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Cellular and Molecular Neurobiology Oct 2021The lack of an effective pharmaceutical agent for spinal cord injury (SCI) is a current problematic situation for clinicians, as the rate of motor vehicle accidents... (Review)
Review
The lack of an effective pharmaceutical agent for spinal cord injury (SCI) is a current problematic situation for clinicians, as the rate of motor vehicle accidents among young adults is on the rise. SCI contributes to the high disability rate. Presently, evidences detailing the precise pathological mechanisms in SCI are limited, compounding to the unavailability of an effective treatment method. Surgery, though not a complete curative method, is useful in managing some of the associated symptoms of secondary SCI. Autophagy and inflammation are contributive factors to both exacerbation and improvement of SCI. The mammalian target of rapamycin (mTOR) signaling pathway is a key player in the regulation of inflammatory response and autophagy. Valproic acid (VPA), a clinically used antiepileptic drug, has been suggested to improve neurological conditions, including SCI. This report reviewed the correlation between mTOR and autophagy, as well as autophagy's role and the therapeutic effects of VPA in SCI. VPA regulates autophagy by potentially inhibiting mTORC1, a complex of mTOR, while also hindering inflammatory response. Conclusively, an effective treatment for SCI could lie in the timely regulation of mTOR signaling pathway, and VPA could be the potential drug that improves SCI owing to its propensity to regulate the mTOR signaling pathway.
Topics: Animals; Autophagy; Recovery of Function; Spinal Cord; Spinal Cord Injuries; TOR Serine-Threonine Kinases; Valproic Acid
PubMed: 32725456
DOI: 10.1007/s10571-020-00929-9 -
BMJ (Clinical Research Ed.) Apr 2018
Topics: Abnormalities, Drug-Induced; Anticonvulsants; Epilepsy; Female; Humans; Pregnancy; Pregnancy Complications; Prenatal Exposure Delayed Effects; Valproic Acid
PubMed: 29669728
DOI: 10.1136/bmj.k1609 -
Neurochemical Research Oct 2016Valproic acid (VPA) has been used to treat epileptic seizures for decades, but it may also possess therapeutic potential in other nervous system diseases. However, VPA...
Valproic acid (VPA) has been used to treat epileptic seizures for decades, but it may also possess therapeutic potential in other nervous system diseases. However, VPA is extensively bound to plasma proteins, asymmetrically transported across the blood-brain barrier and metabolized to toxic species in the liver, which all contribute to its severe off-target adverse effects and possible drug-drug interactions. In this study, we evaluated seven amino acid prodrugs of VPA that were targeted to utilize L-type amino acid transporter 1 (LAT1), if they could alter the brain uptake mechanism and systemic pharmacokinetics of VPA. All prodrugs had affinity for LAT1 studied as competitive inhibition of [C]-L-leucine in human breast cancer (MCF-7) cell line. However, since the ester prodrugs were unstable they were not studied further, instead the corresponding amide prodrugs were used to evaluate their systemic pharmacokinetics in rats and the uptake mechanism via LAT1 into the rat brain. All amide prodrugs were bound to a lesser extent to plasma proteins than VPA and this being independent of the prodrug concentration. Amide prodrugs were also delivered into the brain after intravenous bolus injection. One of the prodrug showed greater brain uptake and high selectivity for LAT1 and it was able to release VPA slowly within the brain. Therefore, it was concluded that the VPA brain concentrations can be stabilized as well as the problematic pharmacokinetic profile can be altered by a LAT1-selective prodrug.
Topics: Amino Acids; Animals; Biological Transport; Blood-Brain Barrier; Brain; Humans; Injections, Intravenous; Prodrugs; Rats; Valproic Acid
PubMed: 27412117
DOI: 10.1007/s11064-016-1996-8 -
Handbook of Clinical Neurology 2023Though clearly described as far back as the 17th century, chronic migraine has defied precise categorization and has continued to develop as an important diagnostic...
Though clearly described as far back as the 17th century, chronic migraine has defied precise categorization and has continued to develop as an important diagnostic concept with significant societal impact. Worldwide prevalence is estimated to be between 1% and 3%, and these patients form a dynamic group cycling between chronic and episodic migraine. Theories of pathogenesis are developing supported by recent imaging and other findings. Of the many determinants of progression to chronic migraine, overuse of acute abortive headache medications may be one of the most important modifiable factors. Treatment strategies, in addition to educational measures, have included various preventive migraine medications such as topiramate, valproate, and onabotulinumtoxinA. CGRP monoclonal antibodies are efficacious for the management of chronic migraine both with and without medication overuse.
Topics: Humans; Migraine Disorders; Prescription Drug Overuse; Valproic Acid
PubMed: 38043961
DOI: 10.1016/B978-0-12-823356-6.00008-1 -
The Journal of Trauma and Acute Care... Aug 2020The leading causes of death in military conflicts continue to be hemorrhagic shock (HS) and traumatic brain injury (TBI). Most of the mortality is a result of patients... (Review)
Review
The leading causes of death in military conflicts continue to be hemorrhagic shock (HS) and traumatic brain injury (TBI). Most of the mortality is a result of patients not surviving long enough to obtain surgical care. As a result, there is a significant unmet need for a therapy that stimulates a "prosurvival phenotype" that counteracts the cellular pathophysiology of HS and TBI to prolong survival. Valproic acid (VPA), a well-established antiepileptic therapy for more than 50 years, has shown potential as one such prosurvival therapy. This review details how VPA's role as a nonselective histone deacetylase inhibitor induces cellular changes that promote survival and decrease cellular pathways that lead to cell death. The review comprehensively covers more than two decades worth of studies ranging from preclinical (mice, swine) to recent human clinical trials of the use of VPA in HS and TBI. Furthermore, it details the different mechanisms in which VPA alters gene expression, induces cytoprotective changes, attenuates platelet dysfunction, provides neuroprotection, and enhances survival in HS and TBI. Valproic acid shows real promise as a therapy that can induce the prosurvival phenotype in those injured during military conflict.
Topics: Animals; Armed Conflicts; Brain Injuries, Traumatic; Gene Expression; Histone Deacetylase Inhibitors; Humans; Kaplan-Meier Estimate; Military Medicine; Military Personnel; Resuscitation; Shock, Hemorrhagic; Valproic Acid; War-Related Injuries
PubMed: 32282756
DOI: 10.1097/TA.0000000000002721 -
Journal of Pharmacological Sciences May 2020Valproic acid is a commonly used drug for many psychiatric disorders, particularly for epilepsy. However, it has been reported that its use is associated with possible...
Valproic acid is a commonly used drug for many psychiatric disorders, particularly for epilepsy. However, it has been reported that its use is associated with possible side effects including hepatotoxicity. The present study investigated the hepatoprotective effect of ellagic acid against valproic acid-induced hepatotoxicity in rats. Ellagic acid (60 mg/kg/day; p.o) was treated for one week, followed by concomitant injection of valproic acid (250 mg/kg/day; i.p.) for another 14 consecutive days to induce hepatocellular damage in adult Sprague-Dawley rats. Valproic acid showed a marked increase in serum enzyme activities, AST, ALT, ALP and GGT. In addition, it significantly increased MDA and NO along with a marked decline in reduced GSH content. At the same time, valproic acid administration resulted in marked elevation in hydroxyproline, TNF-α production and NF-kB expression. These results were confirmed by histopathological examination. Treatment with ellagic acid markedly attenuated valproic acid-induced hepatic injury in rats.
Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Ellagic Acid; Glutathione; Liver; Male; Nitric Oxide; Oxidative Stress; Phytotherapy; Rats, Sprague-Dawley; Valproic Acid
PubMed: 32139333
DOI: 10.1016/j.jphs.2020.01.007 -
Journal of Traditional Chinese Medicine... Apr 2023To investigate the efficacy and mechanisms of Dingxian pill combined with valproic acid (VPA) on pentylenetetrazol-induced chronical epilepsy in rats.
OBJECIVE
To investigate the efficacy and mechanisms of Dingxian pill combined with valproic acid (VPA) on pentylenetetrazol-induced chronical epilepsy in rats.
METHODS
A rat model of epilepsy was established by administering pentylenetetrazol (PTZ) water solution (35 mg/kg). Rats were divided into 4 groups, among which three groups were treated with different drugs once a day for 28 d including Dingxian pill (2.4 g/kg), VPA (0.2 g/kg), or a combination of Dingxian pill (2.4 g/kg) and VPA (0.2 g/kg) respectively, and the control group was given the same volume of saline. Rats in different groups were compared based on animal behavior, electroencephalograms, Morris water maze, immunohistochemistry, transcriptomics and real-time polymerase chain reaction.
RSULTS
The combination therapy of Dingxian pill and VPA inhibited PTZ-induced seizure-like behavior and reduced seizure grades more significantly than VPA alone. Compared with the control group, the learning and memory ability of chronic PTZ-induced epileptic rats was improved in all the drug treatment groups, especially in the group that received both Dingxian pill and VPA. Similar to the results of MWM tests, expression of the neuroexcitability marker gene c-Fos was reduced after Dingxian pill and/or VPA treatment, and the effect was most pronounced in the combined treatment group. Transcriptomic analysis revealed that gene expression in the rodent hippocampus, which is involved in epilepsy, was upregulated by combined treatment with Dingxian pill and VPA, compared with VPA treatment alone.
CONCLUSION
Our results not only highlight the anti-epileptic effects of combined Dingxian pill and VPA treatment, but also shed light on the underlying molecular mechanisms and provide a way to apply Traditional Chinese Medicine in the treatment of epilepsy.
Topics: Rats; Animals; Valproic Acid; Pentylenetetrazole; Epilepsy; Anticonvulsants; Seizures
PubMed: 36994516
DOI: 10.19852/j.cnki.jtcm.20220928.002 -
Zhurnal Nevrologii I Psikhiatrii Imeni... 2017The article summarizes domestic and international studies on the development and clinical investigation of valproates including multiple studies of a research team... (Review)
Review
The article summarizes domestic and international studies on the development and clinical investigation of valproates including multiple studies of a research team directed by the author. Valproate targets are considered in biological and clinical aspects. A spectrum of action and advantages of the brand drug (depakine) compared to generics and other antiepileptic drugs are discussed. A number of recommendations for practitioners about using valproates are proposed.
Topics: Anticonvulsants; Drugs, Generic; Epilepsy; GABA Agents; Humans; Russia; Valproic Acid
PubMed: 29265098
DOI: 10.17116/jnevro2017117111129-134 -
Pakistan Journal of Pharmaceutical... Jul 2018The unpredictable and unfavorable connection of dose and plasma concentration of valproic acid supports the necessity to regularly measure its plasma concentration. The... (Clinical Trial)
Clinical Trial
The unpredictable and unfavorable connection of dose and plasma concentration of valproic acid supports the necessity to regularly measure its plasma concentration. The present study is drug monitoring of valproic acid and comparative evaluation of therapeutic monitoring results of valproic acid for assessment of clinical response, safety and toxicity in different age and gender groups of Chinese epileptic patients. This knowledge will help the clinicians in adjusting the drug dosages of valproic acid in various sub-groups of epileptic patients for enhancing the safety and minimizing the toxicity of valproic acid. A total of 206 plasma samples (126 males and 80 females) of epileptic patients using valproic acid were requested for therapeutic drug monitoring by neurology department of Qilu Hospital. It was found that 29 % of the total samples were found in sub-therapeutic levels, 13% of the samples had toxic levels and 58% of all the samples had valproic acid levels in therapeutic range. The difference in plasma concentration of valproic acid is notably altered in gender and various age groups. However, this requires further investigation. Despite the majority of samples in the therapeutic range, there was an unfavorable clinical response. The outcomes of the current research work exposed that there was a poor correlation between the plasma concentration and clinical response. Careful attention must be applied to specific gender and particular age group on an individual basis in the interpretation of plasma concentration results, in order to facilitate the modification of doses and develop the best approach in treatment and to obtain the desired clinical response because multiple factors can affect the valproic acid plasma concentration. Through these results, it can be concluded that poor correlation exists between valproic acid plasma concentration and clinical response.
Topics: Adult; Age Factors; Aged; Anticonvulsants; Child, Preschool; Drug Monitoring; Epilepsy; Female; Humans; Infant; Male; Sex Factors; Treatment Outcome; Valproic Acid
PubMed: 30203778
DOI: No ID Found -
Journal of Virology Mar 2023The major immediate early enhancer and promoter (MIEP) of human cytomegalovirus (HCMV) drives the transcription of the immediate early one (IE1) and IE2 genes, whose...
The major immediate early enhancer and promoter (MIEP) of human cytomegalovirus (HCMV) drives the transcription of the immediate early one (IE1) and IE2 genes, whose encoded proteins stimulate productive, lytic replication. The MIEP is activated by the virally encoded and tegument-delivered pp71 protein at the start of lytic infections of fully differentiated cells. Conversely, the MIEP is silenced at the start of latent infections within incompletely differentiated myeloid cells in part because tegument-delivered pp71 is sequestered in the cytoplasm in these cells, but also by viral factors that repress transcription from this locus, including the UL138 protein. During both modes of infection, MIEP activity can be increased by the histone deacetylase inhibitor valproic acid (VPA); however, UL138 inhibits the VPA-responsiveness of the MIEP. Here, we show that two families of cellular transcription factors, NF-κB and cAMP response element-binding protein (CREB), together control the VPA-mediated activation and UL138-mediated repression of the HCMV MIEP. Artificial regulation of the HCMV MIEP, either activation or repression, is an attractive potential means to target the latent reservoirs of virus for which there is currently no available intervention. The MIEP could be repressed to prevent latency reactivation or induced to drive the virus into the lytic stage that is visible to the immune system and inhibited by multiple small-molecule antiviral drugs. Understanding how the MIEP is regulated is a critical part of designing and implementing either strategy. Our revelation here that NF-κB and CREB control the responsiveness of the MIEP to the viral UL138 protein and the FDA-approved drug VPA could help in the formulation and execution of promoter regulatory strategies against latent HCMV.
Topics: Humans; Cyclic AMP; Cytomegalovirus; Gene Expression Regulation, Viral; NF-kappa B; Response Elements; Valproic Acid; Viral Proteins
PubMed: 36856444
DOI: 10.1128/jvi.00029-23