Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

Leo, Antonio; Citraro, Rita; Amodio, Nicola; Sarro, Caterina De; Cantafio, Maria Eugenia Gallo; Constanti, Andrew; Sarro, Giovambattista De; Russo, Emilio

doi:10.1007/s13311-017-0550-y

Cited by 32 publications

(31 citation statements)

References 86 publications

(155 reference statements)

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“…However, these effects were transient and faded 5 months after drug washout. The drug showed a longer‐lasting (up to 6 months) improvement of cognitive decline in this model . Finally, fingolimod reduced by half the 2.5‐fold increase in seizure‐induced P‐glycoprotein expression measured 2 days after Li + pilo‐SE in the rat hippocampus (1 mg/kg ip at the time of SE induction, then daily for 2 days).…”

Section: Fingolimodmentioning

confidence: 75%

“…The drug showed a longer-lasting (up to 6 months) improvement of cognitive decline in this model. 263 Finally, fingolimod reduced by half the 2.5-fold increase in seizure-induced P-glycoprotein expression measured 2 days after Li + pilo-SE in the rat hippocampus (1 mg/kg ip at the time of SE induction, then daily for 2 days). This effect was associated with prevention of the threefold increase in hippocampal COX-2 and TNF and resulted in a twofold increased brain delivery of phenytoin, suggesting a potential value of fingolimod as adjuvant therapy for drug resistance to some ASDs.…”

Section: Fingolimodmentioning

confidence: 93%

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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: Fingolimodmentioning

confidence: 75%

Section: Fingolimodmentioning

confidence: 93%

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

et al. 2020

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“…Indeed, our previous data clearly showed that butyrate modulates innate immunity and oxidative stress, suppressing toll-like receptor and nuclear factor-kB activation in liver. [74][75][76][77] In conclusion, we provide evidence of the efficacy of butyrate and its potential utility in the prevention of VPAinduced liver injury. The study of functional data on seizures and animal behavior, and mechanism of actions of VPA and NaB, as HDAC inhibitors, are a part of a project financed by the Italian Ministry of Research (MIUR; prot.…”

Section: Discussionmentioning

confidence: 99%

Butyrate prevents valproate‐induced liver injury: In vitro and in vivo evidence

et al. 2019

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Sodium valproate (VPA), an antiepileptic drug, may cause dose-and time-dependent hepatotoxicity. However, its iatrogenic molecular mechanism and the rescue therapy are disregarded. Recently, it has been demonstrated that sodium butyrate (NaB) reduces hepatic steatosis, improving respiratory capacity and mitochondrial dysfunction in obese mice. Here, we investigated the protective effect of NaB in counteracting VPA-induced hepatotoxicity using in vitro and in vivo models. Human HepG2 cells and primary rat hepatocytes were exposed to high VPA concentration and treated with NaB. Mitochondrial function, lipid metabolism, and oxidative stress were evaluated, using Seahorse analyzer, spectrophotometric, and biochemical determinations.Liver protection by NaB was also evaluated in VPA-treated epileptic WAG/Rij rats, receiving NaB for 6 months. NaB prevented VPA toxicity, limiting cell oxidative and mitochondrial damage (ROS, malondialdehyde, SOD activity, mitochondrial bioenergetics), and restoring fatty acid oxidation (peroxisome proliferator-activated receptor α expression and carnitine palmitoyl-transferase activity) in HepG2 cells, primary hepatocytes, and isolated mitochondria. In vivo, NaB confirmed its activity normalizing hepatic biomarkers, fatty acid metabolism, and reducing inflammation and fibrosis induced by VPA. These data support the protective potential of NaB on VPA-induced liver injury, indicating it as valid therapeutic approach in counteracting this common side effect due to VPA chronic treatment. K E Y W O R D Santiepileptic drug, hepatotoxicity, lipid metabolism, mitochondrial dysfunction, oxidative stress, shortchain fatty acid | 677 PIROZZI et al. | 679 PIROZZI et al. incubated with tert-Butyl hydroperoxide (100 µM) plus H 2 O 2 for 3 hours. The fluorescence measurements were performed with aHTS-7000 Plus plate reader spectrofluorometer (Perkin Elmer, Wellesley, MA, USA) at 485 nm for excitation and 525 nm for emission wavelengths. ROS were quantified as percentage vs control unstimulated cells.

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“…In order to reduce the number of rats used, all experimental groups were subjected to several tests. When the same animal was subjected to several tests, at least one day (range one to three days) was allowed for recovering, as previously reported [25]. All behavioral tests were carried out under controlled environmental conditions, such as temperature, humidity, and light intensity (dim illumination), and all tests, except for passive avoidance, were performed with the support of video-tracking software (EthoVision XT8; Noldus Technology, Wageningen, the Netherlands).…”

Section: Behavioral Testsmentioning

confidence: 99%

“…No foot shock was delivered in this trial. Retention memory is directly linked to the latency to enter into the dark compartment: The better the memory, the greater the latency [25,27].…”

Section: Passive Avoidance (Pa)mentioning

confidence: 99%

Metabolic and Cognitive Effects of Ranolazine in Type 2 Diabetes Mellitus: Data from an in vivo Model

et al. 2020

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Type 2 diabetes mellitus (T2DM) is a risk factor for cognitive impairment. Ranolazine, an anti-ischemic drug used in the treatment of angina pectoris, has been shown to possess hypoglycemic properties in pre-clinical and clinical studies. The aim of this study was to evaluate the effects of ranolazine on glucose metabolism and cognitive function in a T2DM model of Wistar rats. Diabetes was induced by a high fat diet (HFD) and streptozotocin (STZ). The control group received a normal caloric diet (NCD) and sodium citrate buffer. Metformin, an effective hypoglycemic drug, was employed as a positive control. Animals were divided into the following groups: HFD/STZ + Ranolazine, HFD/STZ + Metformin, HFD/STZ + Vehicle, NCD + Vehicle, NCD + Ranolazine, and NCD + Metformin. Rats received ranolazine (20 mg/kg), metformin (300 mg/kg), or water, for 8 weeks. At the end of the treatments, all animals underwent to an intraperitoneal glucose tolerance test (IPGTT) and behavioral tests, including passive avoidance, novel object recognition, forced swimming, and elevate plus maze tests. Interleukin-6 plasma levels in the six treatment groups were assessed by Elisa assay. Body mass composition was estimated by nuclear magnetic resonance (NMR). Glucose responsiveness significantly improved in the HFD/STZ + Ranolazine (p < 0.0001) and HFD/STZ + Metformin (p = 0.003) groups. There was a moderate effect on blood glucose levels in the NCD + Ranolazine and NCD + Metformin groups. Lean body mass was significantly increased in the HFD/STZ + Ranolazine and HFD/STZ + Metformin animals, compared to HFD/STZ + Vehicle animals. Ranolazine improved learning and long-term memory in HFD/STZ + Ranolazine compared to HFD/STZ + Vehicle (p < 0.001) and ameliorated the pro-inflammatory profile of diabetic mice. These results support the hypothesis of a protective effect of ranolazine against cognitive decline caused by T2DM.

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Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

Cited by 32 publications

References 86 publications

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

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

Butyrate prevents valproate‐induced liver injury: In vitro and in vivo evidence

Metabolic and Cognitive Effects of Ranolazine in Type 2 Diabetes Mellitus: Data from an in vivo Model

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