Statins as Neuroprotectants: A Comparative In Vitro Study of Lipophilicity, Blood-Brain-Barrier Penetration, Lowering of Brain Cholesterol, and Decrease of Neuron Cell Death

Sierra, Saleta; Ramos, María C.; Molina, Pilar; Esteo, Cynthia; Vázquez, José Antonio; Burgos, Javier S.

doi:10.3233/jad-2010-101179

Cited by 180 publications

(137 citation statements)

References 37 publications

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“…For this analysis, statins were divided into two categories, according to higher (simvastatin only, since no studies with fluvastatin are included) vs. lower (all others) propensity to cross the blood-brain barrier. 35 Additional analyses were performed for study duration, study sample size, and risk of bias items, when the data allowed (i.e., when a characteristic varied across studies and six or more studies were available for analysis). Figure 1 shows the literature search and article selection flow chart.…”

Section: Assessment Of Heterogeneity and Meta-regression Analysesmentioning

confidence: 99%

Do Statins Impair Cognition? A Systematic Review and Meta-Analysis of Randomized Controlled Trials

et al. 2015

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BACKGROUND:In 2012, the United States Food and Drug Administration (FDA) issued a warning regarding potential adverse effects of HMG-CoA reductase inhibitors (statins) on cognition, based on the Adverse Events Reporting System and a review of the medical literature. We aimed to synthesize randomized clinical trial (RCTs) evidence on the association between statin therapy and cognitive outcomes. METHODS: We searched MEDLINE, EMBASE, and Cochrane CENTRAL through December 2012, and reviewed published systematic reviews of statin treatment. We sought RCTs that compared statin treatment versus placebo or standard care, and reported at least one cognitive outcome (frequency of adverse cognitive events or measurements using standard neuropsychological cognitive test scores). Studies reporting sufficient information to calculate effect sizes were included in metaanalyses. Standardized and unstandardized mean differences were calculated for continuous outcomes for global cognition and for pre-specified cognitive domains. The main outcome was change in cognition measured by neuropsychological tests; an outcome of secondary interest was the frequency of adverse cognitive events observed during follow-up. RESULTS: We identified 25 RCTs (all placebo-controlled) reporting cognitive outcomes in 46,836 subjects, of which 23 RCTs reported cognitive test results in 29,012 participants. Adverse cognitive outcomes attributable to statins were rarely reported in trials involving cognitively normal or impaired subjects. Furthermore, meta-analysis of cognitive test data (14 studies; 27,643 participants) failed to show significant adverse effects of statins on all tests of cognition in either cognitively normal subjects (standardized mean difference 0.01, 95 % confidence interval, CI, −0.01 to 0.03, p=0.42) or Alzheimer's disease subjects (standardized mean difference −0.05, 95 % CI −0.19 to 0.10, p=0.38). CONCLUSIONS: Statin therapy was not associated with cognitive impairment in RCTs. These results raise questions regarding the continued merit of the FDA warning about potential adverse effects of statins on cognition.

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Section: Assessment Of Heterogeneity and Meta-regression Analysesmentioning

confidence: 99%

Do Statins Impair Cognition? A Systematic Review and Meta-Analysis of Randomized Controlled Trials

et al. 2015

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“…9 Since our data show that atorvastatin exhibits protective effects in the brain, we sought to study a biologic mechanism that could be targeted to deliver atorvastatin to the CNS. One potential mechanism that could facilitate CNS statin delivery is Oatp1a4-mediated transport.…”

Section: Hypoxia/reoxygenation Modulates Blood Gas and Circulating Elmentioning

confidence: 99%

“…A recent comparative in vitro study that evaluated efficacy of statins as neuroprotectants by assessing their chemical structure, theoretical lipophilicity, and ability to protect against neuronal death induced by okadaic acid concluded that both atorvastatin and rosuvastatin were effective in mitigating neuron cell death. 9 However, both these drugs had permeability values close to zero and blood-brain barrier (BBB) penetration estimates of o5%. 9 This study illustrates the critical importance of identifying and characterizing endogenous transport mechanisms that can be targeted to facilitate CNS statin delivery.…”

Section: Introductionmentioning

confidence: 99%

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Hypoxia/Reoxygenation Stress Signals an Increase in Organic Anion Transporting polypeptide 1a4 (Oatp1a4) at the Blood–Brain Barrier: Relevance to CNS Drug Delivery

Thompson

Sanchez-Covarrubias

Slosky

et al. 2014

J Cereb Blood Flow Metab

121

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Cerebral hypoxia and subsequent reoxygenation stress (H/R) is a component of several diseases. One approach that may enable neural tissue rescue after H/R is central nervous system (CNS) delivery of drugs with brain protective effects such as 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (i.e., statins). Our present in vivo data show that atorvastatin, a commonly prescribed statin, attenuates poly (ADP-ribose) polymerase (PARP) cleavage in the brain after H/R, suggesting neuroprotective efficacy. However, atorvastatin use as a CNS therapeutic is limited by poor blood-brain barrier (BBB) penetration. Therefore, we examined regulation and functional expression of the known statin transporter organic anion transporting polypeptide 1a4 (Oatp1a4) at the BBB under H/R conditions. In rat brain microvessels, H/R (6% O 2 , 60 minutes followed by 21% O 2 , 10 minutes) increased Oatp1a4 expression. Brain uptake of taurocholate (i.e., Oap1a4 probe substrate) and atorvastatin were reduced by Oatp inhibitors (i.e., estrone-3-sulfate and fexofenadine), suggesting involvement of Oatp1a4 in brain drug delivery. Pharmacological inhibition of transforming growth factor-b (TGF-b)/activin receptor-like kinase 5 (ALK5) signaling with the selective inhibitor SB431542 increased Oatp1a4 functional expression, suggesting a role for TGF-b/ALK5 signaling in Oatp1a4 regulation. Taken together, our novel data show that targeting an endogenous BBB drug uptake transporter (i.e., Oatp1a4) may be a viable approach for optimizing CNS drug delivery for treatment of diseases with an H/R component.

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“…22 This may be due to the inability of the hydrophilic rosuvastatin to enter the brain. 23 Progesterone has shown neuroprotective effects in animal models of spinal cord injury, stroke and TBI, 24−26 and has shown possible signs of benefit in clinical trials in patients after TBI. 27 Interestingly, progesterone decreases BBB damage after permanent focal ischemia by reducing MMP-2 and MMP-9 activity.…”

mentioning

confidence: 99%

Selective Gelatinase Inhibitor Neuroprotective Agents Cross the Blood-Brain Barrier

Gooyit

Suckow

Schroeder

et al. 2012

ACS Chem. Neurosci.

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SB-3CT, a potent and selective inhibitor of matrix metalloproteinase-2 and -9, has shown efficacy in several animal models of neurological diseases. One of the greatest challenges in the development of therapeutics for neurological diseases is the inability of drugs to cross the blood-brain barrier. A sensitive bioanalytical method based on ultraperformance liquid chromatography with multiple-reaction monitoring detection was developed to measure levels of SB-3CT, its active metabolite, the α-methyl analogue, and its p-hydroxy metabolite in plasma and brain. The compounds are rapidly absorbed and are readily distributed to the brain. The pharmacokinetic properties of these gelatinase inhibitors and the efficacy shown by SB-3CT in animal models of stroke, subarachnoid hemorrhage, and spinal cord injury indicate that this class of compounds holds considerable promise in the treatment of diseases of the central nervous system. KEYWORDS: Gelatinase inhibitors, matrix metalloproteinases, brain delivery, SB-3CT S B-3CT (compound 1, Figure 1), is a thiirane-based inhibitor that is selective for matrix metalloproteinase (MMP)-2 and -9, 1 also known as gelatinases. This compound has shown efficacy in a number of neurological diseases, including blocking laminin degradation by MMP-9 and rescuing neurons from apoptosis after transient focal cerebral ischemia, 2 preventing laminin degradation after subarachnoid hemorrhage, 3 reducing cerebral vasopasm caused by subarachnoid hemorrhage, 4 reducing the infiltration of monocytes into the injured spinal cord, 5 and decreasing extravasation and apoptotic cell death after spinal cord injury. 6 The compounds of the thiirane class have a unique mechanism of action, involving ring-opening of the thiirane ring at the active site of gelatinases and generation of the thiolate, which is a picomolar and tight-binding inhibitor. 7The blood-brain barrier (BBB) forms a physical separation between circulating blood and the brain parenchyma and consists of tight junctions around endothelial cells surrounded by basement membrane. The BBB prevents pathogens and large hydrophilic molecules from entering the brain, while allowing transport of substances needed by the central nervous system (CNS) such as glucose, fatty acids, and vitamins. One of the most challenging issues in the development of therapeutics for neurological diseases is the inability of drugs to cross the BBB. In fact, greater than 98% of small-molecule drugs and 100% of large-molecule therapeutics do not cross the BBB. Only 5% of small-molecule drugs in the Comprehensive Medicinal Chemistry database treat a mere four CNS diseases: depression, schizophrenia, chronic pain, and epilepsy.9,10 The vast majority of CNS disorders, including debilitating diseases

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Statins as Neuroprotectants: A Comparative In Vitro Study of Lipophilicity, Blood-Brain-Barrier Penetration, Lowering of Brain Cholesterol, and Decrease of Neuron Cell Death

Cited by 180 publications

References 37 publications

Do Statins Impair Cognition? A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Do Statins Impair Cognition? A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Hypoxia/Reoxygenation Stress Signals an Increase in Organic Anion Transporting polypeptide 1a4 (Oatp1a4) at the Blood–Brain Barrier: Relevance to CNS Drug Delivery

Selective Gelatinase Inhibitor Neuroprotective Agents Cross the Blood-Brain Barrier

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