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Arquivos de Neuro-psiquiatria Dec 2023Migraine is one of the most prevalent and disabling diseases in the world. Migraine attack treatments and prophylactic treatments of this disease are essential to lessen... (Review)
Review
Migraine is one of the most prevalent and disabling diseases in the world. Migraine attack treatments and prophylactic treatments of this disease are essential to lessen its individual, social, and economic impact. This is a narrative review of the main drugs used for treating migraine, as well as the experimental models and the theoretical frameworks that led to their development. Ergot derivatives, triptans, non-steroid anti-inflammatory drugs, tricyclic antidepressants, beta-blockers,: flunarizine,: valproic acid,: topiramate, onabotulinumtoxin A, ditans, monoclonal antibodies against CGRP and its receptor, and gepants are discussed. Possible therapeutic targets for the development of new drugs that are under development are also addressed. Many of the drugs currently in use for treating migraine were developed for the treatment of other diseases, but have proven effective for the treatment of migraine, expanding knowledge about the disease. With a better understanding of the pathophysiology of migraine, new drugs have been and continue to be developed specifically for the treatment of this disease.
Topics: Humans; Migraine Disorders; Tryptamines; Calcitonin Gene-Related Peptide Receptor Antagonists; Valproic Acid; Anti-Inflammatory Agents, Non-Steroidal
PubMed: 38157876
DOI: 10.1055/s-0043-1777723 -
Molecules (Basel, Switzerland) May 2023Despite the strong anticancer activity of SN38 (7-ethyl-10-hydroxy-camptothecin), the severe side effects and loss of anticancer activity caused by the lack of...
Despite the strong anticancer activity of SN38 (7-ethyl-10-hydroxy-camptothecin), the severe side effects and loss of anticancer activity caused by the lack of selectivity to cancer cells and hydrolysis of ring E prevent its clinical application. To address the issue, herein a multifunctional SN38 derivative (compound ) containing biotin (tumor-targeting group) and valproic acid (histone deacetylase inhibitor, HDACi) was synthesized via click chemistry and evaluated using MTT assay. The in vitro cytotoxicity study showed that compound exhibited superior cytotoxicity than irinotecan against human cervical cancer HeLa cells, albeit it was inferior to SN38. More significantly, compound significantly reduced toxicity in mouse embryonic fibroblast NIH3T3 cells, indicating that compound had the capacity to enhance tumor targeting due to its cell selectivity. Further studies demonstrated that, compared with irinotecan, compound induced similar apoptosis of cancer cells. Consequently, compound can not only improve its tumor-targeting ability mediated by biotin but also exert potent anticancer activity through the effect of SN38 and valproic acid, indicating that the design concept is an effective strategy for the structural modification of SN38.
Topics: Animals; Humans; Mice; Irinotecan; Valproic Acid; Biotin; HeLa Cells; NIH 3T3 Cells; Cell Line, Tumor; Fibroblasts; Camptothecin; Antineoplastic Agents, Phytogenic
PubMed: 37175346
DOI: 10.3390/molecules28093936 -
Experimental & Molecular Medicine Aug 2023Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with impaired social behavior and communication, repetitive behaviors, and restricted...
Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with impaired social behavior and communication, repetitive behaviors, and restricted interests. In addition to genetic factors, environmental factors such as prenatal drug exposure contribute to the development of ASD. However, how those prenatal factors induce behavioral deficits in the adult stage is not clear. To elucidate ASD pathogenesis at the molecular level, we performed a high-resolution mass spectrometry-based quantitative proteomic analysis on the prefrontal cortex (PFC) of mice exposed to valproic acid (VPA) in utero, a widely used animal model of ASD. Differentially expressed proteins (DEPs) in VPA-exposed mice showed significant overlap with ASD risk genes, including differentially expressed genes from the postmortem cortex of ASD patients. Functional annotations of the DEPs revealed significant enrichment in the Wnt/β-catenin signaling pathway, which is dysregulated by the upregulation of Rnf146 in VPA-exposed mice. Consistently, overexpressing Rnf146 in the PFC impaired social behaviors and altered the Wnt signaling pathway in adult mice. Furthermore, Rnf146-overexpressing PFC neurons showed increased excitatory synaptic transmission, which may underlie impaired social behavior. These results demonstrate that Rnf146 is critical for social behavior and that dysregulation of Rnf146 underlies social deficits in VPA-exposed mice.
Topics: Animals; Female; Mice; Pregnancy; Autism Spectrum Disorder; Disease Models, Animal; Proteomics; Ubiquitin-Protein Ligases; Up-Regulation; Valproic Acid; Wnt Signaling Pathway
PubMed: 37524878
DOI: 10.1038/s12276-023-01065-2 -
Phytomedicine : International Journal... Apr 2024Osteosarcoma is the most prevalent malignant bone tumour with a poor prognosis. Shikonin (SHK) is derived from the traditional Chinese medicine Lithospermum that has...
BACKGROUND
Osteosarcoma is the most prevalent malignant bone tumour with a poor prognosis. Shikonin (SHK) is derived from the traditional Chinese medicine Lithospermum that has been extensively studied for its notable anti-tumour effects, including for osteosarcoma. However, its application has certain limitations. Valproic acid (VPA) is a histone deacetylase inhibitor (HDACI) that has recently been employed as an adjunctive therapeutic agent that allows chromatin to assume a more relaxed state, thereby enhancing anti-tumour efficacy.
PURPOSE
This study was aimed to investigate the synergistic anti-tumour efficacy of SHK in combination with VPA and elucidate its underlying mechanism.
METHODS/STUDY DESIGN
CCK-8 assays were utilized to calculate the combination index. Additional assays, including colony formation, acridine orange/ethidium bromide double fluorescent staining, and flow cytometry, were employed to evaluate the effects on osteosarcoma cells. Wound healing and transwell assays were utilized to assess cell mobility. RNA sequencing, PCR, and Western blot analyses were conducted to uncover the underlying mechanism. Rescue experiments were performed to validate the mechanism of apoptotic induction. The impact of SHK and VPA combination treatment on primary osteosarcoma cells was also assessed. Finally, in vivo experiments were conducted to validate its anti-tumour effects and mechanism.
RESULTS
The combination of SHK and VPA synergistically inhibited the proliferation and migration of osteosarcoma cells in vitro and induced apoptosis in these cells. Through a comprehensive analysis involving RNA sequencing, PCR, Western blot, and rescue experiments, we have substantiated our hypothesis that the combination of SHK and VPA induced apoptosis via the ROS-EGR1-Bax axis. Importantly, our in vivo experiments corroborated these findings, demonstrating the potential of the SHK and VPA combination as a promising therapeutic approach for osteosarcoma.
CONCLUSION
The combination of SHK and VPA exerted an anti-tumour effect by inducing apoptosis through the ROS-EGR1-Bax pathway. Repurposing the old drug VPA demonstrated its effectiveness as an adjunctive therapeutic agent for SHK, enhancing its anti-tumour efficacy and revealing its potential value. Furthermore, our study expanded the application of natural compounds in the anti-tumour field and overcame some of their limitations through combination therapy. Finally, we enhanced the understanding of the mechanistic pathways linking reactive oxygen species (ROS) accumulation and apoptosis in osteosarcoma cells. Additionally, we elucidated the role of EGR1 in osteosarcoma cells, offering novel strategies and concepts for the treatment of osteosarcoma.
Topics: Humans; Valproic Acid; Reactive Oxygen Species; bcl-2-Associated X Protein; Apoptosis; Osteosarcoma; Cell Line, Tumor; Bone Neoplasms; Cell Proliferation; Early Growth Response Protein 1; Naphthoquinones
PubMed: 38417243
DOI: 10.1016/j.phymed.2024.155459 -
International Journal of Molecular... Feb 2024Hepatocellular carcinoma (HCC) is among the main causes of death by cancer worldwide, representing about 80-90% of all liver cancers. Treatments available for advanced... (Review)
Review
Hepatocellular carcinoma (HCC) is among the main causes of death by cancer worldwide, representing about 80-90% of all liver cancers. Treatments available for advanced HCC include atezolizumab, bevacizumab, sorafenib, among others. Atezolizumab and bevacizumab are immunological options recently incorporated into first-line treatments, along with sorafenib, for which great treatment achievements have been reached. However, sorafenib resistance is developed in most patients, and therapeutical combinations targeting cancer hallmark mechanisms and intracellular signaling have been proposed. In this review, we compiled evidence of the mechanisms of cell death caused by sorafenib administered alone or in combination with valproic acid and metformin and discussed them from a molecular perspective.
Topics: Humans; Carcinoma, Hepatocellular; Sorafenib; Liver Neoplasms; Valproic Acid; Bevacizumab; Metformin; Cell Death
PubMed: 38339037
DOI: 10.3390/ijms25031760 -
Rhode Island Medical Journal (2013) Dec 2021Valproate is an antiepileptic medication that can be used to manage behavioral symptoms associated with Alzheimer's dementia. We present a rare case of valproate-induced...
INTRODUCTION
Valproate is an antiepileptic medication that can be used to manage behavioral symptoms associated with Alzheimer's dementia. We present a rare case of valproate-induced periorbital edema.
CASE
A 76-year-old man came to the emergency room with agitation and aggression. He was medically cleared and referred to a psychiatric facility where he was treated with haloperidol. When he developed drug-induced parkinsonism, the haloperidol was stopped, and the patient was started on valproate 250 mg twice daily. The day after valproate administration, the patient developed periorbital edema. After ruling out other causes of periorbital edema, adverse drug reaction was suspected. Valproate was discontinued, and the edema rapidly resolved within five days.
CONCLUSION
Periorbital edema is a rare side effect of valproate. It can occur in patients who are being treated with valproate for behavioral changes in Alzheimer's disease. The edema resolves with discontinuation of the medication.
Topics: Aged; Aggression; Alzheimer Disease; Edema; Humans; Male; Valproic Acid
PubMed: 34846373
DOI: No ID Found -
Acta Pharmaceutica (Zagreb, Croatia) Sep 2020Results from numerous pre-clinical studies suggest that a well known anticonvulsant drug valproic acid (VPA) and other short-chain fatty acids (SCFAs) cause significant... (Review)
Review
Results from numerous pre-clinical studies suggest that a well known anticonvulsant drug valproic acid (VPA) and other short-chain fatty acids (SCFAs) cause significant inhibition of cancer cell proliferation by modulating multiple signaling pathways. First of all, they act as histone deacetylase (HDAC) inhibitors (HDIs), being involved in the epigenetic regulation of gene expression. Afterward, VPA is shown to induce apoptosis and cell differentiation, as well as regulate Notch signaling. Moreover, it up-regulates the expression of certain G protein-coupled receptors (GPCRs), which are involved in various signaling pathways associated with cancer. As a consequence, some pre-clinical and clinical trials were carried out to estimate anticancer effectiveness of VPA, in monotherapy and in new drug combinations, while other SCFAs were tested in pre-clinical studies. The present manuscript summarizes the most important information from the literature about their potent anticancer activities to show some future perspectives related to epigenetic therapy.
Topics: Anticonvulsants; Antineoplastic Agents; Apoptosis; Cell Differentiation; Cell Proliferation; Epigenesis, Genetic; Fatty Acids, Volatile; Histone Deacetylase Inhibitors; Humans; Neoplasms; Valproic Acid
PubMed: 32074065
DOI: 10.2478/acph-2020-0021 -
Biomedicine & Pharmacotherapy =... Oct 2021Valproic acid (VPA) is an approved drug for managing epileptic seizures, bipolar disorders, and migraine. VPA has been shown to elevate the level of gamma-aminobutyric... (Review)
Review
Valproic acid (VPA) is an approved drug for managing epileptic seizures, bipolar disorders, and migraine. VPA has been shown to elevate the level of gamma-aminobutyric acid (GABA) in the brain through competitive inhibition of GABA transaminase, thus promoting the availability of synaptic GABA and facilitating GABA-mediated responses. VPA, which is a small chain of fatty acids, prevents histone deacetylases (HDACs). HDACs play a crucial role in chromatin remodeling and gene expression through posttranslational changes of chromatin-associated histones. Recent studies reported a possible effect of VPA against particular types of cancers. This effect was partially attributed to its role in regulating epigenetic modifications through the inhibition of HDACs, which affect the expression of genes associated with cell cycle control, cellular differentiation, and apoptosis. In this review, we summarize the current information on the actions of VPA in diseases such as diabetes mellitus, kidney disorders, neurodegenerative diseases, muscular dystrophy, and cardiovascular disorders.
Topics: Animals; Anticonvulsants; Apoptosis; Epigenesis, Genetic; GABA Agents; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Valproic Acid
PubMed: 34463268
DOI: 10.1016/j.biopha.2021.112021 -
Seizure Dec 2019Numerous studies have shown that the risk of fracture is increased by long-term antiepileptic drugs (AEDs). Valproic acid (VPA) is one of the most commonly used AEDs. In... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Numerous studies have shown that the risk of fracture is increased by long-term antiepileptic drugs (AEDs). Valproic acid (VPA) is one of the most commonly used AEDs. In this meta-analysis, we aimed to assess the effects of VPA on bone mineral density (BMD) and bone metabolism.
METHODS
PubMed, Embase, Cochrane and Web of Science databases were searched from inception to January 2019 for articles focusing on the effects of VPA on BMD and bone metabolism in adults or children. A meta-analysis was performed using RevMan 5. 3 software.
RESULTS
18 studies were included in the meta-analysis. The BMD of lumber spine (MD= -0.06, 95%CI: -0.09 to -0.03, P < 0.0001) and femoral neck (MD= -0.05, 95% CI= -0.08 to -0.01, P = 0.02) was markedly decreased in the VPA group compared to healthy controls. Serum bone-specific alkaline phosphatase (BALP) level (SMD = 0.85, 95% CI: 0.30-1.40, P = 0.002) was notably increased in the VPA group compared to healthy groups. In the child group, the serum parathyroid hormone (PTH) level was higher than in healthy groups (SMD= -0.22, 95% CI: -0.40 to -0.04, P = 0.02); besides, the serum 25-hydroxy vitamin D3 (25(OH)D3) level was decreased (SMD= -0.22, 95% CI: -0.40 to -0.04, P = 0.02), while no significant alteration of these parameters was noted in the adult VPA group (P ≥ 0.05).
CONCLUSIONS
VPA may reduce the BMD of lumbar spine and femoral neck in patients with epilepsy while increasing the serum BALP level. Serum PTH level are increased and serum 25(OH)D3 level decreased in children with epilepsy treated with VPA. These parameters were unaltered in adults.
Topics: Anticonvulsants; Bone Density; Bone and Bones; Epilepsy; Humans; Valproic Acid
PubMed: 31756600
DOI: 10.1016/j.seizure.2019.10.017 -
Revista Do Colegio Brasileiro de... 2022to recognize the effects of valproic acid (VPA), an epigenetic drug, on the bladder healing process, in rats.
PURPOSE
to recognize the effects of valproic acid (VPA), an epigenetic drug, on the bladder healing process, in rats.
METHOD
twenty male Wistar rats were divided in two groups: experimental (A), treated with VPA (150mg/Kg/day), and control (B) with 0.9% sodium chloridrate. Healing was analyzed on the third and seventh days, evaluating the inflammatory reaction, collagen synthesis and angiogenesis.
RESULTS
inflammatory reaction on the third day was minimal and acute in both groups. On the seventh day, it was subacute in both groups, moderate intensity in group A and minimal in group B (p=0.0476). Collagen III intensity, marked by immunohistochemistry, was similar in both groups. Collagen I intensity on the third day was similar in both groups, but on the seventh day it was higher in experimental than control (p=0.0476). Collagen evaluation by picrosiriusred allowed to verify that the presence of collagen III was similar in both groups (p=0.3312) on the third day, and it was higher in control on the seventh day (p=0.0015). Collagen I showed similarity on the third day (p=0.3100), and it was higher in control on the seventh day (p=0.0015). Vessel marked with anti-SMA counting showed fewer vessels on the third (p=0.0034) and seventh day (p=0.0087) in experimental group. The lower intensity of angiogenesis was confirmed with anti-CD34, on the third day (p=0,0006) and on the seventh day (p=0,0072).
CONCLUSION
VPA determined alterations in the bladder healing process, in rats, with lower collagen density and less angiogenic activity, but without compromising the integrity of the organ.
Topics: Male; Rats; Animals; Valproic Acid; Rats, Wistar; Urinary Bladder; Inflammation; Wound Healing
PubMed: 36449944
DOI: 10.1590/0100-6991e-20223399-en