Platinum-Induced Peripheral Neuropathy (PIPN): ROS-Related Mechanism, Therapeutic Agents, and Nanosystems

Abstract

Platinum (Pt) drugs (e.g., oxaliplatin, cisplatin) are applied in the clinic worldwide for the treatment of various cancers. However, platinum-induced peripheral neuropathy (PIPN) caused by the accumulation of Pt in the peripheral nervous system limits the clinical application, whose prevention and treatment are still a huge challenge. To date, Pt-induced reactive oxygen species (ROS) generation has been studied as one of the primary mechanisms of PIPN, whose downregulation would be feasible to relieve PIPN. This review will discuss ROS-related PIPN mechanisms including Pt accumulation in the dorsal root ganglia (DRG), ROS generation, and cellular regulation. Based on them, some antioxidant therapeutic drugs will be summarized in detail to alleviate the Pt-induced ROS overproduction. More importantly, we focus on the cutting-edge nanotechnology in view of ROS-related PIPN mechanisms and will discuss the rational fabrication of tailor-made nanosystems for efficiently preventing and treating PIPN. Last, the future prospects and potential breakthroughs of these anti-ROS agents and nanosystems will be briefly discussed.

Delayed Onset Muscle Soreness and Critical Neural Microdamage-Derived Neuroinflammation

“…The current author proposes that primary afferent peripheral terminal hyperexcitation with “leakiness” at Piezo2 is such a pathological condition in DOMS. Accordingly, it is not surprising that platinum-analogue drugs also elevate ROS production as the primary mechanism of platinum-induced peripheral neuropathy [ 110 ] with the activation of the NF-kappa B pathway [ 111 ].…”

Chemotherapy for pain: reversing inflammatory and neuropathic pain with the anticancer agent mithramycin A

“…Excessive ROS generation induced by platinum agents such as oxaliplatin, that leads to oxidative stress and mitochondrial dysfunction, contribute to the development of CIPN. 45,76 DRG neurons exposed to oxaliplatin in vitro induced a dose-dependent and time-dependent mitochondrial production of ROS. 50,63 Given the observed enrichment of ETC components following MTM rescue, we investigated whether DRG neurons increased their content of ROS in response to oxaliplatin treatment in vivo and if MTM treatment could reverse this effect.…”

“…Platinum-based chemotherapy agents like cisplatin and oxaliplatin accumulate and form DNA adducts in DRG that induce DNA/ mitochondrial damage, enhancing reactive oxygen species (ROS) production while activating nociceptor-associated channels. 45,63,76,102 Exactly how oxaliplatin or other platinum chemotherapy increase mitochondrial ROS is poorly understood. Nevertheless, increased mitochondrial ROS levels are associated with cisplatin's and oxaliplatin's neurotoxicity in painful CIPN.…”

Miswired Proprioception in Amyotrophic Lateral Sclerosis in Relation to Pain Sensation (and in Delayed Onset Muscle Soreness)—Is Piezo2 Channelopathy a Principal Transcription Activator in Proprioceptive Terminals Besides Being the Potential Primary Damage?

“…In line with the aforementioned, platinum analogue chemotherapeutic drug-induced ROS production contributes to peripheral neuropathy [ 118 ], with NF-κB pathway activation [ 119 ]. The ROS derived NF-κB activation may also have a role in muscle cells as well, with associated NGF upregulation on them [ 120 ].…”