Dataset Information

Phyllathin From Phyllanthus Amarus Ameliorates Epileptic Convulsion and Kindling Associated Post-Ictal Depression in Mice via Inhibition of NF-κB/TLR-4 Pathway.

ABSTRACT:

Background

Epilepsy is a chronic, complex, unprovoked, and recurrent disorder of the nervous system that affected several people worldwide. Phyllanthus amarus (PA) has been documented to have neuroprotective potential.

Aim

To evaluate the potential of standardized extract of PA and its possible mechanism of action against the Pentylenetetrazol (PTZ)-induced convulsion and kindling associated post-ictal depression in experimental mice.

Materials and methods

Phyllathin was isolated from methanolic extract of PA and well-characterized using HPTLC, ESI-MS/MS, and LC/MS. Phyllathin containing a standardized extract of PA (50, 100, and 200 mg/kg) was administered in convulsed and kindled mice, followed by an assessment of various parameters.

Results

The spectral analysis confirmed the molecular formula and weight of phyllanthin as C₂₄H₃₄O₆ and 418.2342 Da. PA (100 and 200 mg/kg) significantly ameliorated PTZ-induced (p < 0.05) duration, onset of tonic-clonic convulsion, and mortality in mice. It also significantly attenuated (p < 0.05) PTZ-induced kindling in mice. Alteration in brain GABA, dopamine, and glutamate, Na⁺K⁺ATPase, Ca⁺²-ATPase activities, and oxido-nitrosative stress in kindled mice was significantly restored (p < 0.05) by PA treatment. It also significantly (p < 0.05) down-regulated brain mRNA expressions of NF-κB, TNF-α, IL-1β, COX-2, and TLR-4. Histological aberrations induced by PTZ in the brain of a kindled rat was significantly (p < 0.05) ameliorated by PA.

Conclusion

Phyllanthin containing a standardized extract of PA exerts its antiepileptic potential via balancing excitatory (glutamate) and inhibitory (GABA) brain monoamines, voltage-gated ion channels (Na⁺K⁺/Ca⁺²-ATPase) and inhibition of NF-κB/TLR-4 pathway to ameliorate neuroinflammation (TNF-α, IL-1β, and COX-2) in experimental mice.

SUBMITTER: Tao Z

PROVIDER: S-EPMC7412921 | biostudies-literature | 2020 Jul-Sep

REPOSITORIES: biostudies-literature

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Publications

Phyllathin From Phyllanthus Amarus Ameliorates Epileptic Convulsion and Kindling Associated Post-Ictal Depression in Mice via Inhibition of NF-κB/TLR-4 Pathway.

Tao Zhang Z Chun-Yan Hu H Hua Peng P Bin-Bin Yang Y Xiaoping Tang T

Dose-response : a publication of International Hormesis Society 20200701 3

<h4>Background</h4>Epilepsy is a chronic, complex, unprovoked, and recurrent disorder of the nervous system that affected several people worldwide. <i>Phyllanthus amarus</i> (PA) has been documented to have neuroprotective potential.<h4>Aim</h4>To evaluate the potential of standardized extract of PA and its possible mechanism of action against the Pentylenetetrazol (PTZ)-induced convulsion and kindling associated post-ictal depression in experimental mice.<h4>Materials and methods</h4>Phyllathin ...[more]

PMID: 32821254

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Project description:BackgroundPhyllanthus amarus has been used widely in various traditional medicines to treat swelling, sores, jaundice, inflammatory diseases, kidney disorders, diabetes and viral hepatitis, while its pharmacological and biochemical mechanisms underlying its anti-inflammatory properties have not been well investigated. The present study was carried out to investigate the effects of 80% ethanolic extract of P. amarus on pro-inflammatory mediators release in nuclear factor-kappa B (NF-кB), mitogen activated protein kinase (MAPK) and phosphatidylinositol 3-kinase/Akt (PI3K-Akt) signaling activation in lipopolysaccharide (LPS)-induced U937 human macrophages.MethodsThe release of prostaglandin E2 (PGE2) and pro-inflammatory cytokines, tumor necrosis factor (TNF)-α and interleukin (IL)-1β in a culture supernatant was determined by ELISA. Determination of cyclooxygenase-2 (COX-2) protein and the activation of MAPKs molecules (JNK, ERK and p38 MAPK), NF-κB and Akt in LPS-induced U937 human macrophages were investigated by immunoblot technique. The relative gene expression levels of COX-2 and pro-inflammatory cytokines were measured by using qRT-PCR. The major metabolites of P. amarus were qualitatively and quantitatively analyzed in the extract by using validated reversed-phase high performance liquid chromatography (HPLC) methods.ResultsP. amarus extract significantly inhibited the production of pro-inflammatory mediators (TNF-α, IL-1β, PGE2) and COX-2 protein expression in LPS-induced U937 human macrophages. P. amarus-pretreatment also significantly downregulated the increased mRNA transcription of pro-inflammatory markers (TNF-α, IL-1β, and COX-2) in respective LPS-induced U937 macrophages. It downregulated the phosphorylation of NF-κB (p65), IκBα, and IKKα/β and restored the degradation of IκBα, and attenuated the expression of Akt, JNK, ERK, and p38 MAPKs phosphorylation in a dose-dependent manner. P. amarus extract also downregulated the expression of upstream signaling molecules, TLR4 and MyD88, which play major role in activation of NF-κB, MAPK and PI3K-Akt signaling pathways. The quantitative amounts of lignans, phyllanthin, hypophyllahtin and niranthin, and polyphenols, gallic acid, geraniin, corilagin, and ellagic acid in the extract were determined by HPLC analysis.ConclusionThe study revealed that P. amarus targeted the NF-κB, MAPK and PI3K-Akt signaling pathways to exert its anti- inflammatory effects by downregulating the prospective inflammatory signaling mediators.

Project description:BackgroundThere is evidence that immune inflammation plays an important role in the of epilepsy. The toll-like receptor 4 (TLR4)/nuclear factor kappa beta (NF-κB) signaling pathway is a target for the treatment of epilepsy. TAK-242 is a potent TLR4 inhibitor with neuroprotective effects. No study has examined whether TAK-242 has a protective effect on epilepsy.MethodsMale C57BL/6 mice were randomly divided into the following 3 groups: (I) the control group; (II) the model [pentetrazol (PTZ)] group; and (III) the treatment group [PTZ + TAK-242 (3 mg/kg)], with 8 mice in each group. A mouse model of epilepsy was established via the intraperitoneal injection of PTZ (37 mg/kg). The behavioral changes of the mice were observed and scored using the Racine grading criteria. TAK-242 (3 mg/kg) was administered to establish the treatment model. The control group was intraperitoneally injected with normal saline at the same dose as the PTZ epileptogenic dose, and 3 mg/kg of normal saline was intragastrically administered. The messenger RNA (mRNA) and protein expressions of TLR4, NF-κB, and the NF-κB downstream gene tumor necrosis factor alpha (TNF-α) in the mouse brain tissues were detected by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot.ResultsCompared to the control group, the mice in the model group showed generalized tonic convulsion and involuntary falling after PTZ modeling. The results of the hematoxylin and eosin (H&E) staining showed that the treatment group had a higher number of normal neurons than the model group, and the neuronal cell morphology in the treatment group was closer to the control group. However, the occurrence of generalized tonic convulsion and involuntary falling in the mice in the treatment group was significantly improved. Comparing the Western Blot and RT-qPCR results, we detected higher TLR4, NF-KB, TNF-α protein and mRNA expression levels in the model group than the treatment group, and there was no significant difference between the control group and the treatment group.ConclusionsTAK-242 treatment ameliorates epileptic symptoms in mice, and the mechanism by which this occurs may be related to the inhibition of the TLR4/NF-κB inflammatory pathway.

Project description:Hypoxic ischemic encephalopathy (HIE) is the most common brain injury following hypoxia and/or ischemia caused by various factors during the perinatal period, resulting in detrimental neurological deficits in the nervous system. Tanshinone IIA (Tan‑IIA) is a potential agent for the treatment of cardiovascular and cerebrovascular diseases. In this study, the efficacy of Tan‑IIA was investigated in a newborn mouse model of HIE. The dynamic mechanism of Tan‑IIA was also investigated in the central nervous system of neonate mice. Intravenous injection of Tan‑IIA (5 mg/kg) was administered and changes in oxidative stress, inflammation and apoptosis‑associated proteins in neurons. Histology and immunohistochemistry was used to determine infarct volume and the number of damaged neurons by Fluoro‑Jade C staining. The effects of Tan‑IIA on mice with HIE were evaluated by body weight, brain water content, neurobehavioral tests and blood‑brain barrier permeability. The results demonstrated that the apoptosis rate was decreased following Tan‑IIA administration. Expression levels of pro‑apoptotic proteins, caspase‑3 and caspase‑9 and P53 were downregulated. Expression of Bcl‑2 anti‑apoptotic proteins was upregulated by Tan‑IIA treatment in neuro. Results also found that Tan‑IIA treatment decreased production of inflammatory cytokines such as interleukin‑1, tumor necrosis factor‑α, C‑X‑C motif chemokine 10, and chemokine (C‑C motif) ligand 12. Oxidative stress was also reduced by Tan‑IIA in neurons, as determined by the expression levels of superoxide dismutase, glutathione and catalase, and the production of reactive oxygen species. The results demonstrated that Tan‑IIA treatment reduced the infarct volume and the number of damaged neurons. Furthermore, body weight, brain water content and blood‑brain barrier permeability were markedly improved by Tan‑IIA treatment of newborn mice following HIE. Furthermore, the results indicated that Tan‑IIA decreased Toll‑like receptor‑4 (TLR‑4) and nuclear factor‑κB (NF‑κB) expression in neurons. TLR‑4 treatment of neuronal cell in vitro addition stimulated NF‑κB activity, and further enhanced the production of inflammatory cytokines and oxidative stress levels in neurons. In conclusion, these results suggest that Tan‑IIA treatment is beneficial for improvement of HIE through TLR‑4‑mediated NF‑κB signaling.

Dataset Information

Phyllathin From Phyllanthus Amarus Ameliorates Epileptic Convulsion and Kindling Associated Post-Ictal Depression in Mice via Inhibition of NF-κB/TLR-4 Pathway.

Background

Aim

Materials and methods

Results

Conclusion

Publications

Phyllathin From Phyllanthus Amarus Ameliorates Epileptic Convulsion and Kindling Associated Post-Ictal Depression in Mice via Inhibition of NF-κB/TLR-4 Pathway.

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