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A novel therapeutic approach for treatment of catamenial epilepsy.

ABSTRACT: Many women with epilepsy experience perimenstrual seizure exacerbation, referred to as catamenial epilepsy. There is no effective treatment for this condition, proposed to result from withdrawal of neurosteroid-mediated effects of progesterone. A double-blind, multicenter, phase III, clinical trial of catamenial epilepsy has failed to find a beneficial effect of progesterone. The neurosteroid-mediated effects of progesterone have been extensively studied in relation to catamenial epilepsy; however, the effects mediated by progesterone receptor activation have been overlooked. We determined whether progesterone increased excitatory transmission in the hippocampus via activation of progesterone receptors, which may play a role in regulating catamenial seizure exacerbation. In a double-blind study using a rat model of catamenial epilepsy, we found that treatment with RU-486, which blocks progesterone and glucocorticoid receptors, significantly attenuated neurosteroid withdrawal-induced seizures. Furthermore, progesterone treatment as well as endogenous rise in progesterone during estrous cycle increased the expression of GluA1 and GluA2 subunits of AMPA receptors in the hippocampi, and enhanced the AMPA receptor-mediated synaptic transmission of CA1 pyramidal neurons. The progesterone-induced plasticity of AMPA receptors was blocked by RU-486 treatment and progesterone also failed to increase AMPA receptor expression in progesterone receptor knockout mice. These studies demonstrate that progesterone receptor activation regulates AMPA receptor expression and may play a role in catamenial seizure exacerbation.

SUBMITTER: Joshi S

PROVIDER: S-EPMC5803337 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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A novel therapeutic approach for treatment of catamenial epilepsy.

Joshi Suchitra S Sun Huayu H Rajasekaran Karthik K Williamson John J Perez-Reyes Edward E Kapur Jaideep J

Neurobiology of disease 20171221

Many women with epilepsy experience perimenstrual seizure exacerbation, referred to as catamenial epilepsy. There is no effective treatment for this condition, proposed to result from withdrawal of neurosteroid-mediated effects of progesterone. A double-blind, multicenter, phase III, clinical trial of catamenial epilepsy has failed to find a beneficial effect of progesterone. The neurosteroid-mediated effects of progesterone have been extensively studied in relation to catamenial epilepsy; howev ...[more]

PMID: 29274741

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Project description:BACKGROUND:Mitochondrial disease is a family of genetic disorders characterized by defects in the generation and regulation of energy. Epilepsy is a common symptom of mitochondrial disease, and in the vast majority of cases, refractory to commonly used antiepileptic drugs. Ferroptosis is a recently-described form of iron- and lipid-dependent regulated cell death associated with glutathione depletion and production of lipid peroxides by lipoxygenase enzymes. Activation of the ferroptosis pathway has been implicated in a growing number of disorders, including epilepsy. Given that ferroptosis is regulated by balancing the activities of glutathione peroxidase-4 (GPX4) and 15-lipoxygenase (15-LO), targeting these enzymes may provide a rational therapeutic strategy to modulate seizure. The clinical-stage therapeutic vatiquinone (EPI-743, ?-tocotrienol quinone) was reported to reduce seizure frequency and associated morbidity in children with the mitochondrial disorder pontocerebellar hypoplasia type 6. We sought to elucidate the molecular mechanism of EPI-743 and explore the potential of targeting 15-LO to treat additional mitochondrial disease-associated epilepsies. METHODS:Primary fibroblasts and B-lymphocytes derived from patients with mitochondrial disease-associated epilepsy were cultured under standardized conditions. Ferroptosis was induced by treatment with the irreversible GPX4 inhibitor RSL3 or a combination of pharmacological glutathione depletion and excess iron. EPI-743 was co-administered and endpoints, including cell viability and 15-LO-dependent lipid oxidation, were measured. RESULTS:EPI-743 potently prevented ferroptosis in patient cells representing five distinct pediatric disease syndromes with associated epilepsy. Cytoprotection was preceded by a dose-dependent decrease in general lipid oxidation and the specific 15-LO product 15-hydroxyeicosatetraenoic acid (15-HETE). CONCLUSIONS:These findings support the continued clinical evaluation of EPI-743 as a therapeutic agent for PCH6 and other mitochondrial diseases with associated epilepsy.

Project description:PurposeRefractory pediatric leukemia remains one of the leading causes of death in children. Intensification of current chemotherapy regimens to improve the outcome in these children is often limited by the effects of drug resistance and cumulative toxicity. Hence, the search for newer agents and novel therapeutic approaches are urgently needed to formulate the next-generation early-phase clinical trials for these patients.Materials and methodsA comprehensive library of antimicrobials, including eight HIV protease inhibitors (nelfinavir [NFV], saquinavir, indinavir, ritonavir, amprenavir, atazanavir, lopinavir, and darunavir), was tested against a panel of pediatric leukemia cells by in vitro growth inhibition studies. Detailed target modulation studies were carried out by Western blot analyses. In addition, drug synergy experiments with conventional and novel antitumor agents were completed to identify effective treatment regimens for future clinical trials.ResultsSeveral of the HIV protease inhibitors showed cytotoxicity at physiologically relevant concentrations (half-maximal inhibitory concentration values ranging from 1-24 µM). In particular, NFV was found to exhibit the most potent antileukemic properties across all cell lines tested. Mechanistic studies show that NFV leads to the induction of autophagy and apoptosis possibly through the induction of endoplasmic reticulum stress. Furthermore, interference with cell signaling pathways, including Akt and mTOR, was also noted. Finally, drug combination studies have identified agents with potential for synergy with NFV in its antileukemic activity. These include JQ1 (BET inhibitor), AT101 (Bcl-2 family inhibitor), and sunitinib (TK inhibitor).ConclusionHere, we show data demonstrating the potential of a previously unexplored group of drugs to address an unmet therapeutic need in pediatric oncology. The data presented provide preclinical supportive evidence and rationale for future studies of these agents for refractory leukemia in children.

Project description:We have used human umbilical vein endothelial cell line (HUVEC) as a model to investigate the effect of ultrasound (US) activated micro-bubbles on sensitizing the tumour response to radiation and to check the implication of this approach on gene expression. The use of micro-bubbles in cancer therapy is a novel approach that is being recently investigated, and patterns of gene expressions were not yet characterized. Gene analysis has identified about 19,264 genes; where, 239 – 517 genes have shown more than two folds up-regulation in response to the different treatments. This included a number of genes that are known to be involved in apoptosis and ceramide-induced apoptosis pathways, such as Sphingomyelin phosphodiesterase 2, neutral sphingomyelinase (SMPD2), sphingomyelin phosphodiesterase 1, acid lysosomal (ASM; SMPD1), UDP-galactose ceramide galactosyltransferase (UGT8), cytochrome c oxidase (COX6B1), Caspase-9 and mitogen-activated protein kinase kinase 1 (MAP2K1). To verify these results, we have performed Real time RT-PCR, which indicated an up-regulation that ranged from 2 to 200 folds, specifically in the combined treatment of US, 3.3% micro-bubbles and 8 Gy. The observed higher levels of expression of UGT8, SMPD2 and Caspase 9-alpha when compared to the control or to radiation only indicated the involvement of ceramide, which possibly induces apoptosis . These results support the hypothesis that micro-bubbles play a role in increasing sensitization to radiation, and can prove to be an effective cancer therapeutic approach. Gene analysis has identified about 19,264 genes; where, 239 – 517 genes have shown more than two folds up-regulation in response to the different treatments. This included a number of genes that are known to be involved in apoptosis and ceramide-induced apoptosis pathways, such as Sphingomyelin phosphodiesterase 2, neutral sphingomyelinase (SMPD2), sphingomyelin phosphodiesterase 1, acid lysosomal (ASM; SMPD1), UDP-galactose ceramide galactosyltransferase (UGT8), cytochrome c oxidase (COX6B1), Caspase-9 and mitogen-activated protein kinase kinase 1 (MAP2K1). To verify these results, we have performed Real time RT-PCR, which indicated an up-regulation that ranged from 2 to 200 folds, specifically in the combined treatment of US, 3.3% micro-bubbles and 8 Gy. The observed higher levels of expression of UGT8, SMPD2 and Caspase 9-alpha when compared to the control or to radiation only indicated the involvement of ceramide, which possibly induces apoptosis . These results support the hypothesis that micro-bubbles play a role in increasing sensitization to radiation, and can prove to be an effective cancer therapeutic approach.

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A novel therapeutic approach for treatment of catamenial epilepsy.

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A novel therapeutic approach for treatment of catamenial epilepsy.

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