Artemisinin Alleviates Bortezomib Induced Peripheral Neuropathy With The Involvement Of Preventing Schwann Cell Lysosomal Dysfunction

Bortezomib(BTZ),a proteasome inhibitor,is the first-line treatment for multiple myeloma,but has a 40-60% incidence of peripheral neuropathy.Bortezomib-induced peripheral neuropathy(BIPN)is a kind of peripheral neurotoxic symptom mainly characterized by neuropathologic pain,which is the main cause of BTZ reduction and even withdrawal.The occurrence of BIPN is one of the main problems in the course of drug therapy for multiple myeloma,but there is a lack of effective intervention methods.Our previous study found that lysosome dysfunction in Schwann cells is an important pathological factor of BIPN.Torin 1 can significantly relieve the symptoms of BIPN in mice through activating the lysosome activity in Schwann cells.However,Torin 1 has poor bioavailability and unstable activity,making it difficult to make a drug.Therefore,it is urgent to further search for drugs that can activate lysosome function and evaluate its effect on alleviating BIPN.DQ-Red-BSA staining was used to quantify lysosome activity in Schwann cells after BTZ treatment,and a lysosome active drug screening model was constructed based on high-content imaging analysis system.FDA-approved drugs were screened.The results of drug screening showed that 23 drugs could reverse the decrease of lysosome activity in Schwann cells induced by BTZ,among which Artemisinin(ART)was stronger.This study further verified the effect of Artemisinin on lysosome activity in Schwann cells and evaluated the improvement of BIPN in mice.DQ-Red-BSA staining was used to detect lysosome function and Western blot was used to detect lysosome protein hydrolase expression.Histomorphology,neurophysiology and mechanical hypersensitivity were used to determine the changes of BIPN symptoms in Artemisinin and BTZ combined administration group.The results showed that BTZ significantly decreased protein expression of Cathepsin G,a hydrolysosomal enzyme in Schwann cells,and Artemisinin administration reversed the downregulation of Cathepsin G protein.Artemisinin was able to significantly reverse the expression of Cathepsin G and Cathepsin A,hydrolysosome hydrolases of sciatic nerve in BIPN mice.Transmission electron microscopy and electrophysiology of the tail nerve showed that BTZ significantly increased sciatic nerve desyelination,leading to mechanical hypersensitivity.The velocity and amplitude of caudal nerve conduction were significantly decreased.After two weeks of daily treatment with Artemisinin(20 mg/kg),the mechanical pain threshold,demyelination degree and caural nerve conduction function were significantly improved,and showed a dose-effect relationship.In addition,Artemisinin did not attenuate the inhibitory effect of BTZ on multiple myeloma RPMI8226 cells.These results suggest that Artemisinin may have a potential effect on the intervention of BIPN.Downstream m TOR signaling pathway is related to myelination and lysosome function of peripheral nerves.Further mechanism studies have found that BTZ can activate m TOR and its downstream p S6 K and inhibit the expression of transcription factor EB(TFEB)and its entry into the nucleus.Artemisinin inhibited BTZ-induced m TOR signaling pathway activation and promoted TFEB entry,suggesting that Artemisinin might activate Schwann cell lysosomes by inhibiting m TOR.In conclusion,Artemisinin may alleviates BIPN by reversing BTZ-induced lysosome dysfunction in Schwann cells,and its mechanism may be related to inhibiting the m TOR signaling pathway in Schwann cells.Artemisinin is a potential treatment for BIPN.