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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS062832-05
Application #
8306285
Study Section
Special Emphasis Panel (ZRG1-MNPS-C (09))
Program Officer
Bosetti, Francesca
Project Start
2008-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$285,469
Indirect Cost
$88,594
Name
Henry Ford Health System
Department
Type
DUNS #
073134603
City
Detroit
State
MI
Country
United States
Zip Code
48202
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
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
Zhang, Li; Chopp, Michael; Zhang, Rui Lan et al. (2010) Erythropoietin amplifies stroke-induced oligodendrogenesis in the rat. PLoS One 5:e11016
Zhang, Li; Zhang, Zheng Gang; Buller, Ben et al. (2010) Combination treatment with VELCADE and low-dose tissue plasminogen activator provides potent neuroprotection in aged rats after embolic focal ischemia. Stroke 41:1001-7
Jia, Longfei; Chopp, Michael; Zhang, Li et al. (2010) Erythropoietin in combination of tissue plasminogen activator exacerbates brain hemorrhage when treatment is initiated 6 hours after stroke. Stroke 41:2071-6
Morris, D C; Chopp, M; Zhang, L et al. (2010) Thymosin beta4 improves functional neurological outcome in a rat model of embolic stroke. Neuroscience 169:674-82
Zhang, Li; Chopp, Michael; Jia, Longfei et al. (2009) Atorvastatin extends the therapeutic window for tPA to 6 h after the onset of embolic stroke in rats. J Cereb Blood Flow Metab 29:1816-24
Athiraman, Hemanthkumar; Jiang, Quan; Ding, Guang Liang et al. (2009) Investigation of relationships between transverse relaxation rate, diffusion coefficient, and labeled cell concentration in ischemic rat brain using MRI. Magn Reson Med 61:587-94
Li, Lian; Jiang, Quan; Ding, Guangliang et al. (2009) MRI identification of white matter reorganization enhanced by erythropoietin treatment in a rat model of focal ischemia. Stroke 40:936-41
Ding, Guangliang; Jiang, Quan; Li, Lian et al. (2008) Angiogenesis detected after embolic stroke in rat brain using magnetic resonance T2*WI. Stroke 39:1563-8

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