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Published on: September 9, 2020
Curcumin attenuates glutamate-induced HT22 cell death by suppressing MAP kinase signaling
Hyun-Woo Suh1, Seongman Kang, Ki-Sun Kwon
1Laboratory of Functional Proteomics, Korea Research Institute of Bioscience and Biotechnology, 52 Oun-dong, Yusong, Taejon, 305-333, Korea.
Abstract:
Glutamate induces cell death by upsetting the cellular redox homeostasis, termed oxidative glutamate toxicity, in a mouse hippocampal cell line, HT22. Extracellular signal-regulated kinases (ERK) 1/2 are known key players in this process. Here we characterized the roles of both MAP kinases and cell cycle regulators in mediating oxidative glutamate toxicity and the neuroprotective mechanisms of curcumin in HT22 cells. c-Jun N-terminal kinase (JNK) and p38 kinase were activated during the glutamate-induced HT22 cell death, but at a later stage than ERK activation. Treatment with a JNK inhibitor, SP600125, or a p38 kinase inhibitor, SB203580, partly attenuated this cell death. Curcumin, a natural inhibitor of JNK signaling, protected the HT22 cells from glutamate-induced death at nanomolar concentrations more efficiently than SP600125. These doses of curcumin affected neither the level of intracellular glutathione nor the level of reactive oxygen species, but inactivated JNK and p38 significantly. Moreover, curcumin markedly upregulated a cell-cycle inhibitory protein, p21cip1, and downregulated cyclin D1 levels, which might help the cell death prevention. Our results suggest that curcumin has a neuroprotective effect against oxidative glutamate toxicity by inhibiting MAP kinase signaling and influencing cell-cycle regulation.
Insights
Curcumin protects against glutamate-induced cell death by inhibiting stress-activated protein kinases (SAP kinases) and modulating cell cycle regulators. This natural compound offers neuroprotection by targeting key signaling pathways involved in oxidative stress.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Glutamate can induce cell death via oxidative stress in neuronal cells.
- Extracellular signal-regulated kinases (ERK) are implicated in this process.
- Understanding the roles of other MAP kinases and cell cycle regulators is crucial.
Purpose of the Study:
- To investigate the roles of c-Jun N-terminal kinase (JNK) and p38 kinase in oxidative glutamate toxicity.
- To explore the neuroprotective mechanisms of curcumin in HT22 cells.
- To determine if curcumin affects MAP kinase signaling and cell cycle regulation.
Main Methods:
- Utilized HT22 mouse hippocampal cell line.
- Induced oxidative glutamate toxicity.
- Administered JNK inhibitor (SP600125) and p38 kinase inhibitor (SB203580).
- Treated cells with varying concentrations of curcumin.
- Assessed levels of intracellular glutathione and reactive oxygen species.
- Measured activation of JNK and p38.
- Analyzed expression of cell-cycle proteins p21cip1 and cyclin D1.
Main Results:
- JNK and p38 kinases were activated during glutamate-induced cell death, subsequent to ERK activation.
- Inhibitors of JNK and p38 partially protected cells.
- Curcumin demonstrated potent neuroprotection at nanomolar concentrations, surpassing SP600125 efficacy.
- Curcumin inactivated JNK and p38 without altering glutathione or reactive oxygen species levels.
- Curcumin upregulated p21cip1 and downregulated cyclin D1, suggesting cell cycle regulation involvement.
Conclusions:
- Curcumin exerts neuroprotective effects against oxidative glutamate toxicity.
- The mechanism involves inhibition of MAP kinase signaling (JNK and p38).
- Curcumin also influences cell-cycle regulation, contributing to cell death prevention.
