Kaempferol alleviates LD-mitochondrial damage by promoting autophagy: Implications in Parkinson's disease

Abstract

Emerging evidence indicates that unexpected lipid droplet (LD) deposition and peroxidation can accelerate organelle stress and plays a crucial role in the pathogenesis of neurodegenerative diseases (NDDs). In our previous study, we confirmed that kaempferol (Ka), a natural flavonoid small molecule, exhibited neuroprotective effects on mice with LPS-induced Parkinson's disease (PD). In addition, previous studies have shown that autophagy plays an important role in the regulation of cellular LD deposition. In the current study, we showed that Ka protected against TH + neuronal loss and behavioral deficits in MPTP/p-induced PD mice, accompanied by reduced lipid oxidative stress in the substantia nigra pars compacta (SNpc). In cultured neuronal cells, Ka exhibited a relatively safe concentration range and significantly suppressed LD accumulation and cellular apoptosis induced by MPP + . Further study indicated that the protective effect of Ka was dependent on autophagy, specifically lipophagy. Critically, Ka promoted autophagy to mediate LD degradation in lysosomes, which then alleviated lipid deposition and peroxidation and the resulting mitochondrial damage, consequently reducing neuronal death. Furthermore, AAV-shAtg5-mediated Atg5 knockdown abolished the neuroprotective effects of Ka against lipid oxidation in PD mice. This work demonstrates that Ka prevents dopaminergic neuronal degeneration in PD via the inhibition of lipid peroxidation-mediated mitochondrial damage by promoting lipophagy and provides a potential novel therapeutic strategy for PD and related NDDs.

Kaempferol Has Potent Protective and Antifibrillogenic Effects for α-Synuclein Neurotoxicity In Vitro

“…In previous studies [ 10 , 11 , 12 ], kaempferol has shown neuroprotective effects in animal models of PD. In these studies, the researchers used a concentration of 5 µM or higher of kaempferol.…”

“…Kaempferol was also reported to increase the resistance of DA neurons to neuroinflammation [ 11 ]. In addition, kaempferol apparently prevented lipid droplet toxicity in vitro and ameliorated DA neuronal loss and behavioral deficits in a PD mouse model; these effects were found to be autophagy-dependent [ 11 , 12 ]. However, the effect of kaempferol on α-Syn-related neurotoxicity induced via the autophagy pathway has not yet been investigated.…”

Quercetin hinders microglial activation to alleviate neurotoxicity via the interplay between NLRP3 inflammasome and mitophagy

“…During the last 4 min, duration of immobility (hanging passively and motionless) was recorded with TailSuspScan (Clever Sys). The rotarod test was performed as described in our previous work [ 39 ]. In brief, mice were acclimatized to the rotarod for 2 consecutive days then were tested at 20 rpm for 300 s for other 3 consecutive days.…”

CB2R Activation Regulates TFEB-Mediated Autophagy and Affects Lipid Metabolism and Inflammation of Astrocytes in POCD

“…Growing evidence suggests that lipid accumulation and inflammation in brain astrocytes are associated with an increase in neurodegenerative diseases, aging-related disorders, and brain damage, including but not limited to AD, PD, and traumatic brain injury ( 4 , 24 – 26 ). Clinical evidence shows that the serum levels of lipids and inflammatory factors were highly elevated in aging patients undergoing surgery ( 27 – 29 ).…”