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Diabetic retinopathy (DR) is a serious microvascular complication of diabetes and a major cause of blindness in the developing world. Early DR is characterized by vascular neuroinflammation, cell apoptosis and breakdown of the blood-retinal barrier (BRB). However, optimal treatment options and associated mechanisms remain unclear. Niaspan, which is widely used in the prevention and treatment of hyperlipidemia-associated diseases, has been reported to inhibit inflammation. However, the effects of Niaspan and the mechanisms underlying the anti-inflammatory effects of Niaspan on DR have yet to be reported. The present study aimed to investigate the anti-inflammatory effects and mechanisms of Niaspan in a rat model of DR. Rats with DR exhibited a significant increase in BRB breakdown, retinal apoptosis, and tumor necrosis factor-ɑ (TNF-ɑ) and nuclear factor-kB (NF-kB) expression. In addition, the expression levels of inducible nitric oxide synthase (iNOS) and intercellular cell adhesion molecule-1 (ICAM-1) were increased in the retinas of DR rats compared with in the normal control group. In conclusion, treatment with Niaspan significantly improved clinical and histopathological outcomes; decreased the expression levels of TNF-ɑ, NF-kB, iNOS and ICAM-1; and decreased apoptosis and BRB breakdown, as compared with in the retinas of DR rats. The present study is the first, to the best of our knowledge, to demonstrate that Niaspan treatment ameliorates DR by inhibiting inflammation, and also suggests that the TNF-ɑ pathway may contribute to the beneficial effects of Niaspan treatment. [ABSTRACT FROM AUTHOR]

Background and objective: We investigated axonal plasticity in the bilateral motor cortices and the long term therapeutic effect of Niaspan on axonal remodeling after stroke in type-1 diabetic (T1DM) rats. Experimental approaches: T1DM was induced in young adult male Wistar rats via injection of streptozotocin. T1DM rats were subjected to 2 h transient middle cerebral artery occlusion (MCAo) and were treated with 40 mg/kg Niaspan or saline starting 24 h after MCAo and daily for 28 days. Anterograde tracing using biotinylated dextran amine (BDA) injected into the contralateral motor cortex was performed to assess axonal sprouting in the ipsilateral motor cortex area. Functional outcome, SMI-31 (a pan-axonal microfilament marker), Bielschowsky silver and synaptophysin expression were measured. In vitro studies using primary cortical neuron (PCN) cultures and in vivo BDA injection into the brain to anterogradely label axons and terminals were employed. Results: Niaspan treatment of stroke in T1DM–MCAo rats significantly improved functional outcome after stroke and increased SMI-31, Bielschowsky silver and synaptophysin expression in the ischemic brain compared to saline treated T1DM–MCAo rats (p

Introduction: Niaspan, an extended-release formulation of Niacin (vitamin B3), has been widely used to increase high density lipoprotein (HDL) cholesterol and to prevent cardiovascular diseases and stroke. In this study, we tested whether Niaspan administered acutely after stroke is neuroprotective. Methods: Adult male rats (n=8/group) were subjected to 2 h of middle cerebral artery occlusion (MCAo) and treated with or without different doses of Niaspan (20, 40 or 80 mg/kg) at 2 and 24 h after MCAo. A battery of functional outcome tests was performed, and serum HDL and triglycerides were measured. Rats were sacrificed at 7 days after MCAo and lesion volumes were measured. The optimal dose of Niaspan treatment of stroke was chosen for immunostaining: deoxynucleotidyl transferase–mediated dUTP nick-end labeling (TUNEL), cleaved caspase-3, tumor necrosis factor alpha (TNF-alpha), vascular endothelial growth factor (VEGF) and phosphorylated phosphatidylinositol 3-kinase (p-PI3K). Another set of rats (n=4/group) were killed at 7 days after MCAo for Western blot assay. Results: Niaspan dose-dependently reduced infarct volume and improved functional outcome after stroke. No significant difference in HDL and triglyceride levels was detected between Niaspan treatments and MCAo control groups. Niaspan treatment significantly decreased the number of TUNEL-positive cells (105±17) and cleaved caspase-3 expression (381±33) in the ischemic brain compared to MCAo control (165±18; 650±61, respectively; p≤0.05). Niaspan treatment significantly reduced the expression of TNF-alpha (9.7±1.1% vs. 16±2.2%; p≤0.05) and negative correlations were observed between the functional tests and the expression of TNF-alpha (r=−0.71, p≤0.05). Niaspan treatment also significantly increased the expression of VEGF (5.2±0.9%) and PI3K/Akt (0.381±0.04%) in the ischemic brain compared with non-treated MCAo control (2.6±0.4%; 0.24±0.03, respectively; p≤0.05). The functional outcome was positively correlated with p-PI3K (r=0.7, p≤0.05). Conclusions: Treatment of stroke with Niaspan at 2 h after MCAo reduces infarct volume and improves neurological outcome and provides neuroprotection. The neuroprotective effects of Niaspan were associated with reduction of apoptosis and attenuation of TNF-alpha expression. VEGF and the PI3K/Akt pathway may contribute to the Niaspan-induced neuroprotection after stroke.

We investigated the treatment of experimental autoimmune encephalomyelitis (EAE) in mice with Niaspan, an agent used to elevate high-density lipoprotein (HDL). EAE mice were treated with Niaspan starting on the immunization or clinical onset day. Neurological functional recovery was significantly increased in the Niaspan treated mice (100 mg/kgbw) compared to the controls. Inflammatory infiltrates were significantly reduced in the Niaspan treatment group compared to the EAE controls. HDL level, intact myelin area, newly formed oligodendrocytes, regenerating axons, gene and protein levels of sonic hedgehog (Shh)/Gli1 were significantly increased in the Niaspan treated mice compared to EAE controls. These data indicate that Niaspan treatment improved functional recovery after EAE, possibly, via reducing inflammatory infiltrates and demyelination areas, and stimulating oligodendrogenesis and axonal regeneration. Niaspan-mediated activation of Shh/Gli1 pathway may promote functional recovery post-EAE.

Ischemic stroke is a major cause of death and long-term disability world wide. Development of effective therapy has been the target of intense research. Accumulating preclinical literature has shown that substantial functional improvement after stroke can be achieved using subacutely administered cell-based and pharmacological therapies. This review provides an update on bone marrow-derived mesenchymal stem cells (BMSCs), human umbilical cord blood cells (HUCBCs) and select pharmacological agents presently in clinical use for other indications, to promote recovery processes in the sub-acute and chronic phases after stroke. This review paper also focuses on molecular mechanisms underlying the cell-based and pharmacological restorative processes which enhance angiogenesis, arteriogenesis, neurogenesis and white matter remodeling following cerebral ischemia as well as an analysis of the interaction/coupling among these restorative events. In addition, the role of microRNAs (miRNAs) mediating the intercellular communication between exogenously administered cells and parenchymal cells, and their effects on the regulation of angiogenesis and neuronal progenitor cell proliferation and differentiation, and brain plasticity after stroke will be described.

The current study examined the effects of niacin and a single bout of aerobic exercise on plasma glucose, insulin, and C-peptide in sedentary, nondiabetic postmenopausal women. As a crossover design, 17 participants underwent four different trials: rest during the no-niacin condition (R), exercise during the no-niacin condition (E), rest during the with-niacin condition (RN), and exercise during the with-niacin condition (EN). All participants took 1,000 mg/day of extended-release niacin for 4 weeks during the with-niacin conditions (RN and EN). The exercise treatment consisted of a single bout of treadmill walking at 60% heart rate reserve until 400 kcal were expended. Blood samples were collected at 24 hours after each trial and analyzed for changes in plasma glucose, insulin, and C-peptide. A two by two analysis of variance was used to examine the changes in dependent variables, and the Bonferroni adjustment was employed as the post hoc test. The level of statistical significance was set at P,0.05. There was no significant interaction between exercise and niacin, nor was there a main effect of exercise for changes in glucose, insulin, or C-peptide. However, there was a significant main effect for niacin as mean glucose, insulin, and C-peptide values significantly increased with niacin; glucose increased 10.6% (P=0.001), from 95.03±10.67 mg/dL to 105.07±13.56 mg/dL; insulin increased 61.8% (P=0.001), from 16.98±12.49 μU/mL to 27.48±14.84 μU/mL; and C-peptide increased 46.1% (P=0.001), from 1.65±0.75 ng/mL to 2.41±0.97 ng/mL. Although niacin was generally well tolerated, given its adverse effects on glucose, insulin, and C-peptide profiles, the use of niacin should be done so with caution and under medical supervision. [ABSTRACT FROM AUTHOR]

Ischemic stroke is responsible for many deaths and long-term disability world wide. Development of effective therapy has been the target of intense research. Accumulating preclinical literature has shown that substantial functional improvement after stroke can be achieved using subacutely administered cell-based and pharmacological therapies. This review will discuss some of the latest findings on bone marrow-derived mesenchymal stem cells (BMSCs), human umbilical cord blood cells (HUCBCs) and offlabel use of some pharmacological agents, to promote recovery processes in the subacute and chronic phases following stroke. This review paper also focuses on molecular mechanisms underlying the cell-based and pharmacological restorative processes which enhance angiogenesis, arteriogenesis, neurogenesis and white matter remodeling following cerebral ischemia as well as an analysis of the interaction/coupling among these restorative events. In addition, the role of microRNAs (miRNAs) mediating the intercellular communication between exogenously administered cells and parenchymal cells, and their effects on the regulation of angiogenesis and neuronal progenitor cell proliferation and differentiation, and brain plasticity after stroke are described. [ABSTRACT FROM AUTHOR]

White matter remodeling plays an important role in neurological recovery after stroke. Bone marrow stromal cells (BMSCs) and Niaspan, an agent which increases high density lipoprotein (HDL), each induces neurorestorative effects and promotes white matter remodeling after stroke in non-diabetic rats. In this study, we test whether combination of BMSCs with Niaspan induces an enhanced white matter remodeling in the ischemic brain of diabetic rats. Research design and methods: Type-1 diabetes (T1DM) rats were subjected to transient middle cerebral artery occlusion (MCAo) and treated with or without BMSCs; Niaspan; and the combination of BMSCs + Niaspan daily for 14 days after MCAo. Immunostaining for white matter remodeling and synaptic protein expression including NG2; CNPase; BS (Bielschowsky silver); LFB (luxol fast blue); Synaptophysin and SMI-31 immunostaining were performed. Results: BMSC monotherapy did not regulate NG2 and CNPase expression compared to T1DM control rats. Both, combination of BMSCs + Niaspan treatment, and Niaspan monotherapy significantly increase NG2 and CNPase expression compared to T1DM control. While combination BMSC+Niaspan, BMSC monotherapy and Niaspan monotherapy groups all increase BS, LFB, synaptophysin, and SMI-31 expression in the ischemic brain compared to T1DM-MCAo control. In addition, the combination treatment significantly enhances LFB, SMI-31, and Synaptophysin expression compared to BMSC monotherapy. Conclusions: Combination treatment of stroke with BMSCs and Niaspan in T1DM rats increases white matter remodeling and additively increases BMSC monotherapy induced myelination and synaptic plasticity after stroke in T1DM rats. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Abstract: Introduction: Niaspan, an extended-release formulation of niacin (vitamin B3), has been widely used to increase high density lipoprotein (HDL) cholesterol and to prevent cardiovascular diseases and stroke. We have previously demonstrated that Niaspan (40mg/kg) administered at 2h after stroke induces neuroprotection, while low dose Niaspan (20mg/kg) does not reduce infarct volume. Tissue plasminogen activator (tPA) is an effective therapy for acute stroke, but its use remains limited by a narrow therapeutic window. We have previously demonstrated that intravenous administration of tPA 4h after stroke in rats does not reduce infarct volume. In this study, we tested whether combination treatment with low-dose Niaspan (20mg/kg) and tPA administered 4h after embolic stroke in a rat model reduces infarct volume and provides neuroprotection. Methods: Adult male Wistar rats were subjected to embolic middle cerebral artery occlusion (MCAo) and treated with low-dose Niaspan (20mg/kg) alone (n=7), tPA (10mg/kg) alone (n=7), combination of low-dose Niaspan and tPA (n=7), or saline control (n=9), 4h after stroke. A battery of functional outcome tests was performed. Rats were sacrificed at 7days after MCAo and lesion volumes were measured. To investigate the underlying mechanism of combination treatment neuroprotective effect, deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), cleaved caspase-3, tumor necrosis factor alpha (TNF-alpha), and toll-like receptor 4 (TLR-4) immunostaining were performed. Results: Combination treatment with low-dose Niaspan and tPA significantly improved functional outcome compared to the saline control group (p<0.05), while treatment with Niaspan or tPA alone did not significantly improve functional outcome compared to saline control group. Additionally, combination treatment significantly reduced infarct volume compared to saline control group (p=0.006) and infarct volume was significantly correlated with functional outcome (p=0.0008; r=0.63). Monotherapy with Niaspan or tPA did not significantly decrease infarct volume compared to saline control group. Combination treatment reduced apoptosis as measured by significant reduction in the number of TUNEL-positive cells and cleaved caspase-3 expression in the ischemic brain compared to saline control group (p<0.05). Combination treatment also significantly reduced the expression of TNF-alpha and TLR-4 in the ischemic brain compared to Niaspan, tPA and saline treatment groups (p<0.05). A significant interaction between Niaspan and tPA on the TNF-alpha expression was detected (p<0.05), indicating a synergy effect in the combination treatment group. Conclusion: Treatment of stroke with combination of low-dose Niaspan and tPA at 4h after embolic stroke reduces infarct volume, improves neurological outcome and provides neuroprotection. The neuroprotective effects of combination treatment were associated with reduction of apoptosis and attenuation of TNF-alpha and TLR-4 expression. [Copyright &y& Elsevier]

Abstract: Objective: High-mobility group box 1 (HMGB1), an active receptor for advanced glycation endproducts (RAGE), functions as a potent proinflammatory cytokine-like factor that contributes to the pathogenesis of vasculature. Diabetes mellitus (DM) is associated with accelerated development of both microvascular and macrovascular disease and increases the risk of ischemic stroke. Using a model of streptozotocin-induced type-1 diabetes (T1DM) in rats, we investigated the changes in HMGB and RAGE and tested the effects of Niaspan, a slow release form of niacin, on the expression of pro-inflammatory proteins in rats after stroke. Research design and methods: T1DM rats were subjected to transient middle cerebral artery occlusion (MCAo) and treated without or with Niaspan (40 mg/kg) daily for 14 days after MCAo. Non-streptozotocin rats (WT) were also subjected to MCAo. Immunostaining for inflammatory mediators including HMGB1, RAGE, matrix metalloproteinase-9 (MMP-9) and toll-like receptor 4 (TLR4) immunostaining (n=8/group) and Western blotting (n=4/group) were performed. Results: Compared to WT-MCAo rats, T1DM-MCAo rats showed an increased expression of HMGB1 (0.82±0.07 vs. 1.81±0.98, P<0.05), RAGE (1.31±0.22 vs. 3.77±0.72, P<0.05), MMP-9 (0.74±0.08 vs. 1.61±0.09, P<0.05) and TLR4 (2.85±0.22 vs. 6.72±0.44, P<0.05) after stroke. Niaspan treatment significantly attenuated the expression of HMGB1 (1.80±0.98 vs. 1.31±0.01, P<0.05), RAGE (3.77±0.71 vs. 1.78±0.45, P<0.05), MMP-9 (1.61±0.09 vs. 0.97±0.07, P<0.05) and TLR4 (6.72±0.44 vs. 2.28±0.43, P<0.05) in the ischemic brain in T1DM-MCAo rats. Conclusions: T1DM increases HMGB1/RAGE, TLR4 and MMP-9 expression after stroke. Niaspan treatment of stroke in T1DM rats inhibits HMGB1/RAGE, TLR4 and MMP-9 expression which may contribute to the reduced inflammatory response after stroke in T1DM rats. [Copyright &y& Elsevier]

Niacin and exercise positively alter blood lipids and lipoproteins via different mechanisms. However, the effects of niacin combined with exercise on blood lipid and lipoprotein profiles have not been investigated in sedentary postmenopausal women. The current study examined the responses of blood lipids and lipoproteins to niacin and exercise in 18 sedentary postmenopausal women, who underwent four conditions: no-niacin rest, no-niacin exercise, niacin rest, and niacin exercise. Participants ingested 1,000 mg/day of extended-release niacin for 4 weeks during the niacin condition. As an exercise treatment, participants performed a single bout of exercise on a treadmill at 60% heart rate reserve until 400 kcal were expended. Extended-release niacin without the exercise intervention significantly (p < .001) increased high-density lipoprotein cholesterol and high-density lipoprotein-2 cholesterol by 12.4% and 33.3%, respectively, and decreased the total cholesterol to high-density lipoprotein cholesterol ratio by 14.8%. Thus, 4 weeks of 1,000 mg/day of extended-release niacin can improve the blood lipid and lipoprotein profiles in sedentary postmenopausal women. [ABSTRACT FROM PUBLISHER]

Abstract: In this study we examined the effect of combination treatment of experimental stroke with Niaspan, a prolonged-release formulation of Niacin (vitamin B3), and Simvastatin, a cholesterol-lowering drug, on functional outcome, axonal damage, axonal density and the of Iba-1 immunoreactive microglia expression in the ischemic brain of rats. Adult male rats were subjected to 2h middle cerebral artery occlusion (MCAo) and treated with or without Niaspan alone, Simvastatin alone and combination Niaspan and Simvastatin starting 24h after MCAo and daily for 14days. Neurological functional tests were performed. Axonal damage and density were evaluated by Amyloid Precursor Protein (APP) and Bielschowsky silver, respectively. Nogo66 Receptor (NgR) expression and immunoreactive microglia (Iba-1) were also measured in the ischemic brain. Niaspan and Simvastatin monotherapy and combination treatment significantly promote functional outcome after stroke (p <0.05) compared to MCAo control animals. Combination treatment with Niaspan and Simvastatin induces additive but not synergetic effects when compared to Niaspan or Simvastatin monotherapy groups. Combination treatment significantly decreased APP expression and increased Bielschowsky silver expression. NGR and Iba-1 expression were significantly decreased in the ischemic brain. These data suggest that treatment of experimental stroke with combination of Niaspan and Simvastatin significantly improves functional outcome, reduces axonal damage and increases axonal density. Decreased expression of the NGR and reduced activated microglia may contribute to functional recovery after stroke. [Copyright &y& Elsevier]

We tested the hypothesis that Niaspan (a prolonged release formulation of niacin) increases tumor necrosis factor-α-converting enzyme (TACE) expression and Notch signaling activity and promotes arteriogenesis after stroke. Rats were subjected to middle cerebral artery occlusion and were treated with or without Niaspan. Niaspan significantly elevated local cerebral blood flow, and increased arteriogenesis as indicated by increased arterial diameter and vascular smooth muscle cell (VSMC) proliferation in the ischemic brain after stroke. The increased arteriogenesis significantly correlated with the functional outcome after stroke. Niaspan treatment of stroke upregulated TACE, Notch1, and Notch intracellular domain expression in the ischemic brain. To further investigate the mechanisms of Niaspan-induced arteriogenesis, a primary brain arterial culture was used. Niacin treatment significantly increased arterial sprouting and VSMC migration compared with control nontreated arterial cells. Inhibition of TACE by the TACE inhibitor or knockdown of TACE gene expression in brain arterial culture significantly attenuated Niacin-induced arterial sprouting and VSMC migration. In addition, TACE treatment of arterial culture significantly increased arterial VSMC migration and arterial sprouting. Knockdown of Notch1 marginally decreased arterial sprouting and VSMC migration compared with scrambled control. Niaspan promotes arteriogenesis, which is mediated, in part, by TACE.Journal of Cerebral Blood Flow & Metabolism (2009) 29, 911–920; doi:10.1038/jcbfm.2009.11; published online 18 February 2009 [ABSTRACT FROM AUTHOR]

Niacin (nicotinic acid) is the broad-spectrum lipid drug, which lowers the concentration of all atherogenic plasma lipids/lipoproteins and at the same time raises the levels of the protective HDL (high-density lipoprotein). Niaspan™ is a prolonged release (PR) formulation of niacin, which has considerable advantages over both immediate release (IR) and slow release (SR) formulations of this drug. The major early side effect of IR niacin, the flush, is reduced with Niaspan™. The hepatotoxic effects with SR niacin are not present with Niaspan™. It is suitable for once daily prescription at bedtime. Niaspan™ is effective as monotherapy and in combination with other lipid-lowering drugs such as statins and fibrates. It is particularly useful for treatment of the dyslipidaemia of type 2 diabetes, where IR but not PR niacin may deteriorate the diabetic condition. Overall, niacin, now available as the well-tolerable drug formulation Niaspan™, is the unique broad-spectrum lipid drug for the prevention and treatment of clinical atherosclerosis. [ABSTRACT FROM AUTHOR]

Abstract Niacin is an effective lipid-lowering therapy that has been available for more than 40 years. Many studies have proven niacin's effectiveness in decreasing morbidity and mortality and improving the entire lipid profile. However, one of the major drawbacks to niacin therapy has been its side effects—most commonly, flushing and abdominal discomfort. Recently, however, newer formulations of niacin have become available, particularly Niaspan, an extended-release niacin preparation taken once daily, at bedtime, (as opposed to the controlled-release niacin taken twice a day). To date, 5 trials have evaluated Niaspan specifically. All have shown Niaspan to be effective in decreasing total cholesterol, low-density lipoprotein (LDL), triglycerides, and apolipoprotein, and increasing high-density lipoprotein (HDL). Flushing is still a major side effect with Niaspan therapy; however, taking aspirin 30 minutes prior to the dose and taking the dose at bedtime may alleviate this side effect. In a survey of patients who had taken both the controlled-release preparation of niacin (not Niaspan) and the immediate-acting niacin, the majority of the patients preferred the controlled-release formulation. The extended-release preparation should now be considered a realistic option in patients who have hypercholesterolemia. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases are the leading cause of death worldwide. Aging and/or metabolic stress directly impact the cardiovascular system. Over the last few years, the contributions of altered nicotinamide adenine dinucleotide (NAD+) metabolism to aging and other pathological conditions closely related to cardiovascular diseases have been intensively investigated. NAD+ bioavailability decreases with age and cardiometabolic conditions in several mammalian tissues. Compelling data suggest that declining tissue NAD+ is commonly related to mitochondrial dysfunction and might be considered as a therapeutic target. Thus, NAD+ replenishment by either genetic or natural dietary NAD+-increasing strategies has been recently demonstrated to be effective for improving the pathophysiology of cardiac and vascular health in different experimental models, as well as human health, to a lesser extent. Here, we review and discuss recent experimental evidence illustrating that increasing NAD+ bioavailability, particularly by the use of natural NAD+ precursors, may offer hope for new therapeutic strategies to prevent and treat cardiovascular diseases. [ABSTRACT FROM AUTHOR]