Neuroprotective Potential of Raloxifene via G-Protein-Coupled Estrogen Receptors in Aβ-Oligomer-Induced Neuronal Injury

Tetsuhito Nohara; Mayumi Tsuji; Tatsunori Oguchi; Yutaro Momma; Hideaki Ohashi; Miki Nagata; Naohito Ito; Ken Yamamoto; Hidetomo Murakami; Yuji Kiuchi

doi:10.3390/biomedicines11082135

Neuroprotective Potential of Raloxifene via G-Protein-Coupled Estrogen Receptors in Aβ-Oligomer-Induced Neuronal Injury

Biomedicines. 2023 Jul 28;11(8):2135. doi: 10.3390/biomedicines11082135.

Authors

Tetsuhito Nohara^{1

2}, Mayumi Tsuji³, Tatsunori Oguchi^{1

3}, Yutaro Momma^{1

2}, Hideaki Ohashi², Miki Nagata⁴, Naohito Ito^{1

2}, Ken Yamamoto^{1

2}, Hidetomo Murakami², Yuji Kiuchi^{1

3}

Affiliations

¹ Division of Medical Pharmacology, Department of Pharmacology, School of Medicine, Showa University, Tokyo 142-8555, Japan.
² Division of Neurology, Department of Internal Medicine, School of Medicine, Showa University, Tokyo 142-8555, Japan.
³ Pharmacological Research Center, Showa University, Tokyo 142-8555, Japan.
⁴ Department of Hospital Pharmaceutics, School of Pharmacy, Showa University, Tokyo 142-8555, Japan.

Abstract

Amyloid-β (Aβ) is one of the causes of Alzheimer's disease (AD), damaging nerve membranes and inducing neurotoxicity. AD is more prevalent in female patients than in male patients, and women are more susceptible to developing AD due to the decline in estrogen levels around menopause. Raloxifene, a selective estrogen receptor modulator, exhibits protective effects by activating the transmembrane G-protein-coupled estrogen receptor (GPER). Additionally, raloxifene prevents mild cognitive impairment and restores cognition. However, the influence of raloxifene via GPER on highly toxic Aβ-oligomers (Aβo)-induced neurotoxicity remains uncertain. In this study, we investigated the GPER-mediated neuroprotective effects of raloxifene against the neurotoxicity caused by Aβo-induced cytotoxicity. The impact of raloxifene on Aβo-induced cell damage was evaluated using measures such as cell viability, production of reactive oxygen species (ROS) and mitochondrial ROS, peroxidation of cell-membrane phospholipids, and changes in intracellular calcium ion concentration ([Ca²⁺]_i) levels. Raloxifene hindered Aβo-induced oxidative stress and reduced excessive [Ca²⁺]_i, resulting in improved cell viability. Furthermore, these effects of raloxifene were inhibited with pretreatment with a GPER antagonist. Our findings suggest that raloxifene safeguards against Aβo-induced neurotoxicity by modifying oxidative parameters and maintaining [Ca²⁺]_i homeostasis. Raloxifene may prove effective in preventing and inhibiting the progression of AD.

Keywords: Alzheimer’s disease; Aβ oligomers; GPER; neurotoxicity; oxidative stress; raloxifene.

Grants and funding

This research was funded by Grants-in-Aid for Scientific Research (Kakenhi), Japan Society for the Promotion of Science (JSPS), grant number JP19K11698 (M.T.).