Neuroprotective effects of atorvastatin against glutamate‐induced excitotoxicity in primary cortical neurones

Bösel, Julian; Gandor, Florin; Harms, Christoph; Synowitz, Michael; Harms, Ulrike; Djoufack, Pierre Chryso; Megow, Dirk; Dirnagl, Ulrich; Hörtnagl, Heide; Fink, Klaus; Endres, Matthias

doi:10.1111/j.1471-4159.2004.02980.x

Cited by 188 publications

(141 citation statements)

References 60 publications

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“…Atorvastatin attenuated the glutamate-induced increase of intracellular calcium, which was associated with a modulation of N-methyl-D-asparate (NMDA) receptor functions (Boesel et al 2005). Also it is shown that HMG-CoA reductase inhibition causes a profound reduction of neurite length, neurite loss and neuron death in undifferentiated rat cortical neurons (Schulz et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Fluvastatin Alters Psychomotor Performance and Daily Activity but not the Spatial Memory in Rats

Baytan

Alkanat

Özeren

et al. 2006

Tohoku J. Exp. Med.

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BAYTAN, S.H., ALKANAT, M., OZEREN, M., EKINCI, M. and AKGUN, A. Fluvastatin Alters Psychomotor Performance and Daily Activity but not the Spatial Memory in Rats.Tohoku J. Exp. Med., 2006, 209 (4), 311-320 Statins, inhibitors of cholesterol synthesis for treating dyslipidemia and preventing cardiovascular complications, have been shown to alter central nervous system functions. Our aim was to investigate the effects of the fluvastatin, a member of statin family, on psychomotor performance, daily activity and spatial memory. Sprague-Dawley rats were treated with fluvastatin (n = 8) or placebo as a control (n = 11) regardless of sex. Fluvastatin (7.5 mg/kg) was administered orally once a day for four weeks, while the control group was administered only placebo. Psychomotor performance was measured by rotarod tests. No significant difference was observed in the fluvastatin group over the course of weeks, but the control group preferred to stay on the device shorter times ( p < 0.05). For the first three weeks of the drug administration there was a statistical difference between the groups, however no difference was found after the 4th week. There was no difference in the Barnes maze spatial memory test between the groups and also within the groups over the course of time. Daily activity tests revealed that stereotypical and vertical movements of the fluvastatin group were significantly less than the control group in all four weeks. Ambulatory movements and the distances taken by the fluvastatin group were decreased significantly over the course of time ( p < 0.005 and p < 0.001, respectively), but the control group did not reveal any significant change. Our results suggest that fluvastatin altered psychomotor performance and daily activity in rats, but it did not affect the spatial memory. These behavioral changes might be associated with alterations in the composition of the brain lipids caused by fluvastatin. statin; fluvastatin; behavior; Barnes maze; psychomotor

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Section: Discussionmentioning

confidence: 99%

Fluvastatin Alters Psychomotor Performance and Daily Activity but not the Spatial Memory in Rats

Baytan

Alkanat

Özeren

et al. 2006

Tohoku J. Exp. Med.

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“…However, many studies show that statins may have additional neuroprotective properties independent of their effect on cholesterol synthesis. Statins can reduce the region of focal cerebral ischemia [1] and protect cortical neurons from excitotoxity [2] . Recent studies reported that statins can preventively and therapeutically attenuate traumatic brain injury and spinal cord injury.…”

Section: Introductionmentioning

confidence: 99%

Atorvastatin enhances neurite outgrowth in cortical neurons in vitro via up-regulating the Akt/mTOR and Akt/GSK-3β signaling pathways

et al. 2012

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Aim: To investigate whether atorvastatin can promote formation of neurites in cultured cortical neurons and the signaling mechanisms responsible for this effect. Methods: Cultured rat cerebral cortical neurons were incubated with atorvastatin (0.05-10 μmol/L) for various lengths of time. For pharmacological experiments, inhibitors were added 30 min prior to addition of atorvastatin. Control cultures received a similar amount of DMSO. Following the treatment period, phase-contrast digital images were taken. Digital images of neurons were analyzed for total neurite branch length (TNBL), neurite number, terminal branch number, and soma area by SPOT Advanced Imaging software. After incubation with atorvastatin for 48 h, the levels of phosphorylated 3-phosphoinoside-dependent protein kinase-1 (PDK1), phospho-Akt, phosphorylated mammalian target of rapamycin (mTOR), phosphorylated 4E-binding protein 1 (4E-BP1), p70S6 kinase (p70S6K), and glycogen synthase kinase-3β (GSK-3β) in the cortical neurons were evaluated using Western blotting analyses. Results: Atorvastatin (0.05-10 µmol/L) resulted in dose-dependent increase in neurite number and length in these neurons. Pretreatment of the cortical neurons with phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 (30 µmol/L) and wortmannin (5 µmol/L), Akt inhibitor tricribine (1 µmol/L) or mTOR inhibitor rapamycin (100 nmol/L) blocked the atorvastatin-induced increase in neurite outgrowth, suggesting that atorvastatin promoted neurite outgrowth via activating the PI3K/Akt/mTOR signaling pathway. Atorvastatin (10 µmol/L) significantly increased the levels of phosphorylated PDK1, Akt and mTOR in the cortical neurons, which were prevented by LY294002 (30 µmol/L). Moreover, atorvastatin (10 µmol/L) stimulated the phosphorylation of 4E-BP1 and p70S6K, the substrates of mTOR, in the cortical neurons. In addition, atorvastatin (10 µmol/L) significantly increased the phosphorylated GSK-3β level in the cortical neurons, which was prevented by both LY294002 and tricribine. Conclusion: These results suggest that activation of both the PI3K/Akt/mTOR and Akt/GSK-3β signaling pathways is responsible for the atorvastatin-induced neurite outgrowth in cultured cortical neurons.

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“…An in vitro study reported neuronal protection by atorvastatin in glutamate-induced toxicity [75]. Moreover, the observed neuroprotection and recovery in animal models of spinal cord injury [55] and traumatic brain injury [76][77][78] following statin treatment suggest statin-mediated neuroprotection in these animal models of brain injury.…”

Section: Statins Inhibit Axonal Lossmentioning

confidence: 96%

Therapeutic potential of statins in multiple sclerosis: immune modulation, neuroprotection and neurorepair

Marković-Pleše

Singh

2008

Future Neurol.

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Statins as inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A reductase are widely used as cholesterol-lowering drugs. Recent studies provide evidence that the anti-inflammatory activity of statins, which is independent of their cholesterol-lowering effects, may have potential therapeutic implications for neuroinflammatory diseases such as multiple sclerosis (MS), Alzheimer's disease and brain tumors, as well as traumatic spinal cord and brain injuries. Studies with animal models of MS suggest that, in addition to immunomodulatory activities similar to the ones observed with approved MS medications, statin treatment also protects the BBB, protects against neurodegeneration and may also promote neurorepair. Although the initial human studies on statin treatment for MS are encouraging, prospective randomized clinical studies will be required to evaluate their efficacy in the larger patient population. Keywordsblood-brain barrier; immunomodulation; inflammation; multiple sclerosis; neurodegeneration; neuroinflammatory diseases; neurorepair; pleotropic effects; statins Multiple sclerosis (MS) is a chronic CNS disease with a chronic inflammatory response directed against the myelin antigens [1,2]. Immunological studies indicate that autoreactive CD4 + and CD8 + lymphocytes migrate into the CNS following antigen recognition in the peripheral circulation. Once in the CNS, T cells undergo reactivation by abundant myelin antigens and perpetuate an inflammatory response that leads to demyelination and axonal loss †Author for correspondence

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Neuroprotective effects of atorvastatin against glutamate‐induced excitotoxicity in primary cortical neurones

Cited by 188 publications

References 60 publications

Fluvastatin Alters Psychomotor Performance and Daily Activity but not the Spatial Memory in Rats

Fluvastatin Alters Psychomotor Performance and Daily Activity but not the Spatial Memory in Rats

Atorvastatin enhances neurite outgrowth in cortical neurons in vitro via up-regulating the Akt/mTOR and Akt/GSK-3β signaling pathways

Therapeutic potential of statins in multiple sclerosis: immune modulation, neuroprotection and neurorepair

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