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Published on: August 23, 2022
Neuroprotection by dihydrotestosterone in LPS-induced neuroinflammation
Lei Yang1, Renyuan Zhou2, Yu Tong1
1Department of Urology, Jing'an District Central Hospital, Fudan University, Shanghai 200040, China.
Abstract:
Microglia-induced neuroinflammation plays a vital role in the etiology and progression of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and multiple sclerosis. The neuroprotective role of androgens, including testosterone and its metabolite dihydrotestosterone (DHT), has been increasingly demonstrated in these diseases, but few studies investigated the effects of androgen on neuroinflammation. This study investigated the role of DHT in lipopolysaccharide (LPS)-induced neuroinflammation, neuronal damage and behavioral dysfunction, as well as underlying mechanisms. We showed that DHT inhibited LPS-induced release of proinflammatory factors, including TNF-α, IL-1β, IL-6; iNOS, COX-2, NO, and PGE2 in BV2 cells and primary microglia by suppressing the TLR4-mediated NF-κB and MAPK p38 signaling pathways, thus protecting SH-SY5Y neurons from inflammatory damage induced by activated microglia. In an LPS-induced neuroinflammation mouse model, endogenous DHT depletion by castration exacerbated inflammatory responses by upregulating the levels of TNF-α, IL-1β, IL-6, iNOS, and COX-2 in the serum and brain by increasing the LR4-mediated NF-κB and MAPK pathway activation, but these effects were restored by exogenous DHT supplementation. Moreover, DHT also regulated the mRNA levels of the anti-inflammatory cytokines IL-10 and IL-13 in the brain. In addition, DHT modulated the expression of Aβ, the apoptotic proteins caspase-3, Bcl-2, and Bax, and synaptophysin, as well as neuronal damage in LPS-treated mouse brains. Further behavioral tests revealed that DHT ameliorated LPS-induced spatial and learning impairment and motor incoordination, and partly improved the locomotor activity in LPS-injected mice. Therefore, this study suggests that DHT exerts anti-neuroinflammatory and neuroprotective effects; thus, androgen replacement therapy is a potential therapeutic strategy for improving cognitive and behavioral function in neuroinflammation-related diseases.
Insights
Dihydrotestosterone (DHT) reduces neuroinflammation and protects neurons by suppressing inflammatory pathways. Androgen replacement therapy may improve cognitive and behavioral deficits in neurodegenerative diseases.
Area of Science:
- Neuroscience
- Immunology
- Endocrinology
Background:
- Neuroinflammation, driven by microglia, is central to neurodegenerative diseases like Alzheimer's and Parkinson's.
- Androgens, such as dihydrotestosterone (DHT), show neuroprotective potential, but their anti-inflammatory effects remain understudied.
Purpose of the Study:
- To investigate the role of DHT in lipopolysaccharide (LPS)-induced neuroinflammation, neuronal damage, and behavioral dysfunction.
- To elucidate the underlying molecular mechanisms of DHT's action in neuroinflammation.
Main Methods:
- In vitro studies using BV2 cells and primary microglia exposed to LPS.
- In vivo studies using an LPS-induced neuroinflammation mouse model with castration and DHT supplementation.
- Analysis of inflammatory factors, signaling pathways (TLR4-NF-κB, MAPK), apoptotic markers, and behavioral tests.
Main Results:
- DHT inhibited LPS-induced release of pro-inflammatory factors (TNF-α, IL-1β, IL-6) and mediators (NO, PGE2) by suppressing TLR4-mediated NF-κB and MAPK pathways.
- DHT protected neurons from microglial inflammatory damage.
- DHT supplementation reversed inflammation and cognitive/motor deficits in a mouse model of neuroinflammation.
Conclusions:
- DHT exhibits significant anti-neuroinflammatory and neuroprotective properties.
- DHT modulates key inflammatory and apoptotic pathways, offering therapeutic potential.
- Androgen replacement therapy, specifically with DHT, is a promising strategy for neuroinflammation-related diseases.
