Dataset Information

Gastrodin Attenuates Pentylenetetrazole-Induced Seizures by Modulating the Mitogen-Activated Protein Kinase-Associated Inflammatory Responses in Mice.

ABSTRACT: Gastrodin, the major component isolated from the rhizome of the Chinese traditional medicinal herb Gastrodia elata ("Tianma"), has a long history in the treatment of epilepsy and other neurological disorders. However, the molecular mechanisms are not clear. Here, we found that gastrodin ameliorated pentylenetetrazole (PTZ)-induced epileptic seizures with improvement of the electroencephalographic pattern in mice. Further studies demonstrated that gastrodin decreased the levels of the pro-inflammatory cytokines interleukin-1? and tumor necrosis factor-? while increasing interleukin-10, an anti-inflammatory cytokine in the brain. Furthermore, gastrodin attenuated the PTZ-induced microglial activation along with inhibition of mitogen-activated protein kinases, cAMP response element binding protein, and NF-?B. Our data suggest that gastrodin attenuates seizures by modulating the mitogen-activated protein kinase-associated inflammatory responses.

SUBMITTER: Chen L

PROVIDER: S-EPMC5567506 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Gastrodin Attenuates Pentylenetetrazole-Induced Seizures by Modulating the Mitogen-Activated Protein Kinase-Associated Inflammatory Responses in Mice.

Chen Liming L Liu Xinan X Wang Hua H Qu Min M

Neuroscience bulletin 20161201 3

Gastrodin, the major component isolated from the rhizome of the Chinese traditional medicinal herb Gastrodia elata ("Tianma"), has a long history in the treatment of epilepsy and other neurological disorders. However, the molecular mechanisms are not clear. Here, we found that gastrodin ameliorated pentylenetetrazole (PTZ)-induced epileptic seizures with improvement of the electroencephalographic pattern in mice. Further studies demonstrated that gastrodin decreased the levels of the pro-inflamm ...[more]

PMID: 27909971

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Project description:The mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway is an essential component of innate immunity necessary for mediating proinflammatory responses in the setting of sepsis. We previously demonstrated that the mitogen-activated protein kinase 1/2 inhibitor trametinib prevents endotoxin-induced renal injury in mice. We therefore assessed efficacy of trametinib in a more clinically relevant experimental model of sepsis.Controlled in vivo laboratory study.University animal research laboratory.Male C57BL/6 mice.Mice were subjected to cecal ligation and puncture to induce sepsis or underwent sham operation as controls. Six hours after cecal ligation and puncture, mice were randomized to four experimental groups as follows: 1) sham control; 2) sham control + trametinib (1?mg/kg, IP); 3) cecal ligation and puncture; and 4) cecal ligation and puncture + trametinib. All animals received buprenorphine (0.05?mg/kg, SC) and imipenem/cilastatin (14?mg/kg, SC) in 1.5?mL of warm saline (40?mL/kg) at the 6-hour time point. Mice were euthanized at 18 hours after induction of cecal ligation and puncture.Trametinib inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase signaling 6 hours after cecal ligation and puncture attenuated increases in circulating proinflammatory cytokines (tumor necrosis factor-?, interleukin-1?, interleukin-6, and granulocyte macrophage colony-stimulating factor) and hypothermia at 18 hours. Trametinib also attenuated multiple organ injury as determined by serum creatinine, alanine aminotransferase, lactate dehydrogenase, and creatine kinase. At the organ level, trametinib completely restored peritubular capillary perfusion in the kidney. Restoration of microvascular perfusion was associated with reduced messenger RNA expression of well-characterized markers of proximal tubule injury. mitogen-activated protein kinase/extracellular signal-regulated kinase blockade attenuated cecal ligation and puncture-mediated up-regulation of cytokines (tumor necrosis factor-?, interleukin-1?) and restored interleukin-6 to control levels in the renal cortex, indicating the protective effects on the proximal tubule occur primarily through modulation of the proinflammatory response in sepsis.These data reveal that the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor trametinib attenuates systemic inflammation and multiple organ damage in a clinically relevant model of sepsis. Because trametinib has been safely used in humans, we propose that this drug might represent a translatable approach to limit organ injury in septic patients.

Project description:BackgroundApoptosis signal-regulating kinase 1 (ASK1) not only causes neuronal programmed cell death via the mitochondrial pathway but also is an essential component of the signalling cascade during microglial activation. We hypothesize that ASK1 selective deletion modulates inflammatory responses in microglia/macrophages(Mi/Mϕ) and attenuates seizure severity and long-term cognitive impairments in an epileptic mouse model.MethodsMi/Mϕ-specific ASK1 conditional knockout (ASK1 cKO) mice were obtained for experiments by mating ASK1flox/flox mice with CX3CR1creER mice with tamoxifen induction. Epileptic seizures were induced by intrahippocampal injection of kainic acid (KA). ASK1 expression and distribution were detected by western blotting and immunofluorescence staining. Seizures were monitored for 24 h per day with video recordings. Cognition, social and stress related activities were assessed with the Y maze test and the three-chamber social novelty preference test. The heterogeneous Mi/Mϕ status and inflammatory profiles were assessed with immunofluorescence staining and real-time polymerase chain reaction (q-PCR). Immunofluorescence staining was used to detect the proportion of Mi/Mϕ in contact with apoptotic neurons, as well as neuronal damage.ResultsASK1 was highly expressed in Mi/Mϕ during the acute phase of epilepsy. Conditional knockout of ASK1 in Mi/Mϕ markedly reduced the frequency of seizures in the acute phase and the frequency of spontaneous recurrent seizures (SRSs) in the chronic phase. In addition, ASK1 conditional knockout mice displayed long-term neurobehavioral improvements during the Y maze test and the three-chamber social novelty preference test. ASK1 selective knockout mitigated neuroinflammation, as evidenced by lower levels of Iba1+/CD16+ proinflammatory Mi/Mϕ. Conditional knockout of ASK1 increased Mi/Mϕ proportion in contact with apoptotic neurons. Neuronal loss was partially restored by ASK1 selective knockout.ConclusionConditional knockout of ASK1 in Mi/Mϕ reduced seizure severity, neurobehavioral impairments, and histological damage, at least via inhibiting proinflammatory microglia/macrophages responses. ASK1 in microglia/macrophages is a potential therapeutic target for inflammatory responses in epilepsy.

Dataset Information

Gastrodin Attenuates Pentylenetetrazole-Induced Seizures by Modulating the Mitogen-Activated Protein Kinase-Associated Inflammatory Responses in Mice.

Publications

Gastrodin Attenuates Pentylenetetrazole-Induced Seizures by Modulating the Mitogen-Activated Protein Kinase-Associated Inflammatory Responses in Mice.

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