAO) with 22-hour reperfusion and more severe cognitive deficits after 30 minutes tMCAO with 5 months reperfusion. However, the role of astrocytic ET-1 in contributing to poststroke cognitive deficits after tMCAO is largely unknown. Therefore, GET-1 mice were challenged with tMCAO to determine its effect on neurologic and cognitive deficit. The GET-1 mice transiently displayed a sensorimotor deficit after reperfusion that recovered shortly, then more severe deficit in spatial learning and memory was observed at 3 months after ischemia compared with that of the controls. Upregulation of TNF-alpha, cleaved caspase-3, and Thioflavin-S-positive aggregates was observed in the ipsilateral hemispheres of the GET-1 brains as early as 3 days after ischemia. In an in vitro study, ET-1 overexpressing astrocytic cells showed amyloid secretion after hypoxia/ischemia insult, which activated endothelin A (ETA) and endothelin B (ETB) receptors in a PI3K/AKT-dependent manner, suggesting role of astrocytic ET-1 in dementia associated with stroke by astrocyte-derived amyloid production.

PURPOSE: Excitotoxicity has been linked to the pathogenesis of ocular diseases and injuries and may involve early degeneration of both anterior and posterior visual pathways. However, their spatiotemporal relationships remain unclear. We hypothesized that the effects of excitotoxic retinal injury (ERI) on the visual system can be revealed in vivo by diffusion tensor magnetic resonance imagining (DTI), manganese-enhanced magnetic resonance imagining (MRI), and optical coherence tomography (OCT). METHODS: Diffusion tensor MRI was performed at 9.4 Tesla to monitor white matter integrity changes after unilateral N-methyl-D-aspartate (NMDA)-induced ERI in six Sprague-Dawley rats and six C57BL/6J mice. Additionally, four rats and four mice were intravitreally injected with saline to compare with NMDA-injected animals. Optical coherence tomography of the retina and manganese-enhanced MRI of anterograde transport were evaluated and correlated with DTI parameters. RESULTS: In the rat optic nerve, the largest axial diffusivity decrease and radial diffusivity increase occurred within the first 3 and 7 days post ERI, respectively, suggestive of early axonal degeneration and delayed demyelination. The optic tract showed smaller directional diffusivity changes and weaker DTI correlations with retinal thickness compared with optic nerve, indicative of anterograde degeneration. The splenium of corpus callosum was also reorganized at 4 weeks post ERI. The DTI profiles appeared comparable between rat and mouse models. Furthermore, the NMDA-injured visual pathway showed reduced anterograde manganese transport, which correlated with diffusivity changes along but not perpendicular to optic nerve. CONCLUSIONS: Diffusion tensor MRI, manganese-enhanced MRI, and OCT provided an in vivo model system for characterizing the spatiotemporal changes in white matter integrity, the eye-brain relationships and structural-physiological relationships in the visual system after ERI.