Isoliquiritigenin Alleviates Semen Strychni-Induced Neurotoxicity by Restoring the Metabolic Pathway of Neurotransmitters in Rats.

Min Zhang,Pingfei Fang,Lu Wang,Xiaoyu Duan,Bikui Zhang,Yalan Xiang,Miao Yan,Changwei Yu,Jing Wen

doi:10.3389/fphar.2021.762290

Abstract

Acute neurotoxicity of Semen Strychni can result in sudden death in epilepsy. The detoxification method and mechanism of Semen Strychni acute poisoning have not been clarified. This experiment focused on the mechanism of Semen Strychni neurotoxicity and the alleviation effects of isoliquiritigenin. The rats were intraperitoneally injected with Semen Strychni extract (125 mg/kg), followed by oral administration of isoliquiritigenin (50 mg/kg) for 7 days. FJ-B staining was used to evaluate the degree of injury on hippocampus neurons. The concentration of monoamines, amino acids, and choline neurotransmitters, the Dopamine (DA) and 5-hydroxytryptamine (5-HT) metabolic pathway in the hippocampus, cerebellum, striatum, prefrontal cortex, hypothalamus, serum, and plasma were detected by LC-MS/MS. The expression of neurotransmitter metabolic enzymes [catechol-O-methyl transferase (COMT) and monoamine oxidase (MAO)] and neurotransmitter receptors [glutamate N-methyl-D-aspartic acid receptors (NMDARs) and gamma-aminobutyric acid type A receptor (GABRs)] were, respectively determined using ELISA and qRT-PCR. The results indicated that Semen Strychni induced neuronal degeneration in the hippocampal CA1 region. Meanwhile, Semen Strychni inhibited the mRNA expression of NMDAR1, NMDAR2A, NMDAR2B, GABRa1, GABRb2 and reduced the level of MAO, which disrupted the DA and 5-HT metabolic pathway. However, isoliquiritigenin reversed these effects. In summary, isoliquiritigenin showed alleviation effects on Semen Strychni-induced neurotoxicity, which could be attributed to restoring neurotransmitters metabolic pathway, most likely through the activation of NMDA receptors.

Highlights

Semen Strychni, the dried seeds of Strychnos nux-vomica L. (Loganiaceae) with severe toxicity (Lu et al, 2020), has a long history of clinical applications in improving blood circulation, treating cancer and relieving rheumatic pain
The experimental results showed that rats in the 150 mg/kg group died of severe twitches, myotonia, and breathing difficulty after 2 min of administration
Neuronal degeneration was detected by FJ-B staining, which proved that Semen Strychni-induced neurotoxicity could affect the development of neurons and potentially cause cognitive impairment

Summary

Introduction

Semen Strychni, the dried seeds of Strychnos nux-vomica L. (Loganiaceae) with severe toxicity (Lu et al, 2020), has a long history of clinical applications in improving blood circulation, treating cancer and relieving rheumatic pain. (Loganiaceae) with severe toxicity (Lu et al, 2020), has a long history of clinical applications in improving blood circulation, treating cancer and relieving rheumatic pain. It plays an essential role in the treatment of rheumatoid arthritis (Li et al, 2015). Studies indicated that strychnine and brucine, which account for about 70% of Strychnos alkaloids (SAs), are the main biologically active components of Semen Strychni (Lin et al, 2016). The. Isoliquiritigenin Alleviates Semen Strychni Neurotoxicity blood-brain AUC ratios of brucine and strychnine were doserelated, limiting its clinical applications (Wu et al, 2012; Ren et al, 2018). Semen Strychni-induced neurotoxicity makes the central nervous system reflex center more sensitive to afferent stimuli and blocks postsynaptic inhibitory Glycine (Gly) receptors in the spinal cord and brain stem (Guo et al, 2018; Li et al, 2018)

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Results

Discussion

Conclusion