Mechanism underlying linezolid-induced peripheral neuropathy in multidrug-resistant tuberculosis

Abstract

Multidrug-resistant tuberculosis (MDR-TB) remains a main global health concern as there is no comprehensive therapeutic intervention yet and numerous adverse effects follow the therapeutic process. In recent years, linezolid has been frequently used for treating MDR-TB. However, peripheral neuropathy associated with linezolid has reduced patient compliance. The current study explored the mechanism underlying linezolid-induced peripheral neuropathy in MDR-TB. Autophagy plays a neuroprotective role against peripheral nerve injury. We hypothesized that autophagy might also play a neuroprotective role against linezolid-induced peripheral neuropathy. In this study, we collected 12 questionnaires from MDR-TB patients in our hospital, and 10 of them developed linezolid-induced pain. The pain is mainly concentrated in the feet and accompanied by numbness. Subsequently, we used Sprague-Dawley (SD) rats and Schwann cells (SCs) to explore the mechanism. We found that linezolid causes a sparse arrangement of sciatic nerve tissue with associated loss of neurons, myelin sheaths, and down-regulation of LC3B expression. These results were also confirmed by in vitro experiments, showing that linezolid inhibited the proliferation of SCs. And the expression of P-AKT and P62 was elevated, and the expression of LC3B declined compared with the control group. Moreover, chloroquine (CQ), an autophagy inhibitor, also exhibited experimental results similar to linezolid. In summary, we conclude that linezolid-induced peripheral neuropathy is associated with the inhibition of autophagy flux.

Six Months of Bedaquiline-Pretomanid-Linezolid (BPaL) Regimen in Patients with Drug-Resistant Tuberculosis: A Narrative Review

“…High exposure to linezolid was associated with hematologic toxicity. [41] Linezolid has been reported to cause pancytopenia with a significant decrease in hematological parameters, including erythrocytes, leukocytes, Hb, and platelets, after 30 days of using linezolid.…”

Infant Exposure to Antituberculosis Drugs via Breast Milk and Assessment of Potential Adverse Effects in Breastfed Infants: Critical Review of Data

“…Hence, the syndrome may be triggered when patients are concomitantly treated with medications with serotonergic properties such as antidepressants [70]. Because of the occurrence of peripheral and optic neuropathy in rare cases, patients should be advised to report symptoms of visual impairment [71].…”

A Transcriptomic Biomarker Predicting Linezolid-Associated Neuropathy During Treatment of Drug-Resistant Tuberculosis

“…So far, the mechanism of action for linezolid-associated neuropathies is yet to be fully understood. Linezolid was found to inhibit autophagy flux [ 9 ] and mitochondrial protein synthesis [ 10 ], which could have an effect on the peripheral nerves by disrupting their normal function. It is important to note that a dose reduction of linezolid resulted in a decrease of attributed adverse events [ 7 ].…”