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

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.

Efficacy of idebenone in the Treatment of iRBD into Synucleinopathies (EITRS): rationale, design, and methodology of a randomized, double-blind, multi-center clinical study

“…Other non-motor symptoms such as sleep disorder, autonomic dysfunction, cognitive and psychiatric impairment can also be improved. The underlying mechanisms are multitudinous and comprehensive, including the regulation of 5-hydroxytryptamine neurotransmitter and hippocampal function, the protection against oxidative stress injury, the inhibition of apoptosis signal and the activation of mitochondrial function ( 20 , 43 ). It seems that a novel indication of idebenone is promising on preventing or delaying neurodegeneration with its favorable safety and tolerability profiles when administrated in a prodromal stage.…”

Inhibiting EGFR/HER-2 ameliorates neuroinflammatory responses and the early stage of tau pathology through DYRK1A

“…79306) was used to synthesize cDNA by reverse transcription. RT-PCR was then performed using Prime Taq Premix (GeNet Bio) with the cDNA template as previously described ( 7 , 8 , 16 ). The products were electrophoretically separated on a 1.5% agarose gel stained with EcoDye (1:5000, Biofact, Daejeon, Korea).…”

“…The effects of varlitinib on LPS-induced proinflammatory responses were assessed in mouse primary astrocytes isolated as previously described (6)(7)(8)(16)(17)(18)(19)(20). First, whole brains were dissected from C57BL6 mice on postnatal day 1 and filtered through nylon mesh (70 mm).…”

“…The mRNA levels of proinflammatory cytokines and nlrp3 in BV2 microglial cells, primary astrocytes, and LPS-treated wild-type mice were measured by real-time PCR (6)(7)(8)(16)(17)(18)(19)(20). First, cDNA was synthesized with Superscript cDNA Premix Kit II (GeNet Bio).…”

“…The upregulation of these two proteins facilitates NLRP3 inflammasome assembly by enhancing auto-oligomerization, leading to severe LPS-induced neuroinflammation (5). Recent studies have reported that the induction of the proinflammatory cytokines IL-1b, IL-6, and COX-2 by LPS promotes the formation of the NLRP3 inflammasome in BV2 microglia and mouse primary astrocytes (6)(7)(8). These observations indicate that NLRP3, pro-IL-1b, and IL-1b could be important targets for therapeutic drugs for neuroinflammation.…”