Effects of atorvastatin on blood-brain barrier permeability during L-NAME hypertension followed by angiotensin-II in rats.
ABSTRACT Recent studies suggest that 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, can have direct effects on blood vessels beyond their cholesterol-lowering effects. We investigated the effects of atorvastatin on the functional and structural properties of blood-brain barrier (BBB) and the activity of astrocytes during the N(omega)-nitro-L-arginine methyl ester (L-NAME) hypertension followed by angiotensin (ANG) II. We found that decreases in concentration of serum catalase and plasma nitric oxide (NO) induced by L-NAME were significantly ameliorated by atorvastatin, whereas L-NAME-induced serum malondialdehyde and cholesterol concentration increases were significantly reduced by atorvastatin. The content of Evans blue (EB) dye significantly increased in cerebellum, left cerebral cortex and diencephalon regions but atorvastatin markedly reduced the increased BBB permeability to EB in the brain regions of animals treated with L-NAME and L-NAME plus ANG II. Brain vessels of L-NAME-treated animals showed a considerable loss of immunoreactivity of tight junction proteins, zonula occludens (ZO)-1 and occludin. Immunoreactivity for ZO-1 and occludin increased in animals treated with atorvastatin and L-NAME plus atorvastatin. Glial fibrillary acidic protein (GFAP) immunoreactivity was seen in few astrocytes in the brain sections of L-NAME, but immunoreactivity for GFAP increased in L-NAME plus atorvastatin-treated animals. We suggest that long-term L-NAME treatment may affect BBB permeability through disruption of tight junction proteins, at least partly, via decreased NO concentration and increased oxidant capacity; the improvement of BBB integrity and astrocytic activity would be more closely associated with the action of atorvastatin favoring the increase in anti-oxidant capacity and expression of tight junction proteins and GFAP.
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ABSTRACT: Hypercholesterolemia and/or hypertension impair endothelial function in peripheral vasculature; however, their impact on endothelial cells of brain microvessels is unclear. We investigated the effects of hypercholesterolemia on the integrity of the blood-brain barrier (BBB) and the activity of astrocytes during N(omega)-nitro-L-arginine methyl ester (L-NAME) hypertension followed by angiotensin (ANG) II. We found significant decreases in superoxide dismutase levels with all treatments except ANG II and L-NAME plus ANG II, and in catalase concentrations except ANG II and cholesterol plus L-NAME. Nitric oxide (NO) concentrations were significantly decreased by L-NAME but significantly increased by cholesterol. L-NAME-stimulated plasma malondialdehyde (MDA), Ox-LDL, and cholesterol levels were significantly augmented by cholesterol. Glutathione (GSH) levels significantly decreased, while MDA, TNF-alpha, and Ox-LDL levels significantly increased in cholesterol and/or L-NAME. The increase in BBB permeability by acute hypertension in hypercholesterolemic hypertensive animals was less than that observed in chronically hypertensive animals. Brain vessels of L-NAME-treated animals showed a considerable loss of immunoreactivity for tight junction proteins, occludin, and ZO-1. Immunoreactivity for occludin and ZO-1 increased in cholesterol plus L-NAME and decreased in cholesterol. Glial fibrillary acidic protein (GFAP) immunoreactivity was seen in few astrocytes in the brain sections of L-NAME-treated animals, but increased in cholesterol plus L-NAME. Positive immunoreactivity for vascular endothelial growth factor (VEGF) was observed in cholesterol and cholesterol plus L-NAME plus ANG II. We suggest that hypercholesterolemia may affect BBB integrity through increasing the expression of tight junction proteins and GFAP and leading to the production of VEGF, at least partly, via increased NO, TNF-alpha, and catalase in hypertensive conditions.The International journal of neuroscience 01/2009; 119(10):1881-904. · 0.86 Impact Factor
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ABSTRACT: Résumé Introduction L’amlodipine et l’atorvastatine offrent des avantages thérapeutiques au-delà de leur indication primaire, soit la réduction de la pression artérielle et des lipides sanguins, respectivement. L’amlodipine induit l’apoptose des cellules de muscle lisse vasculaire (CMLV) in vivo, contribuant à la régression de l'hypertrophie aortique chez le rat spontanément hypertendu (SHR). L'atorvastatine induit l’apoptose des CMLV in vitro, un effet proportionnel à la dose. Toutefois, cet effet reste à être démontré in vivo. Nous postulons que l’atorvastatine induira la régression de l’hypertrophie aortique via l’apoptose des CMLV chez le SHR, et que la combinaison de l’amlodipine et de l’atorvastatine aura un effet synergique sur la régression de l’hypertrophie aortique via l’apoptose des CMLV chez le SHR. Méthodologie L’amlodipine et l’atorvastatine ont été administrées à des SHR âgés de 11 semaines durant trois ou six semaines, individuellement ou en combinaison. Les points principaux à l'étude étaient le remodelage vasculaire et la pression artérielle. La fragmentation et le contenu en ADN, le stress oxydant, le taux de cholestérol et les niveaux de nitrates ont aussi été mesurés. Résultats Lorsque l’atorvastatine a été administrée seule, une diminution significative du stress oxydant et de la pression artérielle a été observée après trois et six semaines de traitement, respectivement. Par contre, aucune différence n’a pu être décelée quant au remodelage vasculaire. L'amlodipine a réduit la pression artérielle et l'hypertrophie aortique de façon dépendante de la dose. Une diminution significative de l'hyperplasie a été détectée après trois semaines de traitement avec la combinaison, et après six semaines avec une faible dose d'amlodipine. Conclusion Nos résultats ne supportent pas l'hypothèse que l'atorvastatine induit l'apoptose des CMLV in vivo. Par contre, lorsque combinée à l'amlodipine, elle pourrait ajouter un bénéfice supplémentaire au niveau de la réduction de l'hyperplasie aortique. Abstract Background and purpose Antihypertensive drugs such as the calcium channel blocker (CCB) amlodipine and cholesterol lowering agents such as statins exhibit pleiotropic effects. Amlodipine reduces aortic hypertrophy and hyperplasia in spontaneously hypertensive rat (SHR) by inducing a transient wave of apoptosis. Atorvastatin induces apoptosis of vascular smooth muscle cell (VSMC) in vitro, independently of cholesterol synthesis, an effect that remains to be shown in vivo. The present studies were designed to test the hypothesis that atorvastatin can induce vascular remodeling by VSMC apoptosis in vivo in SHR, and to test whether combined therapy with low dose amlodipine would provide synergistic effects on regression of aortic hypertrophy. Experimental approach 11-week old SHR were given atorvastatin and amlodipine, alone or in combination, for three or six weeks. Primary end-points were vascular remodeling and blood pressure. Secondary end-points included DNA fragmentation and content in the aorta, oxidative stress, cholesterol and serum total nitrite and nitrate (NOx) concentrations. Key results Treatment with atorvastatin did not modify vascular structure, although it significantly reduced oxidative stress after three weeks and blood pressure after six weeks. Amlodipine dose-dependently reduced blood pressure and aortic hypertrophy. Significant reduction of cellular hyperplasia was reached after 6 weeks with a low dose of amlodipine alone or after 3 weeks when atorvastatin was combined with low dose amlodipine. Conclusions and implications Our results do not support the notion that atorvastatin induces VSMC apoptosis in vivo, although the data suggest a possible interaction with amlodipine in reducing VSMC hyperplasia in the hypertensive aorta.
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ABSTRACT: This study investigates the effects of levetiracetam (LEV) on the functional and structural properties of blood-brain barrier (BBB) in pentylenetetrazole (PTZ)-kindled rats with cortical dysplasia (CD). Pregnant rats were exposed to 145 cGy of gamma-irradiation on embryonic day 17. In offsprings, kindling was induced by giving subconvulsive doses of PTZ three times per week for 45 days. While all kindled rats with CD died during epileptic seizures evoked by the administration of a convulsive dose of PTZ in 15 to 25 min, one week LEV (80 mg/kg) pretreatment decreased the mortality to 38% in the same setting. LEV caused a remarkable decrease (p<0.01) in extravasation of sodium fluorescein dye into the brain tissue of kindled animals with CD treated with convulsive dose of PTZ. Occludin immunoreactivity and expression remained essentially unchanged in all groups. Immunoreactivity for glial fibrillary acidic protein (GFAP) was observed to be slightly increased by acute convulsive challenge in kindled rats with CD while LEV pretreatment led to GFAP immunoreactivity comparable to that of controls. An increased c-fos immunoreactivity in kindled rats with CD exposed to convulsive PTZ challenge was also observed with LEV pretreatment. Tight junctions were ultrastructurally intact, whereas LEV decreased the increased pinocytotic activity in brain endothelium of kindled rats with CD treated with convulsive dose of PTZ. The present study showed that LEV decreased the increased BBB permeability considerably by diminishing vesicular transport in epileptic seizures induced by convulsive PTZ challenge in kindled animals with CD.Brain research 05/2009; 1281:71-83. · 2.46 Impact Factor