![]() ![]() Mitochondrial dysfunction is a major promoter of OIPN and may be a potential therapeutic target.Įxcessive production of reactive oxygen species (ROS) leads to an imbalance between oxidation and antioxidant systems. In recent years, several in vitro and in vivo OIPN models focused attention on the “mitochondrial toxicity hypothesis” which suggests that impaired mitochondrial function leads to afferent sensory neuron damage. In the PNS, 95% mitochondria are located in axons, mitochondrial dysfunction would lead to chronic energy deficiency of neurons, further result in abnormal spontaneous discharge and compartmental degeneration of DRG primary afferent neurons. The combination could modify the permeability of mitochondrial membrane through affecting proteins such as voltage‐dependent anion‐selective channels,Īnd also inhibit the transcription and replication of mitochondrial DNA that induce the mitochondrial morphological changes, dysfunction, and final apoptosis. Mitochondrial dysfunction plays a key role in the pathophysiology of platinum‐induced peripheral neuropathy.Īfter entering neuronal cells, platinum combine with mitochondrial DNA to form DNA‐platinum adducts. Mitochondria have its own round mitochondrial DNA (mtDNA), encoding 13 proteins that are involved in the synthesis of mitochondrial electron transport chain subunits and the production of cellular energy. Therefore, platinum accumulation in the PNS, especially in DRG, is one of the important mechanisms of OIPN (Figure (Figure1 1). Recent studies have indicated that platinum concentration dose‐dependently increased in the rat DRG and correlated with the degree of neurotoxicity after repeated oxaliplatin administration. Accumulation of these drugs in DRG results in neurological damage. Unlike the central nervous system (CNS), dorsal root ganglion (DRG) lacks the protection of the blood‐brain barrier, so chemotherapy drugs and other toxic drugs can easily enter the sensory neuron cell body of DRG. Once entering systemic circulation, oxaliplatin rapidly hydrolyzed to oxalate ligand and Pt‐diaminocyclohexane (Dach).Īs the major platinum complex in circulation, Pt‐(dach) reaches the organs and tissues by binding to endogenous low‐molecular‐weight species like cysteine, methionine, and glutathione (GSH) and high‐molecular‐weight compounds like albumin, globulin, and hemoglobin.ĭorsal root ganglion is composed of centripetal sensory fibroblasts, which transduce somatosensory and visceral sensations into to the spinal cord. Where does platinum accumulate in the PNS The aim of this review is to summarize the current the current research progress and describe how platinum accumulation is responsible for neuropathy onset and progression.Ģ.1. Oxaliplatin accumulation in the peripheral nervous system (PNS) is considered a key step in neurotoxicity development, but the exact mechanisms are unclear. Due to its dose‐dependent characteristic, symptoms of the chronic OIPN may appear in 42.1% to 69% of patients after 4 to 6 cycles after chemotherapy.ĭespite intense preclinical and clinical work, no drug gets recognition to prevent OIPN, and duloxetine is recommended for the treatment of OIPN by the American Society of Clinical Oncology (ASCO), but adverse drug reactions make it controversial.įor seeking truly effective treatment of OIPN, studies have been committed to explore the potential mechanisms for years. Which significantly reduces the quality of life of cancer survivor. It is a well‐established risk factor of chronic oxaliplatin‐induced peripheral neuropathy (OIPN).Ĭhronic peripheral neuropathy is characterized by bilateral symmetric paresthesia, dysesthesia and pain, mainly on both feet and/or at the ends of both hands (in a “glove‐sock” distribution). It can occur within hours to days after the treatment, with the peak value 3 days and generally recovering within 1 week. Some patients will have discomfort in the oral cavity, throat, jaw, and muscle spasm, with an incidence of 85% to 95%. ![]() ![]() Acute peripheral neuropathy is mainly sensory abnormalities related to cold stimuli, usually occurring in the distal extremities. ![]() However, oxaliplatin can cause peripheral neuropathy during administration, including acute and chronic peripheral neuropathy. Oxaliplatin is widely used in the treatment of various malignant tumors and is the standard drug for adjuvant chemotherapy for colorectal cancer. ![]()
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