 |
|||||
|
|||||
|
|||||
|
|||||
|
|||||
The Journal of Neuroscience, December 3, 2003, 23(35):11104-11111
Previous Article | Next Article
Cellular/Molecular
3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Protect Cortical Neurons from Excitotoxicity
Anna Zacco,1 James Togo,1 Katherine Spence,1 Amanda Ellis,1 Darlene Lloyd,2 Steve Furlong,2 andTimothy Piser1 Departments of 1Neuroscience and 2Molecular Sciences, CNS Discovery Research, AstraZeneca Pharmaceuticals, Wilmington, Delaware 19850
3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, or statins, reduce the incidence of strokes and reduce infarct volume after cerebral ischemia in mice. Excitoxicity caused by overstimulation of glutamate receptors is a major cause of neuronal death after an ischemic brain insult. Experiments presented here explored whether statins protect cultured neurons from excitotoxic death caused by the glutamate receptor agonist NMDA. Treatment with statins preserved NMDA receptor-expressing cortical neurons and potently and substantially reduced lactate dehydrogenase release caused by exposure of embryonic mouse neocortical cultures to NMDA. The rank order of neuroprotective potency was rosuvastatin = simvastatin > atorvastatin = mevastatin > pravastatin, which is similar to the known rank order of potency for inhibition of the HMG-CoA reductase enzyme. Resistance of cultures to NMDA excitotoxicity developed after several days of statin exposure. Neuroprotection by rosuvastatin was coincident with a decrease in cell sterols and occurred with a similar potency as inhibition of cholesterol biosynthesis. Neuroprotection was substantially attenuated by cotreatment with either mevalonate or cholesterol and was mimicked by acute treatment with the cholesterol-extracting agent
-cyclodextrin, suggesting that neuroprotection was mediated by depletion of a cellular pool of cholesterol because of the inhibition of cholesterol biosynthesis. These results suggest the possibility that, in addition to effects on cerebrovascular function, statins have the potential to render cortical neurons more resistant to NMDA-induced excitotoxic death as a result of changes in cell cholesterol homeostasis.
Key words: HMG-CoA reductase; statin; cholesterol; NMDA; excitotoxicity; neuron
Received April 11, 2003; revised September 26, 2003; accepted October 8, 2003.
This article has been cited by other articles:
K. Karki, R. A. Knight, Y. Han, D. Yang, J. Zhang, K. A. Ledbetter, M. Chopp, and D. M. Seyfried
Simvastatin and Atorvastatin Improve Neurological Outcome After Experimental Intracerebral Hemorrhage
Stroke, October 1, 2009; 40(10): 3384 - 3389.
[Abstract] [Full Text] [PDF]
T. Ma, Y. Zhao, Y.-D. Kwak, Z. Yang, R. Thompson, Z. Luo, H. Xu, and F.-F. Liao
Statin's Excitoprotection Is Mediated by sAPP and the Subsequent Attenuation of Calpain-Induced Truncation Events, Likely via Rho-ROCK Signaling
J. Neurosci., September 9, 2009; 29(36): 11226 - 11236.
[Abstract] [Full Text] [PDF]
F. Domoki, B. Kis, T. Gaspar, J. A. Snipes, J. S. Parks, F. Bari, and D. W. Busija
Rosuvastatin induces delayed preconditioning against oxygen-glucose deprivation in cultured cortical neurons
Am J Physiol Cell Physiol, January 1, 2009; 296(1): C97 - C105.
[Abstract] [Full Text] [PDF]
M. S. Kostapanos, H. J. Milionis, and M. S. Elisaf
An Overview of the Extra-Lipid Effects of Rosuvastatin
Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2008; 13(3): 157 - 174.
[Abstract] [PDF]
M. Rodriguez-Yanez, J. Agulla, R. Rodriguez-Gonzalez, T. Sobrino, and J. Castillo
Review: Statins and stroke
Therapeutic Advances in Cardiovascular Disease, June 1, 2008; 2(3): 157 - 166.
[Abstract] [PDF]
J. Ponce, N. P. de la Ossa, O. Hurtado, M. Millan, J. F. Arenillas, A. Davalos, and T. Gasull
Simvastatin Reduces the Association of NMDA Receptors to Lipid Rafts: A Cholesterol-Mediated Effect in Neuroprotection
Stroke, April 1, 2008; 39(4): 1269 - 1275.
[Abstract] [Full Text] [PDF]
C.-H. Hsieh, S.-F. Jeng, M.-W. Hsieh, Y.-C. Chen, C.-S. Rau, T.-H. Lu, and S.-S. Chen
Statin-Induced Heme Oxygenase-1 Increases NF-{kappa}B Activation and Oxygen Radical Production in Cultured Neuronal Cells Exposed to Lipopolysaccharide
Toxicol. Sci., March 1, 2008; 102(1): 150 - 159.
[Abstract] [Full Text] [PDF]
A. A. Khan, X. O. Mao, S. Banwait, K. Jin, and D. A. Greenberg
Neuroglobin attenuates -amyloid neurotoxicity in vitro and transgenic Alzheimer phenotype in vivo
PNAS, November 27, 2007; 104(48): 19114 - 19119.
[Abstract] [Full Text] [PDF]
M. Valenza, J. B. Carroll, V. Leoni, L. N. Bertram, I. Bjorkhem, R. R. Singaraja, S. Di Donato, D. Lutjohann, M. R. Hayden, and E. Cattaneo
Cholesterol biosynthesis pathway is disturbed in YAC128 mice and is modulated by huntingtin mutation
Hum. Mol. Genet., September 15, 2007; 16(18): 2187 - 2198.
[Abstract] [Full Text] [PDF]
A. S. Paintlia, M. K. Paintlia, I. Singh, and A. K. Singh
Immunomodulatory Effect of Combination Therapy with Lovastatin and 5-Aminoimidazole-4-Carboxamide-1-{beta}-D-Ribofuranoside Alleviates Neurodegeneration in Experimental Autoimmune Encephalomyelitis
Am. J. Pathol., September 1, 2006; 169(3): 1012 - 1025.
[Abstract] [Full Text] [PDF]
L. N. Johnson-Anuna, G. P. Eckert, J. H. Keller, U. Igbavboa, C. Franke, T. Fechner, M. Schubert-Zsilavecz, M. Karas, W. E. Muller, and W. G. Wood
Chronic Administration of Statins Alters Multiple Gene Expression Patterns in Mouse Cerebral Cortex
J. Pharmacol. Exp. Ther., February 1, 2005; 312(2): 786 - 793.
[Abstract] [Full Text] [PDF]
A. Cordle and G. Landreth
3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors Attenuate {beta}-Amyloid-Induced Microglial Inflammatory Responses
J. Neurosci., January 12, 2005; 25(2): 299 - 307.
[Abstract] [Full Text] [PDF]
B. C. Kieseier, J. J. Archelos, and H.-P. Hartung
Different Effects of Simvastatin and Interferon Beta on the Proteolytic Activity of Matrix Metalloproteinases
Arch Neurol, June 1, 2004; 61(6): 929 - 932.
[Abstract] [Full Text] [PDF]
|
|
|
|
 |
|