Mechanisms and Clinical Evidence of the Pleiotropic Effects of the Hydroxy-Methyl-Glutaryl-CoA Reductase Inhibitors in Central Nervous System Disorders: A Comprehensive Review

Yanuck, Danielle; Mihos, Christos G.; Santana, Orlando

doi:10.3109/00207454.2012.704455

Cited by 20 publications

(23 citation statements)

References 91 publications

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“…Statins competitively inhibit the rate‐limiting enzyme in cholesterol synthesis but, due to their pleiotropic effects, have also immunomodulatory, neuroprotective, and anti‐inflammatory properties . Such pleiotropic effects have led to the suggestion that statins might be useful in several neurologic diseases, such as stroke, cerebral ischemia, Alzheimer's disease, multiple sclerosis, and epilepsy .…”

Section: Discussionmentioning

confidence: 99%

Protective effects of some statins on epileptogenesis and depressive‐like behavior in WAG/Rij rats, a genetic animal model of absence epilepsy

et al. 2014

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SUMMARYObjective: Statins (3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors) exert cholesterol-independent pleiotropic effects that include antithrombotic, antiinflammatory, and antioxidative properties. Moreover, both in vitro and in vivo studies have shown neuroprotective, antiseizure, and antiexcitotoxic effects of statins, suggesting their potential role in the treatment of neurologic diseases. Only a few studies have investigated whether statins modulate absence seizure activity and epileptogenesis. Methods: We investigated the effects of atorvastatin (5 and 10 mg/kg/day), simvastatin (10 mg/kg/day), and pravastatin (10 and 30 mg/kg/day), given orally for 17 consecutive weeks (starting at 45 days of age), on the development of absence seizures (electroencephalography [EEG] recordings), depressive-like behavior (forced swimming test [FST]), and anxiety levels (open field test [OF]) in Wistar Albino Glaxo/Rijswijk rats (WAG/Rij) rats at the age of 6 months (1 month after suspension). WAG/Rij rats are a genetic animal model of absence epilepsy, epileptogenesis, and mild-depression comorbidity. The effects of statins were also studied after acute intraperitoneal injection for 4 h after administration of various doses in 6-months-old rats. Plasma cholesterol levels were measured throughout drug treatment. Results: We found that early long-term statin treatment possesses antiepileptogenic properties, reduced immobility time in the FST, and reduced anxiety in the OF, whereas they were not effective against established absence seizures when acutely administered. The observed effects were not related to changes in plasma cholesterol levels, which remained unchanged during drug treatment. Significance: Our results suggest that statins administration might be a possible intervention and promising strategy for preventing the epileptogenesis and/or behavioral comorbidity.

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Section: Discussionmentioning

confidence: 99%

Protective effects of some statins on epileptogenesis and depressive‐like behavior in WAG/Rij rats, a genetic animal model of absence epilepsy

et al. 2014

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“…Although, there are no compounds with proved, significant neuroprotective activity, statin therapy has demonstrated benefits in IS patients [80,81]. Numerous papers related to statins indicate reduced risk of stroke by both stabilization of the carotid artery atherosclerotic plaque and a variety of pleiotropic mechanisms including antiinflammatory action and decrease of MMP expression [82].…”

Section: Statinsmentioning

confidence: 99%

The significance of matrix metalloproteinase (MMP)-2 and MMP-9 in the ischemic stroke

Kurzepa

Golab³

et al. 2014

International Journal of Neuroscience

111

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There is a continuous urgent need to explore the pathogenesis and biochemical changes within the infarcted area during acute ischemic stroke (IS). Matrix metalloproteinases (MMPs), prevailing extracellular endopeptideses, can digest proteins located extracellulary, e.g. collagen, proteoglycans, elastin or fibronectin. Among MMPs, gelatinases (MMP-2 and MMP-9) are the most investigated enzymes. Gelatinases possess the ability to active numerous pro-inflammatory agents as chemokine CXCL-8, interleukin 1β or tumor necrosis factor α. Moreover, due to digestion of collagen type IV (the component of basal membranes) and tight junction proteins (TJPs) they facilitate to cross the endothelium by leukocytes. Due to the significant role of gelatinases during brain ischemia, their selective inhibition seems to be an interesting kind of treatment of acute stroke. The synthetic inhibitors of gelatineses decrease the infarct volume in animal models of IS. In clinical practice statins, the lipid-lowering drugs possess the ability to inhibit the activity of MMP-9 during acute IS. This review briefly provides the most important information about the involvement of MMP-2 and MMP-9 in the pathogenesis of brain ischemia.

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“…Statins, best known for lowering cholesterol, also have cholesterol-independent effects, and have been shown to improve endothelial dysfunction, 25-30 reduce vascular wall inflammation, 27, 29, 31-35 and decrease platelet aggregation, 28, 29 and may improve autonomic function and sympathetic reflex regulation. 36 We previously observed a potential benefit and favorable interaction between statin and higher vitamin D levels on migraine.…”

Section: Introductionmentioning

confidence: 99%

Simvastatin and vitamin D for migraine prevention: A randomized, controlled trial

Buettner

Nir

Bertisch

et al. 2015

Annals of Neurology

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Objective To assess efficacy and tolerability of simvastatin plus vitamin D for migraine prevention in adults with episodic migraine. Methods We performed a randomized, double-blind, placebo-controlled trial with a 12-week baseline period and 24-week intervention period in 57 adults with episodic migraine. Participants were randomly assigned to simvastatin 20 mg tablets twice daily plus vitamin D3 1000 international units capsules twice daily or matching placebo tablets and capsules. Results Compared to placebo, participants using simvastatin plus vitamin D3 demonstrated a greater decrease in number of migraine days from the baseline period to intervention weeks 1-12: a change of -8.0 (IQR: -15.0 to -2.0) days in the active treatment group versus +1.0 (IQR: 1.0 to +6.0) days in the placebo group, P<0.001; and to intervention weeks 13-24: a change of -9.0 (IQR: -13 to -5) days in the active group versus +3.0 (IQR: -1.0 to +5.0) days in the placebo group, P<0.001. In the active treatment group, 8 patients (25%) experienced 50% reduction in the number of migraine days at 12 weeks and 9 (29%) at 24 weeks post randomization. In comparison, only 1 patient (3%) in the placebo group (p=0.03) experienced such reduction. Adverse events were similar in both active treatment and placebo groups. Interpretation The results demonstrate that simvastatin plus vitamin D is effective for prevention of headache in adults with episodic migraine. Given statins ability to repair endothelial dysfunction, this economical approach may also reduce the increased risk for vascular diseases among migraineurs.

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Mechanisms and Clinical Evidence of the Pleiotropic Effects of the Hydroxy-Methyl-Glutaryl-CoA Reductase Inhibitors in Central Nervous System Disorders: A Comprehensive Review

Cited by 20 publications

References 91 publications

Protective effects of some statins on epileptogenesis and depressive‐like behavior in WAG/Rij rats, a genetic animal model of absence epilepsy

Protective effects of some statins on epileptogenesis and depressive‐like behavior in WAG/Rij rats, a genetic animal model of absence epilepsy

The significance of matrix metalloproteinase (MMP)-2 and MMP-9 in the ischemic stroke

Simvastatin and vitamin D for migraine prevention: A randomized, controlled trial

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