Quercetin improves the activity of the ubiquitin‐proteasomal system in 150Q mutated huntingtin‐expressing cells but exerts detrimental effects on neuronal survivability

Abstract

Quercetin, a strong free radical scavenger, is investigated for neuroprotective effects in a Neuro 2a cell line conditionally transfected with 16Q huntingtin (Htt) and 150Q Htt, which express the protein upon stimulation. Cells were protected from death by a 20-µM dose of quercetin on the second day of Htt induction, but 30-100-µM doses of the drug caused further toxicity in both 16Q and 150Q cells, as indicated by MTT assay and by significant reductions in the number of cells bearing neurites on the second day. A significant decrease in the number of cells containing aggregate was seen in induced 150Q cells treated with 20 µM but not for those treated with 40 or 50 µM quercetin up to 4 days of induction. Mutated Htt (mHtt)-induced reduction in proteasomal activity of the ubiquitin-proteasomal system (UPS) was significantly attenuated by 20 µM quercetin. However, neither mitochondrial membrane potential loss nor colocalization of 20S proteasome with mHtt aggregate was corrected by quercetin treatment. Our results imply that the neuroprotective effect of quercetin arises out of the upregulation of UPS activity, which causes a decrease in the number of mHtt aggregate-harboring cells. The increased neurotoxicity could result from the continued association of mHtt with 20S proteasome and the failure of quercetin to correct mitochondrial membrane potential loss. These results suggest that, although quercetin at a low dose protects against mHtt-mediated cell death, higher doses are toxic to the cells, clearly demarcating a narrow therapeutic window for this dietary flavonoid.

PI3K/Akt and ERK1/2 Signalling Are Involved in Quercetin-Mediated Neuroprotection against Copper-Induced Injury

“…Natural antioxidants have potential to reestablish redox homeostasis and reduce or prevent metal-induced oxidative damage [ 47 – 49 ]. Besides their ability to act as antioxidants, metal chelators, and modulators of intracellular signalling, flavonoids may inhibit the formation of A β fibrils [ 50 , 51 ] and improve the activity of the ubiquitin-proteasome system [ 52 , 53 ]. Hence, flavonoids, including quercetin, represent a promising multitarget drug option, particularly if applied during the early stage of neurodegenerative processes.…”

Quercetin Potentiates the NGF‐Induced Effects in Cultured PC 12 Cells: Identification by HerboChips Showing a Binding with NGF

“…Several reports mentioned the beneficial functions of quercetin on nerve system [ 22 ]. Those beneficial functions included extension of survivability of neuron by suppressing inflammation [ 23 ] and oxidation stress [ 24 , 25 ]. Here, we showed the potentiation effect of quercetin in NGF-induced neurite outgrowth in cultured PC 12 cells.…”

Tea and Parkinson's disease: Constituents of tea synergize with antiparkinsonian drugs to provide better therapeutic benefits

“…EGCG, which is considered as the most powerful agent from green tea having neuroprotective activity, is used in micromolar concentrations in experimental studies. However, at higher doses, like some other known antioxidants including melatonin and quercetin (Chakraborty et al, 2015), it up-regulates proapoptotic proteins harmful for the cells (Weinreb et al, 2003).…”