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Intranasal dantrolene nanoparticles inhibit inflammatory pyroptosis in 5XFAD mice brains
Background:
This study investigates the effects of intranasal dantrolene nanoparticles on inflammation and programmed cell death by pyroptosis in 5XFAD Alzheimer's Disease (AD) mice.
Methods:
5XFAD and wild type (WT) B6SJLF1/J mice were treated with intranasal dantrolene nanoparticles (5 mg/kg), daily, Monday to Friday, for 12 weeks continuously, starting at 9 months of age. Blood and brain were harvested at 13 months of age, one month after completion of 12 weeks intranasal dantrolene nanoparticle treatment. Blood biomarkers function of liver (Alanine transaminase, ALT), kidney (Creatinine), and thyroid (TSH: Thyroid-stimulating hormone) were measured using ELISA. The changes of whole brain tissue proteins on Ca 2+ release channels on membrane of endoplasmic reticulum (type 2 ryanodine and type 1 InsP3 receptors, RyR-2 and InsP3R-1), lipid peroxidation byproduct malondialdehyde (MDA)-modified proteins, 4-HNE, pyroptosis regulatory proteins (NLR family pyrin domain containing 3 (NLRP3), cleaved caspase-1, full length or N-terminal of Gasdermin D (GSDMD), cytotoxic (IL-1, IL-18, IL-6, TNF-a) and cytoprotective (IL-10) cytokines, astrogliosis (GFAP), microgliosis (IBA-1) and synapse proteins (PSD-95, Synapsin-1) were determined using immunoblotting. Body weights were monitored regularly.
Results:
Intranasal dantrolene nanoparticles significantly inhibited the increase of RyR-2 and InsP3R-1 proteins, MDA-modified proteins, 4-NHE, pyroptosis regulatory proteins (NLRP3, cleaved caspase-1, N-terminal GSDMD), cytotoxic cytokine (IL-1β, IL-18, IL-6, TNF-α), biomarkers for astrogliosis (GFAP) and microgliosis (IBA-1), and the decrease of cytoprotective cytokine (IL-10) and synaptic proteins (PSD-95, synpasin-1). Intranasal dantrolene nanoparticles for 12 weeks did not affect blood biomarkers for function of liver, kidney, and thyroid, not did it change body weight significantly.
Conclusion:
Intranasal dantrolene nanoparticles significantly inhibit the increase of RyR-2 and InsP 3 R-1 Ca 2+ channel receptor proteins, ameliorate activation of the pyroptosis pathway and pathological inflammation, and the associated loss of synapse proteins. Intranasal dantrolene nanoparticles for three months did not affect liver, kidney and thyroid functions or cause other side effects.
Insights
Intranasal dantrolene nanoparticles reduced inflammation and pyroptosis in Alzheimer's mice. This treatment protected against synapse loss without impacting organ function or body weight.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Alzheimer's Disease (AD) is characterized by neuroinflammation and programmed cell death.
- Pyroptosis, a pro-inflammatory form of cell death, is implicated in AD pathogenesis.
- Targeting cellular pathways involved in pyroptosis may offer therapeutic benefits for AD.
Purpose of the Study:
- To investigate the efficacy of intranasal dantrolene nanoparticles in mitigating inflammation and pyroptosis in a mouse model of Alzheimer's Disease.
- To assess the impact of this treatment on key molecular markers of AD pathology and neuronal function.
Main Methods:
- 5XFAD mice and wild-type littermates received daily intranasal dantrolene nanoparticles for 12 weeks.
- Evaluated changes in protein levels related to calcium release channels, lipid peroxidation, pyroptosis, inflammation, and synaptic function via immunoblotting.
- Assessed blood biomarkers for liver, kidney, and thyroid function, and monitored body weight.
Main Results:
- Dantrolene nanoparticles significantly reduced markers of pyroptosis (NLRP3, caspase-1, GSDMD), inflammation (IL-1β, IL-18, IL-6, TNF-α), astrogliosis (GFAP), and microgliosis (IBA-1).
- Treatment preserved levels of the anti-inflammatory cytokine IL-10 and synaptic proteins (PSD-95, Synapsin-1).
- No significant adverse effects were observed on liver, kidney, or thyroid function, nor on body weight.
Conclusions:
- Intranasal dantrolene nanoparticles effectively inhibit pyroptosis and neuroinflammation in an AD mouse model.
- The treatment preserves synaptic integrity and shows a favorable safety profile.
- Dantrolene nanoparticles represent a promising therapeutic strategy for Alzheimer's Disease.
