Valproic Acid and Epilepsy: From Molecular Mechanisms to Clinical Evidences

After more than a century from its discovery, valproic acid (VPA) still represents one of the most efficient antiepileptic drugs (AEDs). Pre and post-synaptic effects of VPA depend on a very broad spectrum of actions, including the regulation of ionic currents and the facilitation of GABAergic over glutamatergic transmission. As a result, VPA indirectly modulates neurotransmitter release and strengthens the threshold for seizure activity. However, even though participating to the anticonvulsant action, such mechanisms seem to have minor impact on epileptogenesis. Nonetheless, VPA has been reported to exert anti-epileptogenic effects. Epigenetic mechanisms, including histone deacetylases (HDACs), BDNF and GDNF modulation are pivotal to orientate neurons toward a neuroprotective status and promote dendritic spines organization. From such broad spectrum of actions comes constantly enlarging indications for VPA. It represents a drug of choice in child and adult with epilepsy, with either general or focal seizures, and is a consistent and safe IV option in generalized convulsive status epilepticus. Moreover, since VPA modulates DNA transcription through HDACs, recent evidences point to its use as an anti-nociceptive in migraine prophylaxis, and, even more interestingly, as a positive modulator of chemotherapy in cancer treatment. Furthermore, VPA-induced neuroprotection is under investigation for benefit in stroke and traumatic brain injury. Hence, VPA has still got its place in epilepsy, and yet deserves attention for its use far beyond neurological diseases. In this review, we aim to highlight, with a translational intent, the molecular basis and the clinical indications of VPA.

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Valproic Acid Protects Primary Dopamine Neurons from MPP+-Induced Neurotoxicity: Involvement of GSK3βPhosphorylation by Akt and ERK through the Mitochondrial Intrinsic Apoptotic Pathway

BioMed Research International ◽

10.1155/2017/8124501 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Chi Zhang ◽

Xianrui Yuan ◽

Zhongliang Hu ◽

Songlin Liu ◽

Haoyu Li ◽

...

Keyword(s):

Valproic Acid ◽

Molecular Mechanisms ◽

Glycogen Synthase ◽

Neurological Diseases ◽

Neuroprotective Effect ◽

Dopamine Neurons ◽

Intrinsic Apoptotic Pathway ◽

Apoptotic Pathway ◽

Neuroprotective Effects ◽

Mitogen Activated Protein

Valproic acid (VPA), a drug widely used to treat manic disorder and epilepsy, has recently shown neuroprotective effects in several neurological diseases, particularly in Parkinson’s disease (PD). The goal of the present study was to confirm VPA’s dose-dependent neuroprotective propensities in the MPP+model of PD in primary dopamine (DA) neurons and to investigate the underlying molecular mechanisms using specific mitogen-activated protein kinases (MAPKs) and phosphatidylinositol 3-kinase- (PI3K-) Akt signaling inhibitors. VPA reversed MPP+-induced mitochondrial apoptosis and counteracted MPP+-induced extracellular signal-regulated kinase (ERK) and Akt repression and inhibited glycogen synthase kinase 3β(GSK3β) activation through induction of GSK3βphosphorylation. Moreover, inhibitors of the PI3K and MAPK pathways abolished GSK3βphosphorylation and diminished the VPA-induced neuroprotective effect. These findings indicated that VPA’s neuroprotective effect in the MPP+-model of PD is associated with GSK3βphosphorylation via Akt and ERK activation in the mitochondrial intrinsic apoptotic pathway. Thus, VPA may be a promising therapeutic candidate for clinical treatment of PD.

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POS0428 REGULATION OF IFN SIGNATURE BY HDAC CLASS IIa-CD52 AXIS IN SYSTEMIC SCLEROSIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2869 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 442.2-443

Author(s):

M. Rudnik ◽

A. Hukara ◽

P. Blyszczuk ◽

O. Distler ◽

G. Kania

Keyword(s):

Valproic Acid ◽

Systemic Sclerosis ◽

Pathway Analysis ◽

Histone Deacetylases ◽

Molecular Mechanisms ◽

Cell Receptor ◽

Type I ◽

Illumina Hiseq ◽

Induced Expression ◽

Protein Levels

Background:Systemic sclerosis (SSc) is associated with an interferon (IFN) signature, which is defined by a higher expression of IFN-stimulated genes (mainly in response to IFNα). Histone deacetylases (HDACs) are a family of epigenetic modifiers mediating immune function. HDACs function via diverse molecular mechanisms, including direct inhibition of gene transcription or indirectly through modulation of nuclear transcription factors such as NF-κB and STATs. CD52 protein regulates T cell receptor and NF-κB signalling. Previously, we showed downregulation of CD52 in SSc monocytes, however, the influence of CD52 on IFN signalling has not been studied yet.Objectives:We investigated the role of CD52 in the regulation of IFN response in monocytes. Moreover, we explored the regulatory mechanisms of CD52 expression to identify the involvement of HDACs in that process.Methods:RNAseq of CD14+ monocytes isolated from peripheral blood of lcSSc (n=5, age=54.4±6.7), dcSSc patients (n=5, age=51.8±7.2) and age- and sex-matched healthy controls (HC) (n=5, age=50.8±9.7) was performed using Illumina HiSeq 4000 platform. Differentially expressed genes were computed using DeSEQ2 algorithm. Gene ontology and pathway analysis were performed using Metacore software and ShinyApp. CD52 activity in monocytes was blocked by monoclonal antibody Alemtuzumab [10ug/ml] and IFN signature genes expression was assessed upon IFNα stimulation [1ng/ml] by qPCR and ELISA. HDAC-dependent regulation of CD52 expression in CD14+ monocytes from HC was analysed on mRNA and protein levels after treatment with pan-HDAC inhibitor valproic acid and HDAC class IIa inhibitor TMP269 [both 2.5μM].Results:Pathway analysis revealed significant alterations in interferon signalling in SSc monocytes. Monocytes treated with Alemtuzumab and IFNα showed induced expression of STAT1 (p=0.023, N=4), CXCL9 (p=0.062, N=4) and CXCL10 (p=0.005, N=4). RNAseq revealed a specific HDAC expression pattern in SSc monocytes with induced expression of HDAC4, 6, 10, 11 (p<0.05) and reduced HDAC1, 3 and 8 (p<0.05). CD52 mRNA was significantly decreased after IFNα stimulation (p=0.001, N=3). Treatment with valproic acid and HDAC class IIa inhibitor TMP269 resulted in decreased phosphorylation of STAT1 (p<0.01, N=4) followed by a declined level of CXCL10 (p<0.01, N=4) and restored level of CD52 mRNA (p<0.001, N=4).Conclusion:Our findings demonstrated a new aspect of pro-inflammatory type I IFN signalling in SSc. We described a novel regulation feedback loop in monocytes, in which CD52 suppresses IFN signature, while its expression is inhibited by IFN-induced HDAC activity (mainly HDAC class IIa). Therefore, targeting the CD52-IFN-HDAC axis might serve as a novel therapeutic strategy in SSc.Disclosure of Interests:Michal Rudnik: None declared, Amela Hukara: None declared, Przemyslaw Blyszczuk: None declared, Oliver Distler Speakers bureau: Actelion, Bayer, Boehringer Ingelheim, Medscape, Novartis, Roche, Menarini, Mepha, MSD, iQone, Novartis, Pfizer, Consultant of: Abbvie, Actelion, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, ChemomAb, Corpuspharma, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, Kymera, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi, UCB, Lilly, Target BioScience, Pfizer, Grant/research support from: Actelion, Bayer, Boehringer Ingelheim, Kymera Therapeutics, Mitsubishi Tanabe, Gabriela Kania: None declared

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Role of Long Non-Coding RNA Polymorphisms in Cancer Chemotherapeutic Response

Journal of Personalized Medicine ◽

10.3390/jpm11060513 ◽

2021 ◽

Vol 11 (6) ◽

pp. 513

Author(s):

Zheng Zhang ◽

Meng Gu ◽

Zhongze Gu ◽

Yan-Ru Lou

Keyword(s):

Molecular Mechanisms ◽

Neurological Diseases ◽

Cellular Processes ◽

Dna And Rna ◽

Chemotherapeutic Response ◽

Non Coding Rna ◽

Response To Chemotherapy ◽

Personalized Oncology ◽

Long Non Coding Rna

Genetic polymorphisms are defined as the presence of two or more different alleles in the same locus, with a frequency higher than 1% in the population. Since the discovery of long non-coding RNAs (lncRNAs), which refer to a non-coding RNA with a length of more than 200 nucleotides, their biological roles have been increasingly revealed in recent years. They regulate many cellular processes, from pluripotency to cancer. Interestingly, abnormal expression or dysfunction of lncRNAs is closely related to the occurrence of human diseases, including cancer and degenerative neurological diseases. Particularly, their polymorphisms have been found to be associated with altered drug response and/or drug toxicity in cancer treatment. However, molecular mechanisms are not yet fully elucidated, which are expected to be discovered by detailed studies of RNA–protein, RNA–DNA, and RNA–lipid interactions. In conclusion, lncRNAs polymorphisms may become biomarkers for predicting the response to chemotherapy in cancer patients. Here we review and discuss how gene polymorphisms of lncRNAs affect cancer chemotherapeutic response. This knowledge may pave the way to personalized oncology treatments.

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Preliminary Results Regarding Sleep in a Zebrafish Model of Autism Spectrum Disorder

Brain Sciences ◽

10.3390/brainsci11050556 ◽

2021 ◽

Vol 11 (5) ◽

pp. 556

Author(s):

Madalina Andreea Robea ◽

Alin Ciobica ◽

Alexandrina-Stefania Curpan ◽

Gabriel Plavan ◽

Stefan Strungaru ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Valproic Acid ◽

Social Behavior ◽

Antiepileptic Drug ◽

Alternative Model ◽

Neurological Diseases ◽

Autism Spectrum ◽

Spectrum Disorder ◽

Zebrafish Model ◽

Developmental Defects

Autism spectrum disorder (ASD) is one of the most salient developmental neurological diseases and remarkable similarities have been found between humans and model animals of ASD. A common method of inducing ASD in zebrafish is by administrating valproic acid (VPA), which is an antiepileptic drug that is strongly linked with developmental defects in children. In the present study we replicated and extended the findings of VPA on social behavior in zebrafish by adding several sleep observations. Juvenile zebrafish manifested hyperactivity and an increase in ASD-like social behaviors but, interestingly, only exhibited minimal alterations in sleep. Our study confirmed that VPA can generate specific ASD symptoms, indicating that the zebrafish is an alternative model in this field of research.

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Molecular mechanisms of metabotropic GABAB receptor function

Science Advances ◽

10.1126/sciadv.abg3362 ◽

2021 ◽

Vol 7 (22) ◽

pp. eabg3362

Author(s):

Hamidreza Shaye ◽

Benjamin Stauch ◽

Cornelius Gati ◽

Vadim Cherezov

Keyword(s):

G Protein ◽

Molecular Mechanisms ◽

Gabab Receptor ◽

Neurological Diseases ◽

Activation Mechanism ◽

Allosteric Modulators ◽

Inhibitory Neurotransmitter ◽

Therapeutic Drugs ◽

G Protein Coupled ◽

The Brain

Metabotropic γ-aminobutyric acid G protein–coupled receptors (GABAB) represent one of the two main types of inhibitory neurotransmitter receptors in the brain. These receptors act both pre- and postsynaptically by modulating the transmission of neuronal signals and are involved in a range of neurological diseases, from alcohol addiction to epilepsy. A series of recent cryo-EM studies revealed critical details of the activation mechanism of GABAB. Structures are now available for the receptor bound to ligands with different modes of action, including antagonists, agonists, and positive allosteric modulators, and captured in different conformational states from the inactive apo to the fully active state bound to a G protein. These discoveries provide comprehensive insights into the activation of the GABAB receptor, which not only broaden our understanding of its structure, pharmacology, and physiological effects but also will ultimately facilitate the discovery of new therapeutic drugs and neuromodulators.

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Molecular mechanisms of cell death in neurological diseases

Cell Death and Differentiation ◽

10.1038/s41418-021-00814-y ◽

2021 ◽

Author(s):

Diane Moujalled ◽

Andreas Strasser ◽

Jeffrey R. Liddell

Keyword(s):

Cell Death ◽

Neurodegenerative Diseases ◽

Molecular Mechanisms ◽

Neuronal Development ◽

Neurological Diseases ◽

Treatment Strategies ◽

Current Treatment ◽

Response To Therapy ◽

Signalling Cascades ◽

The Brain

AbstractTightly orchestrated programmed cell death (PCD) signalling events occur during normal neuronal development in a spatially and temporally restricted manner to establish the neural architecture and shaping the CNS. Abnormalities in PCD signalling cascades, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and cell death associated with autophagy as well as in unprogrammed necrosis can be observed in the pathogenesis of various neurological diseases. These cell deaths can be activated in response to various forms of cellular stress (exerted by intracellular or extracellular stimuli) and inflammatory processes. Aberrant activation of PCD pathways is a common feature in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, resulting in unwanted loss of neuronal cells and function. Conversely, inactivation of PCD is thought to contribute to the development of brain cancers and to impact their response to therapy. For many neurodegenerative diseases and brain cancers current treatment strategies have only modest effect, engendering the need for investigations into the origins of these diseases. With many diseases of the brain displaying aberrations in PCD pathways, it appears that agents that can either inhibit or induce PCD may be critical components of future therapeutic strategies. The development of such therapies will have to be guided by preclinical studies in animal models that faithfully mimic the human disease. In this review, we briefly describe PCD and unprogrammed cell death processes and the roles they play in contributing to neurodegenerative diseases or tumorigenesis in the brain. We also discuss the interplay between distinct cell death signalling cascades and disease pathogenesis and describe pharmacological agents targeting key players in the cell death signalling pathways that have progressed through to clinical trials.

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Valproic acid Suppresses Breast Cancer Cell Growth Through Triggering Pyruvate Kinase M2 Isoform Mediated Warburg Effect

Cell Transplantation ◽

10.1177/09636897211027524 ◽

2021 ◽

Vol 30 ◽

pp. 096368972110275

Author(s):

Zhen Li ◽

Lina Yang ◽

Shuai Zhang ◽

Jiaqi Song ◽

Huanran Sun ◽

...

Keyword(s):

Breast Cancer ◽

Valproic Acid ◽

Cancer Therapy ◽

Pyruvate Kinase ◽

Histone Deacetylases ◽

Warburg Effect ◽

Broad Class ◽

Pyruvate Kinase M2 ◽

Breast Cancer Cell Growth ◽

The Warburg Effect

Energy metabolism programming is a hallmark of cancer, and serves as a potent target of cancer therapy. Valproic acid (VPA), a broad Class I histone deacetylases (HDACs) inhibitor, has been used as a therapeutic agent for cancer. However, the detail mechanism about the potential role of VPA on the Warburg effect in breast cancer remains unclear. In this study, we highlight that VPA significantly attenuates the Warburg effect by decreasing the expression of pyruvate kinase M2 isoform (PKM2), leading to inhibited cell proliferation and reduced colony formation in breast cancer MCF-7 and MDA-MB-231 cells. Mechanistically, Warburg effect suppression triggered by VPA was mediated by inactivation of ERK1/2 phosphorylation through reduced HDAC1 expression, resulting in suppressing breast cancer growth. In summary, we uncover a novel mechanism of VPA in regulating the Warburg effect which is essential for developing the effective approach in breast cancer therapy.

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Monoclonal Antibodies as Neurological Therapeutics

Pharmaceuticals ◽

10.3390/ph14020092 ◽

2021 ◽

Vol 14 (2) ◽

pp. 92

Author(s):

Panagiotis Gklinos ◽

Miranta Papadopoulou ◽

Vid Stanulovic ◽

Dimos D. Mitsikostas ◽

Dimitrios Papadopoulos

Keyword(s):

Monoclonal Antibodies ◽

Molecular Mechanisms ◽

Neurological Diseases ◽

Therapeutic Agents ◽

Medical Specialties ◽

Specific Effects ◽

Different Types ◽

Neurological Conditions ◽

Disease Pathways

Over the last 30 years the role of monoclonal antibodies in therapeutics has increased enormously, revolutionizing treatment in most medical specialties, including neurology. Monoclonal antibodies are key therapeutic agents for several neurological conditions with diverse pathophysiological mechanisms, including multiple sclerosis, migraines and neuromuscular disease. In addition, a great number of monoclonal antibodies against several targets are being investigated for many more neurological diseases, which reflects our advances in understanding the pathogenesis of these diseases. Untangling the molecular mechanisms of disease allows monoclonal antibodies to block disease pathways accurately and efficiently with exceptional target specificity, minimizing non-specific effects. On the other hand, accumulating experience shows that monoclonal antibodies may carry class-specific and target-associated risks. This article provides an overview of different types of monoclonal antibodies and their characteristics and reviews monoclonal antibodies currently in use or under development for neurological disease.

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First person – Fanny Jaudon and Martina Albini

Journal of Cell Science ◽

10.1242/jcs.259251 ◽

2021 ◽

Vol 134 (16) ◽

Keyword(s):

Neurotrophic Factor ◽

Neurological Disorders ◽

Molecular Mechanisms ◽

Neurological Diseases ◽

Early Career ◽

First Person ◽

Early Career Researchers ◽

And Function ◽

The University ◽

Selection Of

ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping early-career researchers promote themselves alongside their papers. Fanny Jaudon and Martina Albini are co-first authors on ‘ A developmental stage- and Kidins220-dependent switch in astrocyte responsiveness to brain-derived neurotrophic factor’, published in JCS. Fanny is a postdoc at the University of Trieste in the lab of Lorenzo A. Cingolani at Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genova, Italy, investigating the molecular mechanisms controlling development and function of neuronal circuits and implementing genome-editing approaches for the treatment of neurological disorders. Martina is a PhD student at the Istituto Italiano di Tecnologia in the lab of Fabio Benfenati and Fabrizia Cesca investigating neurotrophin biology and its involvement in neurological diseases.

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AMP-Activated Protein Kinase as a Key Trigger for the Disuse-Induced Skeletal Muscle Remodeling

International Journal of Molecular Sciences ◽

10.3390/ijms19113558 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3558 ◽

Cited By ~ 13

Author(s):

Natalia Vilchinskaya ◽

Igor Krivoi ◽

Boris Shenkman

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Histone Deacetylases ◽

Molecular Mechanisms ◽

Weight Bearing ◽

Mammalian Target Of Rapamycin ◽

Adenosine Monophosphate ◽

Chain Gene ◽

Mtorc1 Signaling ◽

The Impact

Molecular mechanisms that trigger disuse-induced postural muscle atrophy as well as myosin phenotype transformations are poorly studied. This review will summarize the impact of 5′ adenosine monophosphate -activated protein kinase (AMPK) activity on mammalian target of rapamycin complex 1 (mTORC1)-signaling, nuclear-cytoplasmic traffic of class IIa histone deacetylases (HDAC), and myosin heavy chain gene expression in mammalian postural muscles (mainly, soleus muscle) under disuse conditions, i.e., withdrawal of weight-bearing from ankle extensors. Based on the current literature and the authors’ own experimental data, the present review points out that AMPK plays a key role in the regulation of signaling pathways that determine metabolic, structural, and functional alternations in skeletal muscle fibers under disuse.

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