Combination treatment with low-dose Niaspan and tissue plasminogen activator provides neuroprotection after embolic stroke in rats (original) (raw)
Related papers
Niaspan increases angiogenesis and improves functional recovery after stroke
Annals of Neurology, 2007
Objective: High-density lipoprotein (HDL) is implicated in the modulation of angiogenesis. In this study, we investigated whether the Niacin-mediated increase of HDL regulates angiogenesis and thereby improves functional outcome after stroke. Methods: Adult male rats were subjected to middle cerebral artery occlusion and were treated with or without different doses (40 and 80mg/kg) of Niaspan, starting 24 hours after middle cerebral artery occlusion and daily for 14 days. Neurological functional tests were performed, and serum HDL level was measured. Angiogenesis and angiogenic factor expression were measured by immunohistochemistry, corneal neovascularization and capillary tube formation assay, and Western blot, respectively. Results: Niaspan significantly increased HDL level, promoted angiogenesis in the ischemic brain, and improved functional outcome after stroke. Niaspan also significantly increased corneal neovascularization compared with nontreatment control. Mechanisms underlying the Niaspan-induced vascular remodeling were investigated. Niaspan increased the expression of vascular endothelial growth factor and angiopoietin-1 (Ang1), and phosphorylation of Akt, endothelial nitric oxide synthase (NOS), and Tie2 in the ischemic brain. Niacin upregulated Ang1 expression in cultured brain endothelial cells and increased vascular endothelial growth factor, Ang1, and endothelial NOS expression in cultured astrocytes, and dose-dependently increased capillary tube formation compared with nontreatment control. Inhibition of NOS partially decreased Niacin-induced capillary tube formation. Inhibition of phosphoinositide 3-kinase or knockdown of Tie2 substantially and significantly decreased Niacininduced capillary tube formation. Interpretation: Niacin increases HDL and promotes angiogenesis, which may contribute to improvement of functional outcome after stroke. The Ang1/Tie2, phosphoinositide 3-kinase/Akt, and endothelial NOS pathways appear to mediate Niacin-induced angiogenesis.
Ischemic stroke and neuroprotection
Annals of Medical and Health Sciences Research, 2012
It is the third leading cause of death in Western countries. [2] In Africa it accounts for 4-9% of deaths and between 6.5% and 41% of neurological admissions in hospital based studies. [3] Findings from South West Nigeria show that the incidence of stroke rises with age reaching a peak in the 8 th decade in males and 7 th decade in females. [4] Stroke is classified as being either hemorrhagic or ischemic in nature depending on the underlying pathological process responsible. Several studies have documented that the ischemic subtype accounts for the greater number of stroke cases. [5-8] An ischemic stroke occurs when a cerebral vessel occludes, obstructing blood flow to a portion of the brain. The only currently approved medical stroke therapy, tissue plasminogen activator (tPA), is a thrombolytic that targets the thrombus within the blood vessel. Neuroprotective agents, another approach to stroke treatment, have generated as much interest as thrombolytic therapies. Materials and Methods An extensive search of all materials related to the topic was made using library sources including Pubmed and Medline searches. Current research findings were also included.
2013
Abstract: The translation of neuroprotective agents for ischemic stroke from bench-to-bedside has largely failed to produce improved treatments since the development of tissue plasminogen activator (tPA). One possible reason for lack of translation is the failure to acknowledge the greatest risk factor for stroke, age, and other common comorbidities such as hypertension, obesity, and diabetes that are associated with stroke. In this review, we highlight both mechanisms of studying these factors and results of those that have been addressed. We also discuss the potential role of other lifestyle factors associated with an increased stroke risk such as sleep fragmentation and/or deprivation. Furthermore, many proposed therapeutic agents have targeted molecular mechanisms occurring soon after the onset of ischemia despite data indicating delayed patient presentation following ischemic stroke. Modulating inflammation has been identified as a promising therapeutic avenue consistent with p...
Niaspan enhances vascular remodeling after stroke in type 1 diabetic rats
Experimental Neurology, 2011
We investigated the changes and the molecular mechanisms of cerebral vascular damage and tested the therapeutic effects of Niaspan in type-1 streptozotocin induced diabetic (T1DM) rats after stroke. T1DM-rats were subjected to transient middle cerebral artery occlusion (MCAo) and treated without or with Niaspan. Non-streptozotocin rats (WT) were also subjected to MCAo. Functional outcome, blood-brain-barrier (BBB) leakage, brain hemorrhage, immunostaining, and rat brain microvascular endothelial cell (RBEC) culture were performed. Compared to WT-MCAo-rats, T1DM-MCAo-rats did not show an increase lesion volume, but exhibited significantly increased brain hemorrhage, BBB leakage and vascular damage as well as decreased functional outcome after stroke. Niaspan treatment of stroke in T1DM-MCAo-rats significantly attenuated BBB damage, promoted vascular remodeling and improved functional outcome after stroke. T1DM-MCAo-rats exhibited significantly increased Angiopoietin 2 (Ang2) expression, but decreased Ang1 expression in the ischemic brain compared to WT-MCAo-rats. Niaspan treatment attenuated Ang2, but increased Ang1 expression in the ischemic brain in T1DM-MCAo-rats. In vitro data show that the capillary-like tube formation in the WT-RBECs marginally increased compared to T1DM-RBEC. Niaspan and Ang1 treatment significantly increased tube formation compared to non-treatment control. Inhibition of Ang1 attenuated Niacin-induced tube formation in T1DM-RBECs. Niaspan treatment of stroke in T1DM-rats promotes vascular remodeling and improves functional outcome. The Ang1/Ang2 pathway may contribute to Niaspan induced brain plasticity. Niaspan warrants further investigation as a therapeutic agent for the treatment of stroke in diabetics.
Stroke, 2001
Background and Purpose-The proteasome inhibitor PS-519 blocks activation of nuclear factor-B, a major mediator of inflammation. We tested the hypothesis that combination treatment of recombinant human tissue plasminogen activator (rhtPA) and PS-519 extends the therapeutic window for treatment of stroke with rhtPA without increasing incidence of hemorrhagic transformation. Methods-The middle cerebral artery (MCA) of male Wistar rats (nϭ56) was occluded by an embolus. After embolization, animals were randomly divided into the following groups: PS-519 treatment groups: PS-519 was given at 2, 4, or 6 hours after MCA occlusion; rhtPA treatment groups: rhtPA was given at 2 or 4 hours after MCA occlusion; combination treatment groups: PS-519 and rhtPA were given at 2, 4, or 6 hours after MCA occlusion; control group: the same volume of saline was given at 2 hours after MCA occlusion. Results-Administration of PS-519 alone at 2 or 4 hours, but not 6 hours, significantly (PϽ0.05) reduced infarct volume and improved neurological recovery compared with the control group. Administration of rhtPA alone at 2 hours, but not 4 hours, significantly (PϽ0.05) reduced infarct volume and improved neurological recovery compared with the control group. Furthermore, combination treatment with rhtPA and PS-519 even at 6 hours significantly (PϽ0.05) reduced infarct volume, improved neurological recovery, and did not increase the incidence of hemorrhagic transformation compared with the control group or the group treated with PS-519 alone. Conclusions-Our data suggest that combination treatment with PS-519 and rhtPA extends the neuroprotective effect to at least 6 hours after embolization. (Stroke. 2001;32:2926-2931.)
2010
We evaluated the neuroprotective effect of UK-279,276 (also referred to as recombinant neutrophil inhibitory factor), a selective CD11b/CD18 antagonist, in combination with thrombolytic therapy on focal cerebral ischemia. Male Wistar rats (n=88) were subjected to embolic middle cerebral artery occlusion. Animals were randomly assigned to the following groups (n=11 in each group): vehicle treatment alone at 2 or 4 hours, UK-279,276 treatment alone at 2 or 4 hours, recombinant human tissue plasminogen activator (rhtPA) treatment alone at 2 or 4 hours, or the combination of UK-279,276 and rhtPA at 2 or 4 hours. Infarct volume, neurological function, hemorrhagic transformation, neutrophil accumulation, and parenchymal fibrin deposition were measured 7 days after middle cerebral artery occlusion. Treatment with UK-279,276 significantly (P<0.05) improved neurological severity scores, an index of neurological functional deficit, but had no effect on infarct volume compared with vehicle-treated animals. Treatment with rhtPA alone at 2 but not 4 hours significantly (P<0.05) reduced infarct volume and improved neurological function compared with vehicle-treated animals. Combination treatment with UK-279,276 and rhtPA at 2 or 4 hours significantly (P<0.01) reduced infarct volume and enhanced recovery of neurological function compared with control. Neutrophil accumulation and fibrin deposition in the brain parenchyma of combination-treated rats at 2 and 4 hours after stroke were significantly reduced (P<0.05) compared with corresponding vehicle-treated control groups. The neuroprotective effect of the combined treatments was superior to the additive effects from each treatment of rhtPA or UK-279,276 alone. These data suggest that the combination treatment with UK-279,276 and rhtPA may extend the window of thrombolytic therapy for the acute treatment of stroke.
Neuroprotection in Acute Ischemic Stroke: A Battle Against the Biology of Nature
Frontiers in Neurology
Stroke is the second most common cause of global death following coronary artery disease. Time is crucial in managing stroke to reduce the rapidly progressing insult of the ischemic penumbra and the serious neurologic deficits that might follow it. Strokes are mainly either hemorrhagic or ischemic, with ischemic being the most common of all types of strokes. Thrombolytic therapy with recombinant tissue plasminogen activator and endovascular thrombectomy are the main types of management of acute ischemic stroke (AIS). In addition, there is a vital need for neuroprotection in the setting of AIS. Neuroprotective agents are important to investigate as they may reduce mortality, lessen disability, and improve quality of life after AIS. In our review, we will discuss the main types of management and the different modalities of neuroprotection, their mechanisms of action, and evidence of their effectiveness after ischemic stroke.
Stroke, 2013
R ecombinant tissue plasminogen activator (tPA) is the only effective fibrinolytic treatment at the acute stage of ischemic stroke (IS). However, its use remains restricted to carefully selected patients within 4.5 hours after stroke onset and it is associated with an increased risk of brain edema and secondary hemorrhagic transformation (HT). 1-4 Therefore, there is a need for development of treatments that would improve the safety and efficacy of tPA. The disruption of the bloodbrain barrier (BBB) has been shown to be involved in edema and HT after tPA treatment in IS. 5,6 Ischemic injury and tPA display cumulative deleterious effects on the neurovascular unit (BBB, neurons, and astrocytes) at the acute phase of stroke. 5,7 High-density lipoproteins (HDLs) have been proposed as a new neuro-and vasculoprotective treatment in IS. 8,9 Beyond their well-documented action of reverse cholesterol transport, HDLs have pleiotropic effects (ie, anti-inflammatory, antioxidant, and more generally endothelial protective effects). 10,11 We recently reported that intravenous administration of HDLs isolated from human plasma, up to 5 hours after the onset of ischemia, was effective in reducing the infarct volume by maintaining BBB integrity in a rat model of embolic stroke. 8 Background and Purpose-We have previously reported that intravenous injection of high-density lipoproteins (HDLs) was neuroprotective in an embolic stroke model. We hypothesized that HDL vasculoprotective actions on the bloodbrain barrier (BBB) may decrease hemorrhagic transformation-associated with tissue plasminogen activator (tPA) administration in acute stroke. Methods-We used tPA alone or in combination with HDLs in vivo in 2 models of focal middle cerebral artery occlusion (MCAO) (embolic and 4-hour monofilament MCAO) and in vitro in a model of BBB. Sprague-Dawley rats were submitted to MCAO, n=12 per group. The rats were then randomly injected with tPA (10 mg/kg) or saline with or without human plasma purified-HDL (10 mg/kg). The therapeutic effects of HDL and BBB integrity were assessed blindly 24 hours later. The integrity of the BBB was also tested using an in vitro model of human cerebral endothelial cells under oxygen-glucose deprivation. Results-tPA-treated groups had significantly higher mortality and rate of hemorrhagic transformation at 24 hours in both MCAO models. Cotreatment with HDL significantly reduced stroke-induced mortality versus tPA alone (by 42% in filament MCAO, P=0.009; by 73% in embolic MCAO, P=0.05) and tPA-induced intracerebral parenchymal hematoma (by 92% in filament MCAO, by 100% in embolic MCAO; P<0.0001). This was consistent with an improved BBB integrity. In vitro, HDLs decreased oxygen-glucose deprivation-induced BBB permeability (P<0.05) and vascular endothelial cadherin disorganization. Conclusions-HDL injection decreased tPA-induced hemorrhagic transformation in rat models of MCAO. Both in vivo and in vitro results support the vasculoprotective action of HDLs on BBB under ischemic conditions. (Stroke. 2013;44:699-707.) Key Words: blood-brain barrier ■ hemorrhagic transformation ■ high-density lipoproteins ■ ischemic stroke ■ tissue plasminogen activator
Circulation, 2003
Background-Platelet aggregation and fibrin deposition are key events leading to microvascular thrombosis and progressive impairment of downstream microvascular perfusion after stroke. We tested the hypothesis that inhibition of platelet function with a GP IIb/IIIa receptor antagonist would increase the efficacy and safety and increase the time window for thrombolytic therapy for stroke with full-and half-dose tissue plasminogen activator (tPA). Methods and Results-Rats were subjected to embolic middle cerebral artery occlusion. Four hours after ischemia, rats were treated with 7E3 F(abЈ) 2 (6 mg/kg) in combination with tPA at doses of 10 and 5 mg/kg, tPA alone at a dose of 10 or 5 mg/kg, 7E3 F(abЈ) 2 (6 mg/kg) alone, or saline. Combination treatment with 7E3 F(abЈ) 2 and tPA (full-or half-dose) significantly (PϽ0.05) reduced infarct volume and neurological deficits compared with saline-treated rats. However, treatment with 7E3 F(abЈ) 2 or tPA (full-or half-dose) alone did not reduce infarct volume. Quantitative measurements of cerebral microvessels perfused by FITC-dextran revealed that combination treatment with 7E3 F(abЈ) 2 and full-dose tPA significantly (PϽ0.05) increased the percentage of FITC-dextran-perfused vessels compared with saline and full-dose tPA-treated rats. In addition, treatment with 7E3 F(abЈ) 2 in combination with full-dose tPA significantly (PϽ0.05) decreased microvascular platelet accumulation and matrix metalloproteinase 9 immunoreactivity and protected against loss of collagen IV immunoreactivity. Conclusions-Combination treatment with 7E3 F(abЈ) 2 with full-and half-dose tPA at 4 hours after ischemia significantly reduces infarct volume and improves neurological outcome. Enhancement of patency and integrity of cerebral microvessels most likely contributes to the benefits observed with this combination therapy.