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Syringic acid alleviates valproic acid induced autism via activation of p38 mitogen-activated protein kinase: Possible molecular approach

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Sudhanshu Mallan at ISF College of Pharmacy
Sudhanshu Mallan
Shamsher Singh at ISF College of Pharmacy
Shamsher Singh
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Abstract

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder characterized by restrictive and repetitive behavior followed by impairment in social, verbal, and non-verbal interaction and communication. Valproic acid (VPA) is a well-known anti-epileptic drug, but its prenatal exposure to animals causes social impairment, neurotransmitters imbalance, and neuroinflammation with ASD-like phenotypes. Syringic acid (SA) is a polyphenolic compound with anti-inflammatory, anti-apoptotic, antioxidant, and neuromodulator activity. The purpose of study was to investigate the protective effect of Syringic acid (SA) in prenatal VPA-treated rats through behavioral, neuroinflammation, oxidative stress, neurotransmitters, neuronal integrity, and apoptotic marker. Single dose of VPA was administered 600 mg/kg, i.p. on a gestational day (GD) 12th and SA was administrated from PnD 26th to 54th at the dose of 25, 50, and 100 mg/kg, p.o. On PnD 56th behavioral parameters (Pain sensitivity, open field test, narrow beam walks test and social impairment test) were performed and all animals were sacrificed, and brain tissue was isolated for oxidative stress (GSH, CAT, and LPO), neuroinflammation (TNF-α and IL-6) and neurotransmitters (GABA and Glutamate), histopathology (H&E, Nissl), immunohistochemistry (p38 MAPK) analysis. Rat treated with SA dose-dependently prevented behavioral alteration, restored antioxidant enzymes, neurotransmitters level, decreased neuroinflammatory markers, and improved neuronal integrity. Furthermore, immunohistochemistry confirmed the reduced p38 MAPK marker expression by SA in VPA induced autistic behavior.
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6/28/23, 9:07 PM
Syringic acid alleviates valproic acid induced autism via activation of p38 mitogen‐activated protein kinase: Possible molecular approach - Mallan - Environmental Toxicology - Wiley Online Library
https://onlinelibrary.wiley.com/doi/10.1002/tox.23876
1/11
Environmental Toxicology / Early View
RESEARCH ARTICLE
Syringic acid alleviates valproic acid induced autism via activation of p38 mitogen-activated protein kinase: Possible
molecular approach
First published: 26 June 2023
https://doi.org/10.1002/tox.23876
Abstract
Sudhanshu Mallan,Shamsher Singh
Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental disorder characterized by restrictive and repetitive behavior
followed by impairment in social, verbal, and non-verbal interaction and communication. Valproic acid (VPA) is a well-known anti-
epileptic drug, but its prenatal exposure to animals causes social impairment, neurotransmitters imbalance, and neuroinammation
with ASD-like phenotypes. Syringic acid (SA) is a polyphenolic compound with anti-inammatory, anti-apoptotic, antioxidant, and
neuromodulator activity. The purpose of study was to investigate the protective eect of Syringic acid (SA) in prenatal VPA-treated
rats through behavioral, neuroinammation, oxidative stress, neurotransmitters, neuronal integrity, and apoptotic marker. Single
dose of VPA was administered 600 mg/kg, i.p. on a gestational day (GD) 12th and SA was administrated from PnD 26th to 54th at the
dose of 25, 50, and 100 mg/kg, p.o. On PnD 56th behavioral parameters (Pain sensitivity, open eld test, narrow beam walks test and
social impairment test) were performed and all animals were sacriced, and brain tissue was isolated for oxidative stress (GSH, CAT,
and LPO), neuroinammation (TNF-α and IL-6) and neurotransmitters (GABA and Glutamate), histopathology (H&E, Nissl),
immunohistochemistry (p38 MAPK) analysis. Rat treated with SA dose-dependently prevented behavioral alteration, restored
antioxidant enzymes, neurotransmitters level, decreased neuroinammatory markers, and improved neuronal integrity.
Furthermore, immunohistochemistry conrmed the reduced p38 MAPK marker expression by SA in VPA induced autistic behavior.
CONFLICT OF INTEREST STATEMENT
6/28/23, 9:07 PM
Syringic acid alleviates valproic acid induced autism via activation of p38 mitogen‐activated protein kinase: Possible molecular approach - Mallan - Environmental Toxicology - Wiley Online Library
https://onlinelibrary.wiley.com/doi/10.1002/tox.23876
2/11
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Protective Effects of Bee Pollen on Multiple Propionic Acid-Induced Biochemical Autistic Features in a Rat Model
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The neural crest (NC), discovered by Wilhelm His 150 years ago, gives rise to a multipotent migratory embryonic cell population that generates a remarkably diverse and important array of cell types during the development of the vertebrate embryo. These cells originate in the neural plate border (NPB), which is the ectoderm between the neural plate and the epidermis. They give rise to the neurons and glia of the peripheral nervous system, melanocytes, chondrocytes, smooth muscle cells, odontoblasts and neuroendocrine cells, among others. Neurocristopathies are a class of congenital diseases resulting from the abnormal induction, specification, migration, differentiation or death of NC cells (NCCs) during embryonic development and have an important medical and societal impact. In general, congenital defects affect an appreciable percentage of newborns worldwide. Some of these defects are caused by teratogens, which are agents that negatively impact the formation of tissues and organs during development. In this review, we will discuss the teratogens linked to the development of many birth defects, with a strong focus on those that specifically affect the development of the NC, thereby producing neurocristopathies. Although increasing attention is being paid to the effect of teratogens on embryonic development in general, there is a strong need to critically evaluate the specific role of these agents in NC development. Therefore, increased understanding of the role of these factors in NC development will contribute to the planning of strategies aimed at the prevention and treatment of human neurocristopathies, whose etiology was previously not considered.
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Inhibition of the ERK1/2 Phosphorylation by Dextromethorphan Protects against Core Autistic Symptoms in VPA Induced Autistic Rats: In Silico and in Vivo Drug Repurposition Study
Article
  • Apr 2021
The imbalance between excitatory and inhibitory neurotransmitters is explicitly related to the pathophysiology of autism spectrum disorder (ASD). The role of an NMDA receptor antagonist, dextromethorphan, was studied in ameliorating the ASD-like symptoms by regulating the excitatory and inhibitory imbalance using the valproic acid (VPA) model of ASD. Female Wistar rats were administered VPA [600 mg/kg on embryonic day ED-12.5] through intraperitoneal (ip) injection to induce ASD in pups. Autistic pups were then given dextromethorphan (10, 15, and 30 mg/kg; ip) and risperidone (2.5 mg/kg; ip) from PND 23 to 43 in different groups. Behavioral tests (three chamber sociability, self-grooming, Morris water maze, elevated plus maze, open field, rotarod, grip strength), oxidative stress and inflammatory markers, histological evaluation (H&E, Nissil staining), and NMDA and ERK1/2 expression by immunohistochemistry and RT-PCR were done. The in silico modeling of dextromethorphan against PPDA, TCN-201, MK-22, EVT-101 on NMDA receptors was also performed. Dextromethorphan (30 mg/kg) rescued the impaired behavioral patterns including social excitability, hyperactivity, repetitive and restricted behaviors as well as mitigation of the memory and motor coordination. The levels of various oxidative stress markers (GSH, SOD, catalase, MDA) and inflammatory markers (IL-1β, IL-6, IL-10, TNF-α) were ameliorated by different doses of dextromethorphan. It also reduced the neuronal injury score and rescued the overly expressed pERK1/2 and NMDA signaling in both the prefrontal cortex and hippocampus of the autistic pups. In silico results showed favorable binding of dextromethorphan against TCN-201 and MK-22 binding sites. The present study provided experimental evidence for the potential therapeutic role of dextromethorphan in attenuating autism symptomatology in the ASD model of rats. Thus, modulation of the glutamatergic signaling can be a potential target for ASD treatment.
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Syringic acid mitigates myocardial ischemia reperfusion injury by activating the PI3K/Akt/GSK-3β signaling pathway
Article
  • Aug 2020
Syringic acid is an abundant phenolic acid compound that possesses anti-oxidant, anti-microbial, anti-inflammatory, and anti-endotoxic properties. However, the research of pretreatment with syringic acid against myocardial ischemia reperfusion is still limited. Thus, our research revealed the protective effect of syringic acid in the rat model with myocardial ischemia reperfusion injury. Histological analysis was performed by hematoxylin and eosin (H&E). The myocardial systolic function was detected by echocardiographic. Myocardial infarct size was measured by Evans blue and 2,3,5-triphenyltetrazolium chloride (TTC) double staining. The apoptosis index was recorded by Terminal deoxynucleotidyl transferase dUTP nick end labeling staining (TUNEL). The contents of creatine kinase MB (CK-MB) and lactate dehydrogenase (LDH) in the serum were determined by a commercial kit. The expression of the PI3K/Akt/GSK-3β signaling pathway-related molecules and apoptosis-associated indicators was detected by western blotting or real-time PCR. We found that pretreatment with syringic acid obviously increased the myocardial systolic function (LVEF and LVFS) and decreased the infarct size, the apoptosis index as well as the serum level of CK-MB and LDH. Meanwhile, syringic acid also remarkably augmented the contents of p-PI3K, p-Akt, p-GSK-3β, Bcl-2 and mitochondria cytochrome c. However, the expression of caspase-3, -9 and Bax significantly reduced. Interestingly, co-treatment with PI3K inhibitor of LY294002 counteracted those effects induced by syringic acid. In conclusion, pretreatment with syringic acid can mitigate myocardial ischemia reperfusion injury by inhibiting mitochondria-induced apoptosis which is regulated by the PI3K/Akt/GSK-3β signaling pathway.
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Cardioprotective molecular mechanism of syringic acid against isoproterenol induced post- myocardial toxicity in male Albino Wistar rats
Article
  • Nov 2019
Background: Syringic acid (SA) is a natural phenolic compound and act as anti-diabetic, anti-cancer, anti-inflammatory agents. In our current research, investigation was carried out on the effect of SA on post conditioning on isoproterenol (ISO) induced myocardial injury in wistar rats. Methods: Male albino wistar rats were administered with ISO (30 mg/kg bw) to second, third and fourth group rats on 1st and 2nd days (with a 24 h interval) of experimental period. SA and metoprolol were orally given immediately after the second dose of ISO to second and fourth group of rats respectively. Myocardial damage was assessed by estimating the cardiac marker enzymes such as creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH) and gamma glutamyl transferase (GGT), anti-oxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT), inflammatory markers such as nuclear factor-kappa B (NF-kB), tumor necrosis factor-α (TNF-α) and high sensitivity-C reactive protein (hs-CRP) along with body and heart weights. Transmission electron microscopy (TEM) was utilized to find any ultra-structural alterations in the heart tissues. Results: CK-MB, LDH and GGT levels and hs-CRP levels were found to be increased in serum while decreased in hearts of ISO group of rats. SOD and CAT were found to be decreased significantly while NF-kB and TNF-α expression levels were significantly increased in heart tissues of ISO administered rats. Body weights were decreased significantly and heart weights were increased significantly in ISO group of rats. TEM study showed alterations in ISO group hearts. Post-treatment with SA significantly recovered myocardial damage caused by ISO administration. Conclusion: By counteracting with the above mentioned effects of ISO, our natural compound, SA exhibited recovery of myocardial damage caused by ISO administration in wistar rats. This is the first report revealing the cardioprotective activity of SA in post-myocardial infarction in rats.
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