Occlusion of the middle cerebral artery elicits a progressive vascular dysfunction, which contributes to the evolution of brain injury. Thrombolysis with tissue plasminogen activator (tPA) promotes adverse vascular events that limit the therapeutic window of stroke to three hours. Advanced age exacerbates vascular dysfunction after stroke which limits the utilization of tPA. Proteasome inhibitors enhance endothelial nitric oxide synthase (eNOS) expression and improve endothelial function. Our preliminary studies demonstrate that treatment with a proteasome inhibitor, VELCADE, an agent in clinical use for the treatment of cancer, effectively reduces cerebral infarction, and concomitantly reduces secondary thrombosis and microvascular permeability in young rats. In addition, treatment with VELCADE in combination with tPA extends the therapeutic window to at least 6 hours after stroke without increasing hemorrhagic transformation. However, stroke is a major cause of death and disability in the elderly. To mimic clinical situation, we propose to investigate the effect of VECLADE on aged rats.
In Aim 1, we hypothesize that treatment with VELCADE dose dependently reduces infarct volume and neurological functional deficit in aged rats after stroke. Optimal doses of VELCADE extend the therapeutic window for stroke.
In Aim 2, we will investigate the effects of combination treatment with VELCADE and tPA on cerebral infarction, neurological function, thrombolysis, microvascular thrombus formation, vascular patency and integrity in aged rats after embolic stroke. By reducing the adverse vascular events, VELCADE amplifies the thrombolytic effect of tPA, and permits a reduction in the effective therapeutic dose of tPA.
In Aim 3, using eNOS knockout mice and NOS inhibitors, we will examine the mechanisms that underlie the beneficial effects of VELCADE alone or in combination with tPA in the treatment of stroke. We propose that eNOS mediates the neuroprotective effect of VELCADE by down-regulation of pro- coagulation genes and matrix metalloproteinases (MMPs), which provoke thrombosis, and BBB damage. VELCADE counteracts the detrimental effects of delayed administration of tPA on vascular function and consequently improves microcirculation and vascular integrity. Our study may provide fundamental insights into the mechanisms underlying beneficial effects of VELCADE and combination of VELCADE and tPA in embolic stroke, and may lead to a novel treatment strategy for stroke.
Stroke elicits a progressive vascular dysfunction, which contributes to the evolution of brain injury. As the only FDA approved drug for the treatment of acute stroke, tissue plasminogen activator (tPA) potentiates adverse vascular events that limit the therapeutic window of stroke to three hours. Advanced age exacerbates vascular dysfunction after stroke which limits the utilization of tPA. Proteasome inhibitors enhance endothelial nitric oxide synthase (eNOS, an important regulator of vascular homeostasis) expression. Treatment with a potent proteasome inhibitor, VELCADE, an agent in clinical use for the treatment of cancer, effectively reduces the development of adverse vascular events, and concomitantly reduces cerebral infarction. Therefore, in the current application, we propose to investigate the neuroprotective effects of VELCADE alone and incombination with tPA and the mechanisms underlying the beneficial effects in aged rats after embolic stroke.
|Li, Lian; Chopp, Michael; Ding, Guangliang et al. (2016) Diffusion-Derived Magnetic Resonance Imaging Measures of Longitudinal Microstructural Remodeling Induced by Marrow Stromal Cell Therapy after Traumatic Brain Injury. J Neurotrauma :|
|Jiang, Quan; Zhang, Li; Ding, Guangliang et al. (2016) Impairment of the glymphatic system after diabetes. J Cereb Blood Flow Metab :|
|Zhang, Li; Chopp, Michael; Teng, Hua et al. (2014) Combination treatment with N-acetyl-seryl-aspartyl-lysyl-proline and tissue plasminogen activator provides potent neuroprotection in rats after stroke. Stroke 45:1108-14|
|Santra, Manoranjan; Chopp, Michael; Zhang, Zheng Gang et al. (2012) Thymosin Î² 4 mediates oligodendrocyte differentiation by upregulating p38 MAPK. Glia 60:1826-38|
|Zhang, Li; Chopp, Michael; Liu, Xianshuang et al. (2012) Combination therapy with VELCADE and tissue plasminogen activator is neuroprotective in aged rats after stroke and targets microRNA-146a and the toll-like receptor signaling pathway. Arterioscler Thromb Vasc Biol 32:1856-64|
|Zhang, Li; Zhang, Zheng Gang; Chopp, Michael (2012) The neurovascular unit and combination treatment strategies for stroke. Trends Pharmacol Sci 33:415-22|
|Morris, Daniel C; Zhang, Zheng G; Zhang, Jing et al. (2012) Treatment of neurological injury with thymosin Ã½Ã½4. Ann N Y Acad Sci 1269:110-6|
|Bosomtwi, Asamoah; Chopp, Michael; Zhang, Li et al. (2011) Mean microvessel segment length and radius after embolic stroke: Comparison of magnetic resonance imaging (MRI) and laser scanning confocal microscopy (LSCM). Brain Res 1381:217-27|
|Ding, Guangliang; Jiang, Quan; Li, Lian et al. (2010) Cerebral tissue repair and atrophy after embolic stroke in rat: a magnetic resonance imaging study of erythropoietin therapy. J Neurosci Res 88:3206-14|
|Zhang, Li; Chopp, Michael; Zhang, Rui Lan et al. (2010) Erythropoietin amplifies stroke-induced oligodendrogenesis in the rat. PLoS One 5:e11016|
Showing the most recent 10 out of 21 publications