Effect of atorvastatin on behavioral alterations and neuroinflammation during epileptogenesis

Oliveira, Clarissa Vasconcelos de; Grigoletto, Jéssica; Canzian, Julia; Duarte, Thiago; Furian, Ana Flávia; Oliveira, Mauro Schneider

doi:10.1016/j.yebeh.2017.10.021

Cited by 25 publications

(17 citation statements)

References 49 publications

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“…Treatment with atorvastatin after Pi‐SE (10 or 100 mg/kg/d) for 14 days had no protective effect on PTZ seizure susceptibility at the end of the treatment, and no neuroprotective effect . The same treatment in a different group of animals improved depression and object recognition testing, dose‐dependently decreased basal and SE‐induced levels of IL‐1β, IL‐6, TNF, and INF‐γ, and increased IL‐10 levels in the hippocampus and cerebral cortex, indicating anti‐inflammatory effects after an epileptogenic insult . Atorvastatin 20, 40, and 80 mg/kg/d administered during PTZ kindling for 7 weeks 1 hour before PTZ administration reduced severity of PTZ‐kindled seizures, which outlasted atorvastatin treatment, suggesting a disease‐modifying effect.…”

Section: Atorvastatin and Other Statinsmentioning

confidence: 98%

“…149 The same treatment in a different group of animals improved depression and object recognition testing, dose-dependently decreased basal and SE-induced levels of IL-1β, IL-6, TNF, and INFγ, and increased IL-10 levels in the hippocampus and cerebral cortex, indicating anti-inflammatory effects after an epileptogenic insult. 150 Atorvastatin 20, 40, and 80 mg/kg/d administered during PTZ kindling for 7 weeks 1 hour before PTZ administration reduced severity of PTZ-kindled seizures, which outlasted atorvastatin treatment, suggesting a disease-modifying effect. It also reduced brain lipid peroxidation, increased glutathione levels, and prevented PTZ kindling-associated reduction in hippocampal GABA and dopamine and increase in glutamate levels.…”

mentioning

confidence: 95%

“…fModels of blood-brain disruption and/or cortex exposure to albumin. g Dose is for atorvastatin [149][150][151].…”

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confidence: 99%

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Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

et al. 2020

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Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%‐20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease‐modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N‐acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially “repurposable” medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury–treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose–blood level relationship, brain target engagement, and dose‐response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecules or their combinations going forward.

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Section: Atorvastatin and Other Statinsmentioning

confidence: 98%

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confidence: 95%

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Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

et al. 2020

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“…In addition, it is estimated that 30%-40% are refractory to seizure treatment. [1][2][3] Epilepsy is considered a public health problem worldwide and is one of the most frequent neurological disorders. [3] disease.…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3] Epilepsy is considered a public health problem worldwide and is one of the most frequent neurological disorders. [3] disease. [1,4,5] The enzyme HMG-CoA reductase catalyzes the conversion of HMG-CoA to L-mevalonate; statins prevent the biological activities of L-mevalonate due to the aforementioned inhibitory effect.…”

Section: Introductionmentioning

confidence: 99%

The Effect of Statins in Epilepsy: A Systematic Review

Quintana-Pájaro¹,

Ramos-Villegas²,

Cortecero-Sabalza³

et al. 2018

Journal of Neurosciences in Rural Practice

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Background and Objectives:Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, used for the management of hypercholesterolemia and related atherosclerotic diseases. Several studies have indicated the neuroprotective effects of statins on several neuropathological conditions. However, the role of these medications in epilepsy is still unclear. The purpose is to evaluate and summarize the level of evidence on the efficacy of statins in neuronal hyperexcitability and the neuroinflammatory processes of epilepsy.Methods:A systematic review was performed. Eligibility Criteria: This review involved studies conducted in humans and nonhuman experimental models, covering the use of an inhibitor of HMG-CoA reductase, alone or accompanied by another medication, in epilepsy. Information Sources: A systematic literature search was performed in PubMed, Embase, Ebsco Host, Scopus, Science Direct, Medline, and LILACS. Risk of Bias: It was evaluated with the Newcastle–Ottawa Scale and the experimental studies were evaluated using the GRADE tool.Results:Twenty articles of the 183 evaluated were included. Sixteen studies were conducted in animal models and four studies in humans. Most studies in mice reported a reduction in epileptiform activity and reduction in systemic inflammation with the treatment of statins, potentially influencing epilepsy control. Few studies in humans were performed in the geriatric population with variable results (neuroinflammation, seizure prevention, cell death, prevention of kindling, increase in convulsive threshold, increase in latency, decrease in frequency of crisis, and reduction in mortality) related to reduction in the rate of hospitalizations, mortality, and prevention of epilepsy. Studies in mice found a decrease in interleukin-1β (IL-1β), IL-6, and tumor necrosis factor alpha and an increase in IL-10 and endothelial nitric oxide synthase.Conclusions:The possible antiepileptic mechanism of statins may be related to the reduction in neuroinflammation mediated by a decrease in pro-inflammatory cytokines and action in the nitrergic system. Further studies evaluating the impact of statins on seizure control are necessary.

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The influence of statins on the risk of post-stroke epilepsy

Vitturi

Gagliardi

2020

Neurol Sci

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Effect of atorvastatin on behavioral alterations and neuroinflammation during epileptogenesis

Cited by 25 publications

References 49 publications

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

The Effect of Statins in Epilepsy: A Systematic Review

The influence of statins on the risk of post-stroke epilepsy

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