6,7,4'-Trihydroxyflavanone Mitigates Methamphetamine-Induced Neurotoxicity in SH-SY5y Cells via Nrf2/heme Oxyganase-1 and PI3K/Akt/mTOR Signaling Pathways.

Hyun-Su Lee,Gil-Saeng Jeong

doi:10.3390/molecules26092442

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.

Highlights

Methamphetamine (METH) is a highly addictive drug whose abuse has caused significant social and public health issues for decades [1]
Following from a previous study from our group in which the treatment of SHSY5y cells at a density of 1 × 104 /well with THF (Figure 1A) was not cytotoxic [27], we investigated whether THF leads to apoptosis in SH-SY5y cells at a lower density
With THF effectively preserved the effect of METH on SH-SY5y cells in a dose-dependent manner. These results suggest that METH exposure induces the apoptotic pathway by affecting apoptosis-related proteins, while pretreatment with THF restores the effect of METH on SH-SY5y cells

Summary

Introduction

Methamphetamine (METH) is a highly addictive drug whose abuse has caused significant social and public health issues for decades [1]. Various studies have reported that repeated exposure to METH causes severe neurotoxicity, which induces neuronal cell death [3,4]. Accumulating evidences from animal experiments have shown that neuronal toxicity by METH exposure leads to the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease [5,6]. A chronic effect of METH on neurodegenerative diseases has been shown to be associated with the production of reactive oxygen species (ROS) and damage to cellular molecules, including proteins, DNA, and lipids in neuronal cells [7,8]. The removal of accumulating oxidative stress induced by METH exposure using antioxidants may be a promising strategy to attenuate neurotoxicity

Methods

Results

Conclusion