Adjudin prevents neuronal damage and neuroinflammation via inhibiting mTOR activation against pilocarpine-induced status epilepticus

Park, Soo‐Jin; Zhu, Jing; Jeong, Kiho; Kim, Won Joo

doi:10.1016/j.brainresbull.2022.02.009

Cited by 8 publications

(8 citation statements)

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“…18,23 To evaluate the effect of eugenol treatment on SE-induced neuronal damage, eugenol or vehicle solution was treated by intraperitoneal injection per day, starting 1 h after diazepam treatment and continuing daily until three days after SE, as previously described. 9,24 The experimental mice were randomly divided into three groups: sham control (Sham; n = 8), mice treated with vehicle solution for three days after SE (SE3d-Veh; n = 8), and mice treated with eugenol for three days after SE (SE3d-EUG; n = 8). All procedures were approved by the Institutional Committee for the Care and Use of Laboratory Animals at Yonsei University Health System and were performed in accordance with the National Institute of Health guidelines for the Care and Use of Laboratory Animals.…”

Section: Methodsmentioning

confidence: 99%

“…Fixed brains were cryoprotected with 30% sucrose in 0.1 M PB for three days. As previously described, 9 serial coronal sections (20 μm thick) were collected between bregma – 1.46 mm and – 2.30 mm using a cryomicrotome (Leica Microsystems, Wetzlar, Germany). For histological assessment of hippocampal neuronal damage, we randomly selected the three sections for each animal, and then the selected sections were stained with 0.1% cresyl violet solution for 5 min.…”

Section: Methodsmentioning

confidence: 99%

“…Studies have shown that inflammatory processes are characterized by the reactivity of glial cells, such as reactive astrocytes and activated microglia, in epileptic brain tissues, accompanied by severe neuronal damage. [9][10][11] As a brain injury factor, uncontrolled glial activation promotes the release of proinflammatory cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα), leading to neuronal cell loss and maladaptive synaptic plasticity. 12,13 Consequently, these inflammatory processes can trigger seizures and the development of epilepsy.…”

Section: Impact Statementmentioning

confidence: 99%

“…A mouse model of pilocarpine-induced SE was established as previously described. 9 Briefly, adult male C57BL/6 mice (8 weeks old, 22-23 g, Orientbio, Gyeonggi, Korea) were housed under a 12-h light/dark cycle with food and water ad libitum for seven days. After an acclimation phase, to induce SE, mice were intraperitoneally injected with pilocarpine hydrochloride (325 mg/kg; Sigma, St. Louis, MO, USA), preceded by 30 min of scopolamine methyl nitrate (1 mg/kg, i.p.…”

Section: Pilocarpine-induced Sementioning

confidence: 99%

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Eugenol alleviates neuronal damage via inhibiting inflammatory process against pilocarpine-induced status epilepticus

Zhu

Park

Kim

et al. 2023

Exp Biol Med (Maywood)

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Neuroinflammation is one of the most common pathological outcomes in various neurological diseases. A growing body of evidence suggests that neuroinflammation plays a pivotal role in the pathogenesis of epileptic seizures. Eugenol is the major phytoconstituent of essential oils extracted from several plants and possesses protective and anticonvulsant properties. However, it remains unclear whether eugenol exerts an anti-inflammatory effect to protect against severe neuronal damage induced by epileptic seizures. In this study, we investigated the anti-inflammatory action of eugenol in an experimental epilepsy model of pilocarpine-induced status epilepticus (SE). To examine the protective effect of eugenol via anti-inflammatory mechanisms, eugenol (200 mg/kg) was administrated daily for three days after pilocarpine-induced SE onset. The anti-inflammatory action of eugenol was evaluated by examining the expression of reactive gliosis, pro-inflammatory cytokines, nuclear factor-κB (NF-κB), and the nucleotide-binding domain leucine-rich repeat with a pyrin-domain containing 3 (NLRP3) inflammasome. Our results showed that eugenol reduced SE-induced apoptotic neuronal cell death, mitigated the activation of astrocytes and microglia, and attenuated the expression of interleukin-1β and tumor necrosis factor α in the hippocampus after SE onset. Furthermore, eugenol inhibited NF-κB activation and the formation of the NLRP3 inflammasome in the hippocampus after SE. These results suggest that eugenol is a potential phytoconstituent that suppresses the neuroinflammatory processes induced by epileptic seizures. Therefore, these findings provide evidence that eugenol has therapeutic potential for epileptic seizures.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Impact Statementmentioning

confidence: 99%

Section: Pilocarpine-induced Sementioning

confidence: 99%

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Eugenol alleviates neuronal damage via inhibiting inflammatory process against pilocarpine-induced status epilepticus

Zhu

Park

Kim

et al. 2023

Exp Biol Med (Maywood)

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“…Xiao et al (2015) found that IL-1β-induced inflammation and epileptic seizure were suppressed by inhibition of the mTOR signaling pathway in a rat model of MTLE. Drugs that inhibit mTOR pathway activation have also been found to improve neuronal damage and neuroinflammation in the hippocampus (Park et al, 2022). For instance, rapamycin inhibits the inflammatory response by inhibiting microglia activation.…”

Section: Dysregulation Of Mtor Signaling Pathway Increases Neuroinfla...mentioning

confidence: 99%

Advances in the mTOR signaling pathway and its inhibitor rapamycin in epilepsy

et al. 2023

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Introduction: Epilepsy is one of the most common and serious brain syndromes and has adverse consequences on a patient's neurobiological, cognitive, psychological, and social wellbeing, thereby threatening their quality of life. Some patients with epilepsy experience poor treatment effects due to the unclear pathophysiological mechanisms of the syndrome. Dysregulation of the mammalian target of the rapamycin (mTOR) pathway is thought to play an important role in the onset and progression of some epilepsies.Methods: This review summarizes the role of the mTOR signaling pathway in the pathogenesis of epilepsy and the prospects for the use of mTOR inhibitors. Results:The mTOR pathway functions as a vital mediator in epilepsy development through diverse mechanisms, indicating that the it has great potential as an effective target for epilepsy therapy. The excessive activation of mTOR signaling pathway leads to structural changes in neurons, inhibits autophagy, exacerbates neuron damage, affects mossy fiber sprouting, enhances neuronal excitability, increases neuroinflammation, and is closely associated with tau upregulation in epilepsy. A growing number of studies have demonstrated that mTOR inhibitors exhibit significant antiepileptic effects in both clinical applications and animal models. Specifically, rapamycin, a specific inhibitor of TOR, reduces the intensity and frequency of seizures. Clinical studies in patients with tuberous sclerosis complex have shown that rapamycin has the function of reducing seizures and improving this disease. Everolimus, a chemically modified derivative of rapamycin, has been approved as an added treatment to other antiepileptic medicines. Further explorations are needed to evaluate the therapeutic efficacy andThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Sirtuin 3 regulates astrocyte activation by reducing Notch1 signaling after status epilepticus

Zhu,

Park,

Kim

et al. 2024

Glia

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Sirtuin3 (Sirt3) is a nicotinamide adenine dinucleotide enzyme that contributes to aging, cancer, and neurodegenerative diseases. Recent studies have reported that Sirt3 exerts anti‐inflammatory effects in several neuropathophysiological disorders. As epilepsy is a common neurological disease, in the present study, we investigated the role of Sirt3 in astrocyte activation and inflammatory processes after epileptic seizures. We found the elevated expression of Sirt3 within reactive astrocytes as well as in the surrounding cells in the hippocampus of patients with temporal lobe epilepsy and a mouse model of pilocarpine‐induced status epilepticus (SE). The upregulation of Sirt3 by treatment with adjudin, a potential Sirt3 activator, alleviated SE‐induced astrocyte activation; whereas, Sirt3 deficiency exacerbated astrocyte activation in the hippocampus after SE. In addition, our results showed that Sirt3 upregulation attenuated the activation of Notch1 signaling, nuclear factor kappa B (NF‐κB) activity, and the production of interleukin‐1β (IL1β) in the hippocampus after SE. By contrast, Sirt3 deficiency enhanced the activity of Notch1/NF‐κB signaling and the production of IL1β. These findings suggest that Sirt3 regulates astrocyte activation by affecting the Notch1/NF‐κB signaling pathway, which contributes to the inflammatory response after SE. Therefore, therapies targeting Sirt3 may be a worthy direction for limiting inflammatory responses following epileptic brain injury.

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Adjudin prevents neuronal damage and neuroinflammation via inhibiting mTOR activation against pilocarpine-induced status epilepticus

Cited by 8 publications

References 51 publications

Eugenol alleviates neuronal damage via inhibiting inflammatory process against pilocarpine-induced status epilepticus

Eugenol alleviates neuronal damage via inhibiting inflammatory process against pilocarpine-induced status epilepticus

Advances in the mTOR signaling pathway and its inhibitor rapamycin in epilepsy

Sirtuin 3 regulates astrocyte activation by reducing Notch1 signaling after status epilepticus

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