Low‐dose rapamycin‐induced autophagy in cochlear outer sulcus cells

Abstract

ObjectivesAutophagy is an intracellular housekeeping process that degrades cytoplasmic organelles, damaged molecules, and abnormal proteins or pathogens and is essential for normal hearing. Recent studies revealed the essential roles of autophagy in hearing and balance. The aim of this study was to evaluate the activation state of rapamycin‐induced autophagy in cochlear outer sulcus cells (OSCs).MethodsWe used autophagy reporter transgenic mice expressing the green fluorescent protein‐microtubule‐associated protein light chain 3 (GFP‐LC3) fusion protein and counted GFP‐LC3 puncta in cochlear OSCs to evaluate the activation state of autophagy after oral administration of rapamycin.ResultsWe observed basal level GFP‐LC3 expression and an increase in the number of GFP‐LC3 puncta in cochlear OSCs by oral administration of rapamycin. This increase was detected when the daily rapamycin intake was as low as 0.025 mg/kg, and it was dose dependent. The increased number of puncta was more at the basal turn than the apical turn.ConclusionOral intake of low‐dose rapamycin activates autophagy in cochlear OSCs.Level of evidenceNA.

Targeting Autophagy Induction as A possible Protective Mechanism by Verapamil Compared to Rapamycin (Sirolimus) Against Gentamicin -Induced Ototoxicity in Guinea Pigs

“…The ABR results are matched with histopathology in light and SEM where there are variable degrees of HCs death, pathological changes in stria vascularis and degeneration of spiral ganglion which are in line with many studies [22,30,31] . ROS role in gentamicin ototoxicity is documented in different studies [32,33] . When there is imbalance between ROS and intrinsic antioxidants, apoptotic cell death is activated [34] .…”

“…To investigate HCs survival autophagy role, rapamycin has been used [11,12] . We used rapamycin orally according to Saegusa et al who reported effectiveness of oral low dose rapamycin to induce autophagy [33] . There is no definitive oral rapamycin dose in guinea pigs was investigated to induce autophagy, so we depended on the human equivalent dose [35] .…”

Programmed cell death pathways in hearing loss: A review of apoptosis, autophagy and programmed necrosis

“…144 Chika et al demonstrated that oral administration of low-dose rapamycin induced autophagy activation in cochlear outer sulcus cells, suggesting that rapamycin could be a feasible drug to manipulate inner ear cells. 147 Phosphatase and tensin homolog-induced putative kinase 1 also protected hair cells from cisplatin-induced ototoxicity following induction of autophagy. 148 Yin et al found that autophagic activation of HEI-OC1 cells increased the expression of the nuclear binding domain and leucine-rich repeat containing family member X1 (NLRX1) in cisplatin-induced injury.…”

“…Rapamycin treatment reduced ROS levels and hair cells death induced by aminoglycosides (including cisplatin, gentamicin and neomycin), 144‐146 while 3‐MA treatment or ATG5 deletion increased ROS levels and apoptosis 144 . Chika et al demonstrated that oral administration of low‐dose rapamycin induced autophagy activation in cochlear outer sulcus cells, suggesting that rapamycin could be a feasible drug to manipulate inner ear cells 147 . Phosphatase and tensin homolog‐induced putative kinase 1 also protected hair cells from cisplatin‐induced ototoxicity following induction of autophagy 148 …”

Effects of low-dose rapamycin on lymphoid organs of mice prone and resistant to accelerated senescence

“…This happens because the doses normally used to activate autophagy in aging studies are found to be in the range of 2 to 10 mg/kg, which may be high enough to maintain its antiproliferative effect in cells. However, studies such as that by Saegusa et al (2020) show that even small doses such as 0.025 mg/kg of RAPA are capable of activating autophagy in mice in almost the same proportion as a dose 100 times higher than 2.5 mg/kg (32). Therefore, in this study, we aimed to evaluate the potential effects of a low dose of RAPA on the immunosenescent phenotype and the changes associated with this process in senescence-accelerated prone 8 (SAM-P8) and senescence-accelerated resistant 1 (SAM-R1) mice.…”