Niaspan treatment induces neuroprotection after stroke.

Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA.
Neurobiology of Disease (Impact Factor: 5.62). 10/2010; 40(1):277-83. DOI: 10.1016/j.nbd.2010.05.034
Source: PubMed

ABSTRACT 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.
Adult male rats (n=8/group) were subjected to 2h of middle cerebral artery occlusion (MCAo) and treated with or without different doses of Niaspan (20, 40 or 80 mg/kg) at 2 and 24h 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.
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<or=0.05). Niaspan treatment significantly reduced the expression of TNF-alpha (9.7+/-1.1% vs. 16+/-2.2%; p<or=0.05) and negative correlations were observed between the functional tests and the expression of TNF-alpha (r=-0.71, p<or=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<or=0.05). The functional outcome was positively correlated with p-PI3K (r=0.7, p<or=0.05).
Treatment of stroke with Niaspan at 2h 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Tramiprosate, a small aminosulphonate compound, is present in various species of red marine algae. In this study, we examined whether tramiprosate protects neurons and improves functional recovery following ischemic stroke inrats subjected to the intraluminal filament model of MCAO and further explored the underlying mechanisms. Tramiprosate dose-dependently reduced the infarct volume after MCAO, and the therapeutic time window of tramiprosate (50 mg/kg) for cerebral ischemia was at least 6 h. Moreover, functional assays and histochemical staining were performed. Significant neurological functional recovery was found after tramiprosate (50 mg/kg) administration in all three functional assays performed (modified neurological severity score, foot-fault test and adhesive-removal somatosensory test). Tramiprosate significantly attenuated OGD- or NMDA-induced injury in NGF-differentiated PC12 cells and primary cortical neurons. Furthermore, the neuroprotective effect of tramiprosate was partially blunted by the NMDA receptor (NMDAR) antagonist MK801 both in vitro and in vivo, indicating that tramiprosate might confer neuroprotection against stroke via the NMDAR. Based on co-immunoprecipitation and western blotting, tramiprosate decreased the intensity of the association between nNOS and PSD95, and tramiprosate also inhibited the translocation of nNOS from the cytosol to the membrane without affecting the total nNOS expression level both in vitro and in vivo. In conclusion, tramiprosate dose-dependently provides neuroprotection in vitro and in vivo against ischemic stroke, and the neuroprotective effect of tramiprosate may be partially attributed to disruption of the interaction between PSD95 and nNOS and inhibition of nNOS translocation.
    Neuropharmacology 04/2014; · 4.11 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVES:: To determine whether niacin attenuates brain injury and improves neurological outcome after cardiac arrest in rats and if its therapeutic benefits are associated with suppression of the mitogen-activated protein kinase pathway. DESIGN:: Prospective laboratory study. SETTING:: University laboratory. SUBJECTS:: Male Sprague-Dawley rats (n = 77). INTERVENTIONS:: After 6 minutes of no flow time induced by ventricular fibrillation, cardiopulmonary resuscitation was provided and return of spontaneous circulation was achieved. Animals were then administered vehicle, single low dose (360 mg/kg; at 1 hr postreturn of spontaneous circulation), single high dose (1080 mg/kg; at 1 hr), or repeated low dose of niacin (360 mg/kg/d for 3 d; at 1, 24, and 48 hr) through an orogastric tube. MEASUREMENTS AND MAIN RESULTS:: Neurologic deficit scales were scored at 24 hours, 72 hours, and 7 days postreturn of spontaneous circulation. Single high dose of niacin improved neurologic deficit scales at 48 hours and 7 days, and repeated low dose of niacin improved neurologic deficit scales at 7 days. Then, a separate set of animals were killed at 72 hours postreturn of spontaneous circulation, and brain tissues were harvested. Single high dose and repeated low dose of niacin attenuated cellular apoptosis and neuronal damage in hippocampal cornu ammonis 1 and decreased axonal injury and microglial activation in corpus callosum. They increased nicotinamide adenine dinucleotide, reduced nicotinamide adenine dinucleotide phosphate and reduced glutathione levels, and decreased malondialdehyde level in brain tissues. Furthermore, they suppressed the phosphorylations of p38 and c-Jun N-terminal kinase/stress-activated protein kinase and the cleavage of caspase 3. However, they failed to enhance extracellular signal-regulated kinases 1/2 phosphorylation. CONCLUSIONS:: Single high dose and repeated low dose of niacin attenuated brain injury and improved neurological outcome after cardiac arrest in rats. Their therapeutic benefits were associated with suppressions of the phosphorylations of p38 and c-Jun N-terminal kinase/stress-activated protein kinase and the cleavage of caspase 3.
    Critical care medicine 05/2013; · 6.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The ketone body β-hydroxybutyrate (BHB) is an endogenous factor protecting against stroke and neurodegenerative diseases, but its mode of action is unclear. Here we show in a stroke model that the hydroxy-carboxylic acid receptor 2 (HCA2, GPR109A) is required for the neuroprotective effect of BHB and a ketogenic diet, as this effect is lost in Hca2(-/-) mice. We further demonstrate that nicotinic acid, a clinically used HCA2 agonist, reduces infarct size via a HCA2-mediated mechanism, and that noninflammatory Ly-6C(Lo) monocytes and/or macrophages infiltrating the ischemic brain also express HCA2. Using cell ablation and chimeric mice, we demonstrate that HCA2 on monocytes and/or macrophages is required for the protective effect of nicotinic acid. The activation of HCA2 induces a neuroprotective phenotype of monocytes and/or macrophages that depends on PGD2 production by COX1 and the haematopoietic PGD2 synthase. Our data suggest that HCA2 activation by dietary or pharmacological means instructs Ly-6C(Lo) monocytes and/or macrophages to deliver a neuroprotective signal to the brain.
    Nature Communications 01/2014; 5:3944. · 10.02 Impact Factor

Full-text (2 Sources)

Available from
May 22, 2014