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6,7,4'-Trihydroxyflavanone Mitigates Methamphetamine-Induced Neurotoxicity in SH-SY5y Cells via Nrf2/heme Oxyganase-1 and PI3K/Akt/mTOR Signaling Pathways.
Molecules. 2021 Apr 22; 26(9)M

Abstract

Methamphetamine (METH) is a synthetic psychostimulant drug that has detrimental effects on the health of its users. Although it has been investigated as a cause of neurodegenerative disease due to its neurotoxicity, whether small molecules derived from natural products attenuate these side effects remains elusive. 6,7,4'-trihydroxyflavanone (THF) is a flavanone family that possesses various pharmacological activities, including anti-rheumatic, anti-ischemic, anti-inflammatory, anti-osteoclastogenic, and protective effects against METH-induced deactivation of T cells. However, little is known about whether THF protects neuronal cells from METH-induced neurotoxicity. Here, we investigated the protective effects of THF on neurotoxicity induced by METH exposure by enhancing the Nrf2/HO-1 and PI3K/Akt/mTOR signaling pathways in SH-SY5y cells. Treatment with THF did not lead to cytotoxicity, but attenuated METH-induced neurotoxicity by modulating the expression of apoptosis-related proteins, METH-induced oxidative stress, and PI3K/Akt/mTOR phosphorylation in METH-exposed SH-SY5y cells. Moreover, we found THF induced Nrf2 nuclear translocation and HO-1 expression. An inhibitor assay confirmed that the induction of HO-1 by THF attenuates METH-induced neurotoxicity. Therefore, we suggest that THF preserves neuronal cells from METH-induced neurotoxicity by upregulating HO-1 expression through the Nrf2 and PI3K/Akt/mTOR signaling pathways. Thus, THF has therapeutic potential for use in the treatment of METH-addicts suffering from neurodegenerative diseases.

Authors+Show Affiliations

College of Pharmacy, Keimyung University, Daegu 42601, Korea.College of Pharmacy, Keimyung University, Daegu 42601, Korea.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33922144

Citation

Lee, Hyun-Su, and Gil-Saeng Jeong. "6,7,4'-Trihydroxyflavanone Mitigates Methamphetamine-Induced Neurotoxicity in SH-SY5y Cells Via Nrf2/heme Oxyganase-1 and PI3K/Akt/mTOR Signaling Pathways." Molecules (Basel, Switzerland), vol. 26, no. 9, 2021.
Lee HS, Jeong GS. 6,7,4'-Trihydroxyflavanone Mitigates Methamphetamine-Induced Neurotoxicity in SH-SY5y Cells via Nrf2/heme Oxyganase-1 and PI3K/Akt/mTOR Signaling Pathways. Molecules. 2021;26(9).
Lee, H. S., & Jeong, G. S. (2021). 6,7,4'-Trihydroxyflavanone Mitigates Methamphetamine-Induced Neurotoxicity in SH-SY5y Cells via Nrf2/heme Oxyganase-1 and PI3K/Akt/mTOR Signaling Pathways. Molecules (Basel, Switzerland), 26(9). https://doi.org/10.3390/molecules26092442
Lee HS, Jeong GS. 6,7,4'-Trihydroxyflavanone Mitigates Methamphetamine-Induced Neurotoxicity in SH-SY5y Cells Via Nrf2/heme Oxyganase-1 and PI3K/Akt/mTOR Signaling Pathways. Molecules. 2021 Apr 22;26(9) PubMed PMID: 33922144.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 6,7,4'-Trihydroxyflavanone Mitigates Methamphetamine-Induced Neurotoxicity in SH-SY5y Cells via Nrf2/heme Oxyganase-1 and PI3K/Akt/mTOR Signaling Pathways. AU - Lee,Hyun-Su, AU - Jeong,Gil-Saeng, Y1 - 2021/04/22/ PY - 2021/02/28/received PY - 2021/04/14/revised PY - 2021/04/20/accepted PY - 2021/4/30/entrez PY - 2021/5/1/pubmed PY - 2021/5/25/medline KW - 6,7,4′-trihydroxyflavanone KW - HO-1 KW - Nrf2 KW - PI3K KW - SH-SY5y cells KW - methamphetamine KW - neurotoxicity JF - Molecules (Basel, Switzerland) JO - Molecules VL - 26 IS - 9 N2 - Methamphetamine (METH) is a synthetic psychostimulant drug that has detrimental effects on the health of its users. Although it has been investigated as a cause of neurodegenerative disease due to its neurotoxicity, whether small molecules derived from natural products attenuate these side effects remains elusive. 6,7,4'-trihydroxyflavanone (THF) is a flavanone family that possesses various pharmacological activities, including anti-rheumatic, anti-ischemic, anti-inflammatory, anti-osteoclastogenic, and protective effects against METH-induced deactivation of T cells. However, little is known about whether THF protects neuronal cells from METH-induced neurotoxicity. Here, we investigated the protective effects of THF on neurotoxicity induced by METH exposure by enhancing the Nrf2/HO-1 and PI3K/Akt/mTOR signaling pathways in SH-SY5y cells. Treatment with THF did not lead to cytotoxicity, but attenuated METH-induced neurotoxicity by modulating the expression of apoptosis-related proteins, METH-induced oxidative stress, and PI3K/Akt/mTOR phosphorylation in METH-exposed SH-SY5y cells. Moreover, we found THF induced Nrf2 nuclear translocation and HO-1 expression. An inhibitor assay confirmed that the induction of HO-1 by THF attenuates METH-induced neurotoxicity. Therefore, we suggest that THF preserves neuronal cells from METH-induced neurotoxicity by upregulating HO-1 expression through the Nrf2 and PI3K/Akt/mTOR signaling pathways. Thus, THF has therapeutic potential for use in the treatment of METH-addicts suffering from neurodegenerative diseases. SN - 1420-3049 UR - https://www.unboundmedicine.com/medline/citation/33922144/674'_Trihydroxyflavanone_Mitigates_Methamphetamine_Induced_Neurotoxicity_in_SH_SY5y_Cells_via_Nrf2/heme_Oxyganase_1_and_PI3K/Akt/mTOR_Signaling_Pathways_ L2 - https://www.mdpi.com/resolver?pii=molecules26092442 DB - PRIME DP - Unbound Medicine ER -