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International Journal of Molecular... May 2020-adenosylmethionine (SAMe) is involved in many transmethylation reactions in most living organisms and is also required in the synthesis of several substances such as... (Review)
Review
-adenosylmethionine (SAMe) is involved in many transmethylation reactions in most living organisms and is also required in the synthesis of several substances such as monoamine neurotransmitters and the N-methyl-D-aspartate (NMDA) receptor. Due to its important role as an epigenetic modulator, we discuss in some length the process of DNA methylation and demethylation and the critical periods of epigenetic modifications in the embryo, fetus, and thereafter. We also discuss the effects of SAMe deficiency and the attempts to use SAMe for therapeutic purposes such as the treatment of major depressive disorder, Alzheimer disease, and other neuropsychiatric disorders. SAMe is an approved food additive and as such is also used during pregnancy. Yet, there seems to scanty data on the possible effects of SAMe on the developing embryo and fetus. Valproic acid (VPA) is a well-tolerated and effective antiepileptic drug that is also used as a mood stabilizer. Due to its high teratogenicity, it is contraindicated in pregnancy. A major mechanism of its action is histone deacetylase inhibition, and therefore, it acts as an epigenetic modulator, mainly on the brain. This prompted clinical trials using VPA for additional indications i.e., treating degenerative brain disease such as Alzheimer disease, dementia, HIV, and even cancer. Therefore, we discuss the possible effects of VPA and SAMe on the conceptus and early postnatally, during periods of susceptibility to epigenetic modifications. VPA is also used as an inducer of autistic-like behavior in rodents and was found by us to modify gene expression when administered during the first postnatal week but not when administered to the pregnant dams on day 12 of gestation. In contrast, SAMe modified gene expression when administered on day 12 of pregnancy but not postnatally. If administered together, VPA prevented the changes in gene expression induced by prenatal SAMe administration, and SAMe prevented the gene expression changes and autistic-like behavior induced by early postnatal VPA. It is concluded that both VPA and SAMe are powerful epigenetic modifiers with antagonistic actions on the brain that will probably be used in the future more extensively for the treatment of a variety of epigenetic diseases of the nervous system.
Topics: Animals; Autism Spectrum Disorder; Epigenesis, Genetic; Female; Humans; Methionine; Nervous System; Pregnancy; Prenatal Exposure Delayed Effects; Valproic Acid
PubMed: 32466248
DOI: 10.3390/ijms21103721 -
International Journal of Molecular... Mar 2023The mechanisms of treatment-resistant epilepsy remain unclear. We have previously shown that frontline administration of therapeutic doses of lamotrigine (LTG), which...
The mechanisms of treatment-resistant epilepsy remain unclear. We have previously shown that frontline administration of therapeutic doses of lamotrigine (LTG), which preferentially inhibits the fast-inactivation state of sodium channels, during corneal kindling of mice promotes cross-resistance to several other antiseizure medicines (ASMs). However, whether this phenomenon extends to monotherapy with ASMs that stabilize the slow inactivation state of sodium channels is unknown. Therefore, this study assessed whether lacosamide (LCM) monotherapy during corneal kindling would promote future development of drug-resistant focal seizures in mice. Male CF-1 mice ( = 40/group; 18-25 g) were administered an anticonvulsant dose of LCM (4.5 mg/kg, i.p.), LTG (8.5 mg/kg, i.p.), or vehicle (0.5% methylcellulose) twice daily for two weeks during kindling. A subset of mice ( = 10/group) were euthanized one day after kindling for immunohistochemical assessment of astrogliosis, neurogenesis, and neuropathology. The dose-related antiseizure efficacy of distinct ASMs, including LTG, LCM, carbamazepine, levetiracetam, gabapentin, perampanel, valproic acid, phenobarbital, and topiramate, was then assessed in the remaining kindled mice. Neither LCM nor LTG administration prevented kindling: 29/39 vehicle-exposed mice were kindled; 33/40 LTG-exposed mice were kindled; and 31/40 LCM-exposed mice were kindled. Mice administered LCM or LTG during kindling became resistant to escalating doses of LCM, LTG, and carbamazepine. Perampanel, valproic acid, and phenobarbital were less potent in LTG- and LCM-kindled mice, whereas levetiracetam and gabapentin retained equivalent potency across groups. Notable differences in reactive gliosis and neurogenesis were also appreciated. This study indicates that early, repeated administration of sodium channel-blocking ASMs, regardless of inactivation state preference, promotes pharmacoresistant chronic seizures. Inappropriate ASM monotherapy in newly diagnosed epilepsy may thus be one driver of future drug resistance, with resistance being highly ASM class specific.
Topics: Male; Mice; Animals; Valproic Acid; Gabapentin; Levetiracetam; Anticonvulsants; Lamotrigine; Epilepsy; Seizures; Carbamazepine; Phenobarbital; Lacosamide
PubMed: 36902275
DOI: 10.3390/ijms24054848 -
CNS Drugs Jun 2023Antiseizure medication (ASM) as monotherapy or in combination is the treatment of choice for most patients with epilepsy. Therefore, knowledge about the typical adverse...
BACKGROUND
Antiseizure medication (ASM) as monotherapy or in combination is the treatment of choice for most patients with epilepsy. Therefore, knowledge about the typical adverse events (AEs) for ASMs and other coadministered drugs (CDs) is essential for practitioners and patients. Due to frequent polypharmacy, it is often difficult to clinically assess the AE profiles of ASMs and differentiate the influence of CDs.
OBJECTIVE
This retrospective analysis aimed to determine typical AE profiles for ASMs and assess the impact of CDs on AEs in clinical practice.
METHODS
The Liverpool AE Profile (LAEP) and its domains were used to identify the AE profiles of ASMs based on data from a large German multicenter study (Epi2020). Following established classifications, drugs were grouped according to their mode of action (ASMs) or clinical indication (CDs). Bivariate correlation, multivariate ordinal regression (MORA), and artificial neural network (ANNA) analyses were performed. Bivariate correlation with Fisher's z-transformation was used to compare the correlation strength of LAEP with the Hospital Anxiety and Depression Scale (HADS) and Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) to avoid LAEP bias in the context of antidepressant therapy.
RESULTS
Data from 486 patients were analyzed. The AE profiles of ASM categories and single ASMs matched those reported in the literature. Synaptic vesicle glycoprotein 2A (SV2A) and voltage-gated sodium channel (VGSC) modulators had favorable AE profiles, while brivaracetam was superior to levetiracetam regarding psychobehavioral AEs. MORA revealed that, in addition to seizure frequency, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) modulators and antidepressants were the only independent predictors of high LAEP values. After Fisher's z-transformation, correlations were significantly lower between LAEP and antidepressants than between LAEP and HADS or NDDI-E. Therefore, a bias in the results toward over interpreting the impact of antidepressants on LAEP was presumed. In the ANNA, perampanel, zonisamide, topiramate, and valproic acid were important nodes in the network, while VGSC and SV2A modulators had low relevance for predicting relevant AEs. Similarly, cardiovascular agents, analgesics, and antipsychotics were important CDs in the ANNA model.
CONCLUSION
ASMs have characteristic AE profiles that are highly reproducible and must be considered in therapeutic decision-making. Therapy using perampanel as an AMPA modulator should be considered cautiously due to its relatively high AE profile. Drugs acting via VGSCs and SV2A receptors are significantly better tolerated than other ASM categories or substances (e.g., topiramate, zonisamide, and valproate). Switching to brivaracetam is advisable in patients with psychobehavioral AEs who take levetiracetam. Because CDs frequently pharmacokinetically interact with ASMs, the cumulative AE profile must be considered.
TRIAL REGISTRATION
DRKS00022024, U1111-1252-5331.
Topics: Adult; Humans; Anticonvulsants; Levetiracetam; Topiramate; Zonisamide; Retrospective Studies; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Epilepsy; Valproic Acid
PubMed: 37271775
DOI: 10.1007/s40263-023-01013-8 -
Anais Da Academia Brasileira de Ciencias 2021Autism spectrum disorder is associated with alterations in GABAergic and glutamatergic neurotransmission. Here, we aimed to determine the concentration of GABA,...
Autism spectrum disorder is associated with alterations in GABAergic and glutamatergic neurotransmission. Here, we aimed to determine the concentration of GABA, glutamate, glutamine, aspartate, taurine, and glycine in brain tissue and plasma of rats prenatally exposed to valproic acid (VPA), a well-characterized experimental model of autism. Pregnant rats were injected with VPA (600mg/Kg) during the twelfth-embryonic-day. Control rats were injected with saline. On the fourteen-postnatal-day, rats from both groups (males and females) were anesthetized, euthanized by decapitation and their brain dissected out. The frontal cortex, hippocampus, amygdala, brain stem and cerebellum were dissected and homogenized. Homogenates were centrifuged and supernatants were used to quantify amino acid concentrations by HPLC coupled with fluorometric detection. Blood samples were obtained by a cardiac puncture; plasma was separated and deproteinized to quantify amino acid concentration by HPLC. We found that, in VPA rats, glutamate and glutamine concentrations were increased in hippocampus and glycine concentration was increased in cortex. We did not find changes in other regions or in plasma amino acid concentration in the VPA group with respect to control group. Our results suggest that VPA exposure in utero may impair inhibitory and excitatory amino acid transmission in the infant brain.
Topics: Amino Acids; Animals; Autism Spectrum Disorder; Brain; Female; Male; Plasma; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Valproic Acid
PubMed: 33729379
DOI: 10.1590/0001-3765202120190861 -
Molecular Therapy : the Journal of the... Dec 2020The clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 system plays an important role in prokaryotic adaptive immunity. Due to its capacity for...
The clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 system plays an important role in prokaryotic adaptive immunity. Due to its capacity for sequence-specific gene editing, CRISPR-Cas9 has become one of the most important tools widely used for genome editing in molecular biotechnology. However, its clinical application is currently limited by unwanted mutations at off-target sites. Various strategies have been developed for precise control of Cas9 in order to reduce these off-target effects, including chemical-based approaches. From a chemical screening, I observed that valproic acid (VPA) binds to and destabilizes Streptococcus pyogenes Cas9 (SpyCas9) protein in vitro, as well as in cells, while within its therapeutical concentration range under conditions of hyperthermia as demonstrated. Conditions were generated either by an external heat bag or in combination with the photothermal therapeutic agent indocyanine green activated by a near-infrared laser. Use of other histone deacetylase inhibitors failed, suggesting a histone deacetylase inhibition-independent function of VPA. Thus, this finding provides an uncomplicated thermotherapeutical approach for timely regulation of the activity of the CRISPR-Cas9 system at desired locations.
Topics: Bacterial Proteins; CRISPR-Associated Protein 9; CRISPR-Cas Systems; Enzyme Activation; Enzyme Inhibitors; Gene Editing; Hot Temperature; Indocyanine Green; Mutation; Protein Denaturation; Protein Stability; Streptococcus pyogenes; Valproic Acid
PubMed: 32882179
DOI: 10.1016/j.ymthe.2020.08.014 -
The Journal of Medical Investigation :... 2020Background : Cancer stem cell properties are highly relevant to the biology of treatment-resistant cancers. Epigenetic modification regulates gene expressions by...
Background : Cancer stem cell properties are highly relevant to the biology of treatment-resistant cancers. Epigenetic modification regulates gene expressions by chromatin remodeling during malignant transformation. The aim of this study was to elucidate the possible strategy for cancer stem cells focusing on epigenetic modification. Methods : We made cancer sphere from HepG2 cells, and we added Histone deacetylase (HDAC) inhibitor, valproic acid to cancer sphere. And we compared methylation status and the gene expression between normal HepG2 and cancer sphere groups, and between cancer sphere and sphere with HDAC inhibitor treatment groups. Results : Valproic acid (VPA) cancelled this spheroid formation. In comparison between normal HepG2 and cancer sphere, the number of methylation status changes more than 0.1 of beta level was 826 probes, and we could isolate some epithelial-mesenchymal transition (EMT) related genes. And VPA reduced the expressions of EMT related genes in sphere with RT-PCR. On the other hand, in comparison between cancer sphere and sphere with VPA treatment, we detected 29 probe of methylation status change, and VPA reduced the expressions of Bcl-6 in sphere. Conclusions : HDAC inhibitor affected the methylation status of cancer stem cells. Histone-acetylation might overcome treatmet-resistant cancer through the regulation of cancer stem cell. J. Med. Invest. 67 : 70-74, February, 2020.
Topics: DNA Methylation; Epithelial-Mesenchymal Transition; Hep G2 Cells; Histone Deacetylase Inhibitors; Humans; Neoplasms; Neoplastic Stem Cells; Spheroids, Cellular; Valproic Acid
PubMed: 32378621
DOI: 10.2152/jmi.67.70 -
Journal of the Formosan Medical... Apr 2021Therapeutic drug monitoring (TDM) is recommended during treatment with valproic acid (VPA), as is the measurement of free VPA concentration (MfVPA). However, MfVPA is...
BACKGROUND
Therapeutic drug monitoring (TDM) is recommended during treatment with valproic acid (VPA), as is the measurement of free VPA concentration (MfVPA). However, MfVPA is unavailable in many institutions. Based on the highly protein-bound characteristics of VPA, an albumin-adjusted formula has been proposed to predict free VPA concentration (PfVPA). Nevertheless, the factors affecting the accuracy of this formula remain unknown, as does the concordance between MfVPA and PfVPA.
METHODS
Adult patients receiving VPA and undergoing TDM were enrolled. Free and total serum concentration (TVPA) were categorized as subtherapeutic, therapeutic, or supratherapeutic based on the reference range of 5-15 and 50-100 μg/mL, respectively. Concordance was defined as MfVPA and PfVPA, or MfVPA and TVPA, falling within the same category. Multivariate logistic regression with generalized estimating equation was adopted to identify factors affecting concordance, and the receiver operating characteristic curve was applied to determine the cutoff values of predictors.
RESULTS
A total of 98 data points from 51 participants were included for analysis. The concordance of MfVPA and PfVPA, and MfVPA and TVPA, was 72% and 44%, respectively. Blood urea nitrogen (BUN) (0.97 [0.95-0.99], P = 0.01) and TVPA (0.97 [0.95-0.99], P = 0.02) had a significant influence on the concordance of MfVPA and PfVPA. The cutoff values of TVPA and BUN for the accuracy of the albumin-adjusted formula were 56.4 μg/mL and 51.05 mg/dL, respectively.
CONCLUSION
If MfVPA is not available, the albumin-adjusted formula should be applied before VPA dosage adjustment when TVPA is < 56.4 μg/mL and BUN is < 51.05 mg/dL.
Topics: Adult; Albumins; Anticonvulsants; Drug Monitoring; Humans; Reference Values; Valproic Acid
PubMed: 32978045
DOI: 10.1016/j.jfma.2020.09.004 -
The American Journal of Case Reports Dec 2020BACKGROUND Valproic acid is utilized for the management of various disease states, but coagulation changes, such as thrombocytopenia, can limit use. Valproic acid is a...
BACKGROUND Valproic acid is utilized for the management of various disease states, but coagulation changes, such as thrombocytopenia, can limit use. Valproic acid is a highly protein-bound drug. Serum levels of 50-100 mcg/mL are considered therapeutic, with minimal risk of toxicity when maintained within the recommended therapeutic index. We present a case of valproic acid-induced thrombocytopenia associated with spontaneous systemic bleeding. CASE REPORT A 57-year-old woman with history of generalized anxiety disorder and choreiform movements presented to the Emergency Department with 1 day of oral and vaginal bleeding. The patient had been started on valproic acid for choreiform movements 3 weeks prior. On physical exam, the patient was noted to have atraumatic contusions and ecchymosis. A CT head revealed left temporal frontal subdural hematoma (4.5 mm), acute subdural hematoma along the posterior aspect of the interhemispheric falx (5 mm), mass effect on the right lateral ventricle, and an approximately 3 mm right-to-left midline shift. Laboratory testing was notable for platelets 4000/μL, hemoglobin 7.3 g/dL, hematocrit 23.1%, fibrinogen 467 mg/dL, and valproic acid random level 26.3 μg/mL. Thromboelastography releveled normal values except for a decreased maximum amplitude of 33.4 mm. CONCLUSIONS Although the clinical relevance is still debated, few case reports of significant bleeding related to valproic acid-induced thrombocytopenia exist. To the best of our knowledge, this is the first case report of spontaneous systemic bleeding due to valproic acid-induced thrombocytopenia in the setting of normal fibrinogen levels. Furthermore, this report demonstrates the potential risk of thrombocytopenia with subtherapeutic VPA levels.
Topics: Anemia; Female; Hemorrhage; Humans; Middle Aged; Thrombocytopenia; Valproic Acid
PubMed: 33376233
DOI: 10.12659/AJCR.927830 -
Cells Jun 2020The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system has emerged as a powerful technology, with the potential to generate transgenic...
The clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system has emerged as a powerful technology, with the potential to generate transgenic animals. Particularly, efficient and precise genetic editing with CRISPR/Cas9 offers immense prospects in various biotechnological applications. Here, we report that the histone deacetylase inhibitor valproic acid (VPA) significantly increases the efficiency of CRISPR/Cas9-mediated gene editing in mouse embryonic stem cells and embryos. This effect may be caused through globally enhanced chromatin accessibility, as indicate by histone hyperacetylation. Taken together, our results suggest that VPA can be used to increase the efficacy of CRISPR/Cas9 in generating transgenic systems.
Topics: Animals; CRISPR-Cas Systems; Gene Editing; Humans; Mice; Mice, Transgenic; Valproic Acid
PubMed: 32532133
DOI: 10.3390/cells9061447 -
Progress in Neuro-psychopharmacology &... Apr 2024Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized mainly by deficits in social communication and stereotyped and restricted behavior and...
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized mainly by deficits in social communication and stereotyped and restricted behavior and interests with a male to female bias of 4.2/1. Social behavior in ASD animal models is commonly analyzed in males, and seldomly in females, using the widely implemented three-chambers test procedure. Here, we implemented a novel procedure, the Live Mouse Tracker (LMT), combining artificial intelligence, machine learning procedures and behavioral measures. We used it on mice that were prenatally exposed to valproic acid (VPA) (450 mg/kg) at embryonic day 12.5, a widely recognized and potent ASD model that we had previously extensively characterized. We focused on female mice offspring, in which social deficits have been rarely documented when using the 3-CT procedure. We recorded several parameters related to social behavior in these mice, continuously for three days in groups of four female mice. Comparisons were made on groups of 4 female mice with the same treatment (4 saline or 4 VPA) or with different treatments (3 saline and 1 VPA). We report that VPA females show several types of social deficits, which are different in nature and magnitude in relation with time. When VPA mice were placed in the LMT alongside saline mice, their social deficits showed significant improvement as early as 1 h from the start of the experiment, lasting up to 3 days throughout the duration of the experiment. Our findings suggest that ASD may be underdiagnosed in females. They also imply that ASD-related social deficits can be ameliorated by the presence of typical individuals.
Topics: Female; Male; Animals; Mice; Humans; Valproic Acid; Artificial Intelligence; Autism Spectrum Disorder; Social Behavior; Stereotyping; Prenatal Exposure Delayed Effects; Disease Models, Animal; Behavior, Animal
PubMed: 38244714
DOI: 10.1016/j.pnpbp.2024.110948