Idebenone Regulates Aβ and LPS-Induced Neurogliosis and Cognitive Function Through Inhibition of NLRP3 Inflammasome/IL-1β Axis Activation.

Hyun-Ju Lee,Jin-Hee Park,Hyang-Sook Hoe

doi:10.3389/fimmu.2022.749336

Abstract

Idebenone is an analogue of coenzyme Q10, an electron donor in the mitochondrial electron transport chain, and thus may function as an antioxidant to facilitate mitochondrial function. However, whether idebenone modulates LPS- and Aβ-mediated neuroinflammatory responses and cognitive function in vivo is unknown. The present study explored the effects of idebenone on LPS- or Aβ-mediated neuroinflammation, learning and memory and the underlying molecular mechanisms in wild-type (WT) mice and 5xFAD mice, a mouse model of Alzheimer’s disease (AD). In male and female WT mice, idebenone upregulated neuroprotective NRF2 expression, rescued LPS-induced spatial and recognition memory impairments, and reduced NLRP3 priming and subsequent neuroinflammation. Moreover, idebenone downregulated LPS-mediated neurogliosis, reactive oxygen species (ROS) levels, and mitochondrial function in BV2 microglial cells and primary astrocytes by inhibiting NLRP3 inflammasome activation. In 5xFAD mice, idebenone increased neuroprotective NRF2 expression and improved amyloid beta (Aβ)-induced cognitive dysfunction. Idebenone downregulated Aβ-mediated gliosis and proinflammatory cytokine levels in 5xFAD mice by modulating the vicious NLRP3/caspase-1/IL-1β neuroinflammation cycle. Taken together, our results suggest that idebenone targets neuroglial NLRP3 inflammasome activation and therefore may have neuroprotective effects and inhibit the pathological progression of neuroinflammation-related diseases.

Highlights

In the normal adult brain, two types of neuroglial cells, microglia and astrocytes, regulate CNS homeostasis by synchronizing neuronal activity [1]
Male and female WT mice were injected with idebenone (100 mg/kg, i.p.) or vehicle (5% DMSO + 10% polyethylene glycol (PEG) + 20% Tween80) followed by LPS (250 mg/kg, i.p.) or PBS administration 30 min later; this regimen was repeated daily for 7 consecutive days, and immunofluorescence staining was performed with an anti-NRF2 antibody
NRF2 expression was increased in the CA1 and DG of idebenone-treated male WT mice compared with male WT mice injected with LPS only (Figures 1A, B)

Summary

Introduction

In the normal adult brain, two types of neuroglial cells, microglia and astrocytes, regulate CNS homeostasis by synchronizing neuronal activity [1]. Abnormal ROS accumulation induces NLRP3 inflammasome assembly followed by activation of caspase-1 and the subsequent release of the pro-inflammatory cytokines IL-1b and IL-18 [5]. Upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2), a neuroprotective transcription factor, suppresses NLRP3, IL-1b, and IL-18 protein expression in the cerebral cortex in a rat model of middle cerebral artery occlusion [9]. These observations suggest that targeting the vicious NLRP3/IL-1b axis may be a feasible strategy for treating neuroinflammation-related diseases

Methods

Results

Discussion

Conclusion