Contribution Of Cathepsin L To Quinolinic Acid-induced NF-κB Activation And Excitotoxicity In Rats Striatal Neurons

Aim: To study the roles of Cathepsin L in apoptosis and autophagy mediated byglutamate receptors.Methods: The in vivo excitotoxic model was produced with stereotaxicadministration of Quinolinic acid (QA) into unilateral striatum. The neuroprotectiveeffects of the Cathepsin L inhibitor Z-FF-FMK or NaphthaCHO were assessed withCresyl violet staining. The changes in the expression of IκBα, p-IκBα and Cathepsin Lwere assessed with Western blot analysis. Effects of Z-FF-FMK or NaphthaCHO onQA-induced IκBα degradation and phosphorylation were detected with Western blotanalysis, and their effects on QA-induced NF-κB activation were detected withimmunohistochemical analysis. Effects of Z-FF-FMK or NaphthaCHO on QA-inducedchanges in the levels of apoptosis related protein p53, caspase-3, autophagy relatedprotein Beclin1, LC3and P62were detected with Western blot analysis.Results: We have successfully established in vivo model of excitotoxicity by QA.QA-induced loss of striatal neurons were robustly inhibited by Z-FF-FMK orNaphthaCHO. QA induced a decrease in IκBα, increases in the expression of p-IκBαand Cathepsin L. Z-FF-FMK or NaphthaCHO inhibited QA-induced IκBα degradationand phosphorylation, reversed QA-induced activation of NF-κB. Z-FF-FMK orNaphthaCHO inhibited QA-induced up-regulation of apoptosis related protein p53,caspase-3, autophagy related protein Beclin1, the ratio of LC3-II/LC3-I anddown-ragulation of P62in the striatum.Conclusions: These results suggest that Cathepsin L inhibitor has neuroprotectiveeffects by inhibiting glutamate receptors-induced IκBα degradation and phosphorylation,NF-κB nuclear translocation and activation of apoptosis and autophagy.