Parkinson's disease is a common neurodegenerative disease. Although the exact etiology and natural course of this disease have yet to be fully clarified, numerous system-level processes and dysfunctions, have been implicated in the pathogenesis of Parkinson's disease.
Lipid droplets are highly dynamic organelles that emerge from the endoplasmic reticulum (ER) membrane. lipid droplets is involved in fatty acid storage and participate in many diseases. For example, myeloid cells, including macrophages, leukocytes, and eosinophils, form lipid droplets in response to inflammation and stress.
Normally, intracellular lipid droplets are degraded in lysosomes and deliver fatty acids to mitochondria for their consumption as an alternative energy source during periods of nutrient depletion. However, neurons have a low capacity for mitochondrial fatty acid consumption for energy production. This characteristic makes neurons particularly sensitive to lipid droplet accumulation and peroxidation.
Furthermore, the accumulation of lipid droplets enhances the fatty acid oxidation rate and imposes persistent pressure on the mitochondrial electron transport chain. Lipid overload also leads to ROS production by oxidative enzymes. Emerging evidence indicates that unexpected lipid droplet deposition and peroxidation can accelerate organelle stress and plays a crucial role in the pathogenesis of neurodegenerative diseases.
In a previous study, Xiaojuan Han and colleagues found that kaempferol, a natural flavonoid small molecule, exhibited neuroprotective effects on mice with drug-induced Parkinson's disease.
In the current study, the authors showed in-vitro that kaempferol protected against tyrosine hydroxylase neuronal loss and behavioral deficits in methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced Parkinson disease mice, accompanied by reduced lipid oxidative stress in the substantia nigra pars compacta.
Kaempferol-rich food has been linked to a decrease in the risk of developing some types of cancers and cardiovascular disease. Quercetin and kaempferol are among the most ubiquitous polyphenols in fruit and vegetables.
Kaempferol is a chemical produced by Kaempferia galanga, one of four plants called galangal. The extract of Kaempferia galanga causes central nervous system depression, a decrease in motor activity, and a decrease in respiratory rate.
The mice were treated with kaempferol. The rotarod performance time was markedly reduced in MPTP-treated mice, and this effect was prevented by kaempferol. kaempferol also restored the behavioral deficits induced by MPTP, as indicated by the reductions in the turning time and total time in the pole test, without affecting the body weights of the mice.
MPP+, the active metabolite of MPTP, inhibits mitochondrial complex enzymes and causes the cell death that is directly associated with PD. In cultured neuronal cells, kaempferol exhibited a relatively safe concentration range and significantly suppressed lipid droplet accumulation and cellular apoptosis induced by MPP.
Further studies indicated that the protective effect of kaempferol was dependent on autophagy, specifically lipophagy. Critically, kaempferol promoted autophagy to mediate lipid droplet degradation in lysosomes, which then alleviated lipid deposition and peroxidation and the resulting mitochondrial damage, consequently reducing neuronal death.
Furthermore a genetic knockdown abolished the neuroprotective effects of kaempferol against lipid oxidation in Parkinson disease mice.
This work demonstrates that kaempferol prevents dopaminergic neuronal degeneration in Parkinson disease via the inhibition of lipid peroxidation-mediated mitochondrial damage by promoting lipophagy and provides a potential novel therapeutic strategy for Parkinson disease and related NDDs.