Lacosamide reduces HDAC levels in the brain and improves memory: Potential for treatment of Alzheimer's disease

Bang, Shraddha R.; Ambavade, Shirishkumar D.; Jagdale, Priti G.; Adkar, Prafulla P.; Waghmare, A.B.; Ambavade, Prashant D.

doi:10.1016/j.pbb.2015.04.011

Cited by 33 publications

(20 citation statements)

References 27 publications

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“…Lacosamide has an inhibitory activity on histone deacetylase [22], making it worthwhile investigating its in vitro effects on brain cancer, while brivaracetam, a parent compound of levetiracetam, might share with it the same biological effects and both have been recently described to have high brain permeability [23, 24]. …”

Section: Introductionmentioning

confidence: 99%

In vitro antineoplastic effects of brivaracetam and lacosamide on human glioma cells

Rizzo¹,

Donzelli²,

Girgenti³

et al. 2017

J Exp Clin Cancer Res

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BackgroundEpilepsy is a frequent symptom in patients with glioma. Although treatment with antiepileptic drugs is generally effective in controlling seizures, drug-resistant patients are not uncommon. Multidrug resistance proteins (MRPs) and P-gp are over-represented in brain tissue of patients with drug-resistant epilepsy, suggesting their involvement in the clearance of antiepileptic medications. In addition to their anticonvulsant action, some drugs have been documented for cytotoxic effects. Aim of this study was to evaluate possible in vitro cytotoxic effects of two new-generation antiepileptic drugs on a human glioma cell line U87MG.MethodsCytotoxicity of brivaracetam and lacosamide was tested on U87MG, SW1783 and T98G by MTS assay. Expression of chemoresistance molecules was evaluated using flow cytometry in U87MG and human umbilical vein endothelial cells (HUVECs). To investigate the putative anti-proliferative effect, apoptosis assay, microRNA expression profile and study of cell cycle were performed.ResultsBrivaracetam and lacosamide showed a dose-dependent cytotoxic and anti-migratory effects. Cytotoxicity was not related to apoptosis. The exposure of glioma cells to brivaracetam and lacosamide resulted in the modulation of several microRNAs; particularly, the effect of miR-195-5p modulation seemed to affect cell cycle, while miR-107 seemed to be implicated in the inhibition of cells migration. Moreover, brivaracetam and lacosamide treatment did not modulate the expression of chemoresistance-related molecules MRPs1-3-5, GSTπ, P-gp on U87MG and HUVECs.ConclusionBased on antineoplastic effect of brivaracetam and lacosamide on glioma cells, we assume that patients with glioma could benefit by the treatment with these two molecules, in addition to standard therapeutic options.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0546-9) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

In vitro antineoplastic effects of brivaracetam and lacosamide on human glioma cells

Rizzo¹,

Donzelli²,

Girgenti³

et al. 2017

J Exp Clin Cancer Res

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“…Hence, the downstream effects of lacosamide might be different than those of other HDAC inhibitors including valproic acid, which inhibit HDAC1 and other HDACs . Previously, intraperitoneal treatment of rats with 30 mg/kg lacosamide was associated with reduced HDAC1 protein expression in the cerebral cortex . However, histone acetylation was not evaluated in that study.…”

Section: Discussionmentioning

confidence: 89%

“…Recently, lacosamide has been shown to reduce in the rat brain the expression of histone deacetylase (HDAC)1, a member of a family of proteins that remove acetyl groups from lysine on histones . HDACs regulate the degree of DNA compaction and play a key role in gene expression and cell differentiation .…”

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confidence: 99%

Lacosamide at therapeutic concentrations induces histone hyperacetylation in vitro

et al. 2018

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SummaryInhibition of histone deacetylases (HDACs) and subsequent hyperacetylation of histone proteins lead to altered gene expression associated with therapeutic drug effects, but also with teratogenicity. The only US Food and Drug Administration (FDA)–approved antiepileptic drug that has been consistently shown to induce histone hyperacetylation is valproic acid. More recently, lacosamide was reported to interfere with histone modifications, but histone hyperacetylation was not demonstrated. In the current study we evaluated the effects of lacosamide on histone acetylation in vitro. MDA‐MB‐231 (triple‐negative breast cancer) cells and human placental BeWo cells were exposed for 16 hours to 5‐20 μg/ml (20‐80 μm) lacosamide. Histone acetylation was evaluated by western blot analysis. We additionally measured HDAC1 activity in the presence of lacosamide. At 5, 10, and 20 μg/ml, lacosamide enhanced histone acetylation in BeWo cells by 1.7‐fold (p > 0.05), 3.4‐fold (p < 0.05), and 3.0‐fold (p > 0.05), respectively. Histone H3 acetylation and total histones H3 and H4 levels were not significantly modified (p > 0.05). The magnitude of change in histone acetylation in MDA‐MB‐231 cells was smaller (p > 0.05). In contrast to valproic acid, lacosamide did not inhibit HDAC1. Our findings suggest that the effects of lacosamide on gene expression, and the related potential antitumor activity and teratogenicity, may differ from those of valproic acid.

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“…Considering the ability of fingolimod to inhibit HDAC [20] and the role of HDAC inhibitors including valproate and lacosamide in enhancing learning and memory processes and the epigenetic modulation of absence seizure development in this model [27,[75][76][77][78][79], we studied fingolimod ELTT effects on acetylation of Lysine 8 of histone H4 (both 6 and 10 months of age) and found a significant increase temporally linked to the preserved cognitive functions.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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One of the major challenges in the epilepsy field is identifying disease-modifying drugs in order to prevent or delay spontaneous recurrent seizure onset or to cure already established epilepsy. It has been recently reported that fingolimod, currently approved for the treatment of relapsing-remitting multiple sclerosis, has demonstrated antiepileptogenic effects in two different preclinical models of acquired epilepsy. However, to date, no data exist regarding the role of fingolimod against genetic epilepsy. Therefore, we have addressed this issue by studying the effects of fingolimod in WAG/Rij rats, a well-established genetic model of absence epilepsy, epileptogenesis, and neuropsychiatric comorbidity. Our results have demonstrated that an early-long term treatment with fingolimod (1 mg/Kg/day), started before absence seizure onset, has both antiepileptogenic and antidepressant-like effects in the WAG/Rij rats. However, these effects were transitory, since 5 months after treatment discontinuation, both absence seizure and depressive like-behavior returned to control level.Furthermore, a temporary reduction of mTOR signaling pathway activity, indicated by reduced p-mTOR and p-p70S6k levels and by an increased p-AKT in WAG/Rij rats of 6 months of age accompanied the transitory antiepileptogenic fingolimod effects. Surprisingly, fingolimod has demonstrated longer-lasting positive effects on cognitive decline in this strain. This effect was accompanied by an increased acetylation of Lysine 8 of histone H4 (both 6 and 10 months of age). In conclusion, our results support the antiepileptogenic effects fingolimod. However, these antiepileptogenic effects were transitory. Moreover, fingolimod might also have a positive impact on animal behavior and particularly in protecting the development of memory decline.

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Lacosamide reduces HDAC levels in the brain and improves memory: Potential for treatment of Alzheimer's disease

Cited by 33 publications

References 27 publications

In vitro antineoplastic effects of brivaracetam and lacosamide on human glioma cells

In vitro antineoplastic effects of brivaracetam and lacosamide on human glioma cells

Lacosamide at therapeutic concentrations induces histone hyperacetylation in vitro

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

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