Rutin prevents seizures in kainic acid-treated rats: evidence of glutamate levels, inflammation and neuronal loss modulation

Chang, Anna; Chang, Yi; Wang, Su‐Jane

doi:10.1039/d2fo01490d

Cited by 8 publications

(14 citation statements)

References 72 publications

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“…Therefore, increasing GluN2A expression or inhibiting GluN2B expression is a favorable potential mechanism for alleviating excitotoxic brain injury [ 67 , 68 ]. In this study, we observed that administration of KA decreased the protein level of GluN2A and increased the protein level of GluN2B in the rat cortex, which is consistent with previous studies [ 69 , 70 ]. Furthermore, our results showed that the protein expression level of GluN2A was preserved, while GluN2B was significantly repressed in the cortex of KA-treated rats pretreated with eupatilin compared to those without eupatilin intervention.…”

Section: Discussionsupporting

confidence: 93%

Inhibition of Synaptic Glutamate Exocytosis and Prevention of Glutamate Neurotoxicity by Eupatilin from Artemisia argyi in the Rat Cortex

Chiu

et al. 2022

IJMS

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The inhibition of synaptic glutamate release to maintain glutamate homeostasis contributes to the alleviation of neuronal cell injury, and accumulating evidence suggests that natural products can repress glutamate levels and associated excitotoxicity. In this study, we investigated whether eupatilin, a constituent of Artemisia argyi, affected glutamate release in rat cortical nerve terminals (synaptosomes). Additionally, we evaluated the effect of eupatilin in an animal model of kainic acid (KA) excitotoxicity, particularly on the levels of glutamate and N-methyl-D-aspartate (NMDA) receptor subunits (GluN2A and GluN2B). We found that eupatilin decreased depolarization-evoked glutamate release from rat cortical synaptosomes and that this effect was accompanied by a reduction in cytosolic Ca2+ elevation, inhibition of P/Q-type Ca2+ channels, decreased synapsin I Ca2+-dependent phosphorylation and no detectable effect on the membrane potential. In a KA-induced glutamate excitotoxicity rat model, the administration of eupatilin before KA administration prevented neuronal cell degeneration, glutamate elevation, glutamate-generating enzyme glutaminase increase, excitatory amino acid transporter (EAAT) decrease, GluN2A protein decrease and GluN2B protein increase in the rat cortex. Taken together, the results suggest that eupatilin depresses glutamate exocytosis from cerebrocortical synaptosomes by decreasing P/Q-type Ca2+ channels and synapsin I phosphorylation and alleviates glutamate excitotoxicity caused by KA by preventing glutamatergic alterations in the rat cortex. Thus, this study suggests that eupatilin can be considered a potential therapeutic agent in the treatment of brain impairment associated with glutamate excitotoxicity.

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Section: Discussionsupporting

confidence: 93%

Inhibition of Synaptic Glutamate Exocytosis and Prevention of Glutamate Neurotoxicity by Eupatilin from Artemisia argyi in the Rat Cortex

Chiu

et al. 2022

IJMS

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“…on the 8th day. The doses and schedules for drug administration were selected based on previous studies and pilot experiments (Friedman et al, 1994;Spigolon et al, 2010;Chang et al, 2022). Before KA injection, the body weights of the rats in the control and NRICM101 groups were measured, and liver, kidney and blood samples were collected from the control and NRICM101 rats after they were sacri ced for hematoxylin-eosin (H&E) staining and serum alanine transaminase (ALT) and aspartate transaminase (AST) measurement, respectively.…”

Section: Seizure Model Establishment and Drug Treatmentmentioning

confidence: 99%

“…The glutamate levels in the cortex and hippocampus tissues were measured using HPLC as described previously (Chang et al, 2022;Jean et al, 2022). The brain tissue (50 mg) was homogenized in HEPES buffer medium and centrifuged at 15,000 × g for 10 min at 4°C.…”

Section: Hplcmentioning

confidence: 99%

Taiwan Chingguan Yihau (NRICM101) prevents kainic acid-induced seizures in rats by modulating neuroinflammation and the glutamatergic system

Hung,

Chiu,

Chen

et al. 2024

Preprint

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Taiwan Chingguan Yihau (NRICM101) is a Traditional Chinese medicine (TCM) formula used to treat coronavirus disease 2019; however, its impact on epilepsy has not been revealed. Therefore, the present study evaluated the anti-epileptogenic effect of orally administered NRICM101 on kainic acid (KA)-induced seizures in rats and investigated its possible mechanisms of action. Sprague‒Dawley rats were administered NRICM101 (300 mg/kg) by oral gavage for 7 consecutive days before receiving an intraperitoneal injection of KA (15 mg/kg). NRICM101 considerably reduced the seizure behavior and electroencephalographic seizures induced by KA in rats. NRICM101 also significantly decreased the neuronal loss and glutamate increase and increased GLAST, GLT-1, GAD67, GDH and GS levels in the cortex and hippocampus of KA-treated rats. In addition, NRICM101 significantly suppressed astrogliosis (as determined by decreased GFAP expression); neuroinflammatory signaling (as determined by reduced HMGB1, TLR-4, IL-1β, IL-1R, IL-6, p-JAK2, p-STAT3, TNF-α, TNFR1 and p-IκB levels, and increased cytosolic p65-NFκB levels); and necroptosis (as determined by decreased p-RIPK3 and p-MLKL levels) in the cortex and hippocampus of KA-treated rats. The effects of NRICM101 were similar to those of carbamazepine, a well-recognized antiseizure drug. Furthermore, no toxic effects of NRICM101 on the liver and kidney were observed in NRICM101-treated rats. The results indicate that NRICM101 has antiepileptogenic and neuroprotective effects through the suppression of the inflammatory cues (HMGB1/TLR4, Il-1β/IL-1R1, IL-6/p-JAK2/p-STAT3, and TNF-α/TNFR1/NF-κB) and necroptosis signaling pathways (TNF-α/TNFR1/RIP3/MLKL) associated with glutamate level regulation in the brain and is innocuous. Our findings highlight the promising role of NRICM101 in the management of epilepsy.

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“…The glutamate levels in the cortex were measured using HPLC as described previously [35]. Briefly, rats (n = 6 rats per group) were sacrificed by decapitation, and the brains were quickly removed and dissected on ice, and the cortex and hippocampus were stored at −80 • C. The frozen cortex was homogenized in HEPES buffer medium and centrifuged at 15,000× g for 10 min at 4 • C. The supernatant (10 µL) was filtered through a 0.22 µm membrane filter and injected into an HPLC instrument (HTEC-600, Eicom, Kyoto, Japan).…”

Section: High-performance Liquid Chromatography (Hplc) Assay Of Gluta...mentioning

confidence: 99%

“…Expressed proteins of interest were visualized by enhanced chemiluminescence solution (Amersham Biosciences Corp., Amersham, Buckinghamshire, UK). The films were scanned using a scanner and quantified with ImageJ software (Version 1.53k, NIH Image, National Institutes of Health, Bethesda, MD, USA), after which the protein/β-actin ratio was calculated [35,37]. The measurements of β-actin were conducted on sister blots, with each blot loaded with 30 µg of protein per lane.…”

Section: Protein Isolation and Western Blottingmentioning

confidence: 99%

Gypenoside XVII Reduces Synaptic Glutamate Release and Protects against Excitotoxic Injury in Rats

Lu,

Lin,

Chiu

et al. 2024

Biomolecules

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Excitotoxicity is a common pathological process in neurological diseases caused by excess glutamate. The purpose of this study was to evaluate the effect of gypenoside XVII (GP-17), a gypenoside monomer, on the glutamatergic system. In vitro, in rat cortical nerve terminals (synaptosomes), GP-17 dose-dependently decreased glutamate release with an IC50 value of 16 μM. The removal of extracellular Ca2+ or blockade of N-and P/Q-type Ca2+ channels and protein kinase A (PKA) abolished the inhibitory effect of GP-17 on glutamate release from cortical synaptosomes. GP-17 also significantly reduced the phosphorylation of PKA, SNAP-25, and synapsin I in cortical synaptosomes. In an in vivo rat model of glutamate excitotoxicity induced by kainic acid (KA), GP-17 pretreatment significantly prevented seizures and rescued neuronal cell injury and glutamate elevation in the cortex. GP-17 pretreatment decreased the expression levels of sodium-coupled neutral amino acid transporter 1, glutamate synthesis enzyme glutaminase and vesicular glutamate transporter 1 but increased the expression level of glutamate metabolism enzyme glutamate dehydrogenase in the cortex of KA-treated rats. In addition, the KA-induced alterations in the N-methyl-D-aspartate receptor subunits GluN2A and GluN2B in the cortex were prevented by GP-17 pretreatment. GP-17 also prevented the KA-induced decrease in cerebral blood flow and arginase II expression. These results suggest that (i) GP-17, through the suppression of N- and P/Q-type Ca2+ channels and consequent PKA-mediated SNAP-25 and synapsin I phosphorylation, reduces glutamate exocytosis from cortical synaptosomes; and (ii) GP-17 has a neuroprotective effect on KA-induced glutamate excitotoxicity in rats through regulating synaptic glutamate release and cerebral blood flow.

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Rutin prevents seizures in kainic acid-treated rats: evidence of glutamate levels, inflammation and neuronal loss modulation

Abstract: Rutin, a naturally derived flavonoid molecule with known neuroprotective properties, has been demonstrated to have anticonvulsive potential, but the mechanism of this effect is still unclear. The current study aimed...

Cited by 8 publications

References 72 publications

Inhibition of Synaptic Glutamate Exocytosis and Prevention of Glutamate Neurotoxicity by Eupatilin from Artemisia argyi in the Rat Cortex

Inhibition of Synaptic Glutamate Exocytosis and Prevention of Glutamate Neurotoxicity by Eupatilin from Artemisia argyi in the Rat Cortex

Taiwan Chingguan Yihau (NRICM101) prevents kainic acid-induced seizures in rats by modulating neuroinflammation and the glutamatergic system

Gypenoside XVII Reduces Synaptic Glutamate Release and Protects against Excitotoxic Injury in Rats

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