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Valproate-Induced Rodent Model of Autism Spectrum Disorder: Immunogenic Effects and Role of Microglia
Published in Raj Bawa, János Szebeni, Thomas J. Webster, Gerald F. Audette, Immune Aspects of Biopharmaceuticals and Nanomedicines, 2019
Prabha Awale, James C. K. Lai, Srinath Pashikanthi, Alok Bhushan
The mechanisms by which valproic acid (VPA) induces ASD-like behaviors are currently not well understood. The anti-seizure effect of VPA (an established anti-epilepsy drug) is reportedly to elevate brain levels of the inhibitory neurotransmitter, γ-aminobutyric acid (GABA) although the underlying mechanisms have yet to be resolved. In addition, valproate also directly inhibits voltage gated sodium channels, thereby suppressing the high frequency firing of neurons [26]. Furthermore, VPA has histone deacetylase (HDAC) inhibitory activity: Prenatal exposure to VPA causes transient hyperacetylation of H3 and H4 that consequently leads to postnatal behavioral impairments in the offspring [27]. HDAC belongs to the metalloenzyme family: This observed HDAC inhibition by VPA might be due to chelation of carboxylate in VPA with zinc in the active site as observed with classic HDAC inhibitors [28]. Thus, strategies aimed at preventing these electrostatic interactions will lead to the preservation of the HDAC activity and the minimization of the teratogenic effect. By contrast, exposure of mice to valpromide, (a VPA analog lacking histone deacetylase inhibition activity) does not induce transient hyperacetylation or affect their behavior [27]. These studies suggest inhibition of HDAC by VPA during a crucial period of neurogenesis is associated with ASD-like pathologies.
Drugs for Treatment of Neurological and Psychological Conditions
Published in Richard J. Sundberg, The Chemical Century, 2017
In the 1960s, two other drugs that are currently recommended as first line treatments were found. These are carbamazepine and valproate. Carbamazepine was developed by Geigy and introduced in Europe in the early 1960s. It was not approved in the United States until 1974. Sodium valproate was discovered by a small Swiss pharmaceutical company when the corresponding acid was used as the solvent for a testing a series of other compounds. When all showed positive effects, the researchers suspected that valproic acid was the active constituent. This proved to be the case. The development of the drug was undertaken by Sanofi and it was introduced in Europe in the 1970s. Its structure is remarkably simple compared to most other antiepileptic drugs. Both carbamazepine and valproate have significant side effects. Carbamazepine is teratogenic and has a rate of liver failure of about 16/100,000. Valproate can lead to obesity, is teratogenic and has liver toxicity, especially in children. Nevertheless, both are among the most used antiepileptic drugs at the present time.
Metabolomics profiling of valproic acid-induced symptoms resembling autism spectrum disorders using 1H NMR spectral analysis in rat model
Published in Journal of Toxicology and Environmental Health, Part A, 2022
Hyang Yeon Kim, Yong-Jae Lee, Sun Jae Kim, Jung Dae Lee, Suhkmann Kim, Mee Jung Ko, Ji-Woon Kim, Chan Young Shin, Kyu-Bong Kim
There have been many studies on neurotoxicity and its causal factors (Li and Li 2021; Tsai et al. 2021; Wilson et al. 2021). Although many etiologies for ASD have been proposed, the precise causal mechanism for this disorder remains unknown. In addition, single-gene disorders, inborn errors in metabolism, heavy metals, and maternal drug exposure are known to increase the risk of ASD development (Ghaziuddin and Al-Owain 2013; Hill et al. 2015; Rossignol and Frye 2014; Shin et al. 2021). Exposure to drugs, such as valproic acid (VPA), may also be associated with ASD development (Williams et al. 2001). Clinical investigators reported that administration of VPA during pregnancy increased the risk of incidence of neural tube defects, including ASD (Christensen et al. 2013; Williams et al. 2001). Valproic acid is used to treat epilepsy and bipolar disorder, as well as modulating gamma-aminobutyric acid (GABA) neurotransmission and preventing migraine headaches. In a follow-up study of children exposed to VPA during pregnancy, the rate of ASD was elevated approximately 8-fold concomitant with reduction in number of eye motor neurons, shortened tail regions in the facial nucleus, and decreased number of Purkinje cells (Baker et al. 2015). It is of interest that several investigators noted treatment with VPA during pregnancy led to fetal valproate syndrome (FVS), which results in abnormal and delayed development, organ malformations, and deficits in social function or communication ASD (Christensen et al. 2013; Williams et al. 2001).