Bortezomib, a first-generation proteasome inhibitor widely used in chemotherapy for hematologic malignancy, has effective anti-cancer activity but often causes severe peripheral neuropathy. Although bortezomib-induced peripheral neuropathy (BIPN) is a dose-limiting toxicity, there are no recommended therapeutics for its prevention or treatment. One of the most critical problems is a lack of knowledge about pathological mechanisms of BIPN. Here, we summarize the known mechanisms of BIPN based on preclinical evidence, including morphological abnormalities, involvement of non-neuronal cells, oxidative stress, and alterations of transcriptional programs in both the peripheral and central nervous systems. Moreover, we describe the necessity of advancing studies that identify the potential efficacy of approved drugs on the basis of pathological mechanisms, as this is a convincing strategy for rapid translation to patients with cancer and BIPN.

Background: Oxaliplatin is an important drug used in the treatment of colorectal cancer. However, it frequently causes severe acute and chronic peripheral neuropathies. We recently reported that repeated administration of oxaliplatin induced cold hyperalgesia in the early phase and mechanical allodynia in the late phase in rats, and that oxalate derived from oxaliplatin is involved in the cold hyperalgesia. In the present study, we examined the effects of Ca²⁺ channel blockers on oxaliplatin-induced cold hyperalgesia in rats. Methods: Cold hyperalgesia was assessed by the acetone test. Oxaliplatin (4 mg/kg), sodium oxalate (1.3 mg/kg) or vehicle was injected i.p. on days 1 and 2. Ca²⁺ (diltiazem, nifedipine and ethosuximide) and Na⁺ (mexiletine) channel blockers were administered p.o. simultaneously with oxaliplatin or oxalate on days 1 and 2. Results: Oxaliplatin (4 mg/kg) induced cold hyperalgesia and increased in the transient receptor potential melastatin 8 (TRPM8) mRNA levels in the dorsal root ganglia (DRG). Furthermore, oxalate (1.3 mg/kg) significantly induced the increase in TRPM8 protein in the DRG. Treatment with oxaliplatin and oxalate (500 μM for each) also increased the TRPM8 mRNA levels and induced Ca²⁺ influx and nuclear factor of activated T-cell (NFAT) nuclear translocation in cultured DRG cells. These changes induced by oxalate were inhibited by nifedipine, diltiazem and mexiletine. Interestingly, co-administration with nifedipine, diltiazem or mexiletine prevented the oxaliplatin-induced cold hyperalgesia and increase in the TRPM8 mRNA levels in the DRG. Conclusions: These data suggest that the L type Ca²⁺ channels/NFAT/TRPM8 pathway is a downstream mediator for oxaliplatin-induced cold hyperalgesia, and that Ca²⁺ channel blockers have prophylactic potential for acute neuropathy.

Background: Oxaliplatin is a platinum-based chemotherapy drug characterized by the development of acute and chronic peripheral neuropathies. The chronic neuropathy is a dose-limiting toxicity. We previously reported that repeated administration of oxaliplatin induced cold hyperalgesia in the early phase and mechanical allodynia in the late phase in rats. In the present study, we investigated the involvement of NR2B-containing N-methyl-D-aspartate (NMDA) receptors in oxaliplatin-induced mechanical allodynia in rats.Results: Repeated administration of oxaliplatin (4 mg/kg, i.p., twice a week) caused mechanical allodynia in the fourth week, which was reversed by intrathecal injection of MK-801 (10 nmol) and memantine (1 μmol), NMDA receptor antagonists. Similarly, selective NR2B antagonists Ro25-6981 (300 nmol, i.t.) and ifenprodil (50 mg/kg, p.o.) significantly attenuated the oxaliplatin-induced pain behavior. In addition, the expression of NR2B protein and mRNA in the rat spinal cord was increased by oxaliplatin on Day 25 (late phase) but not on Day 5 (early phase). Moreover, we examined the involvement of nitric oxide synthase (NOS) as a downstream target of NMDA receptor. L-NAME, a non-selective NOS inhibitor, and 7-nitroindazole, a neuronal NOS (nNOS) inhibitor, significantly suppressed the oxaliplatin-induced pain behavior. The intensity of NADPH diaphorase staining, a histochemical marker for NOS, in the superficial layer of spinal dorsal horn was obviously increased by oxaliplatin, and this increased intensity was reversed by intrathecal injection of Ro25-6981.Conclusion: These results indicated that spinal NR2B-containing NMDA receptors are involved in the oxaliplatin-induced mechanical allodynia.

Immune checkpoint inhibitors (ICIs) play a central role in various cancers. ICIs can cause immune-related adverse events (irAEs). As severe irAEs can be life-threatening, biomarkers for estimating irAE onset are crucial. The neutrophils-to-lymphocytes ratio (NLR) reflects the systemic immune condition and known as a prognostic marker in ICI treatment. Our study evaluated if the NLR corresponded with irAEs, and its feasibility as a biomarker for irAE onset. We retrospectively analyzed 275 cancer patients treated with anti-PD-1 monotherapy. We observed 166 irAEs in 121 patients. The NLR was significantly elevated during irAEs. Patients experiencing interstitial pneumonitis showed NLR elevation 4 weeks before initial symptoms and diagnosis. Analyzing receiver operating characteristics curves revealed that elevated NLR distinguished subsequent pneumonitis severity with high accuracy (AUC 0.93, sensitivity 88.9%, specificity 88.2%, cut-off 2.37, p = 0.0004). After a severe irAE occurred, two NLR trends were observed. Patients who showed a prompt reduction in elevated NLRs had favorable progression-free survival (hazard ratio 0.32, 95% CI 0.10–1.01, p = 0.0140) and overall survival (hazard ratio 0.23, 95% CI 0.06–0.86, p = 0.0057) compared to the patients who maintained elevated NLRs. These findings suggest that continuous monitoring of NLR trends may predict irAE onset and severity and subsequent prognosis.

Although transplantation procedures have been developed for patients with end-stage hepatic insufficiency or other diseases, allograft rejection still threatens patient health and lifespan. Over the last few decades, the emergence of immunosuppressive agents such as calcineurin inhibitors (CNIs) and mammalian target of rapamycin (mTOR) inhibitors have strikingly increased graft survival. Unfortunately, immunosuppressive agent-related neurotoxicity commonly occurs in clinical practice, with the majority of neurotoxicity cases caused by CNIs. The possible mechanisms through which CNIs cause neurotoxicity include increasing the permeability or injury of the blood–brain barrier, alterations of mitochondrial function, and alterations in the electrophysiological state. Other immunosuppressants can also induce neuropsychiatric complications. For example, mTOR inhibitors induce seizures, mycophenolate mofetil induces depression and headaches, methotrexate affects the central nervous system, the mouse monoclonal immunoglobulin G2 antibody (used against the cluster of differentiation 3) also induces headaches, and patients using corticosteroids usually experience cognitive alteration. Therapeutic drug monitoring, individual therapy based on pharmacogenetics, and early recognition of symptoms help reduce neurotoxic events considerably. Once neurotoxicity occurs, a reduction in the drug dosage, switching to other immunosuppressants, combination therapy with drugs used to treat the neuropsychiatric manifestation, or blood purification therapy have proven to be effective against neurotoxicity. In this review, we summarize recent topics on the mechanisms of immunosuppressive drug-related neurotoxicity. In addition, information about the neuroprotective effects of several immunosuppressants is also discussed.

The painful peripheral neuropathy occurring frequently during chemotherapy with paclitaxel or oxaliplatin is one of their dose-limiting factors. We reported previously that substance P is involved in the pathogenesis of pulmonary hypersensitivity reaction to paclitaxel in rats, and an antiallergic agent pemirolast reverses this reaction via the blockade of release of substance P. In the present study, we investigated the involvement of substance P in paclitaxel-induced peripheral neuropathy compared with that by oxaliplatin. In von Frey and acetone tests in rats repeated administration of paclitaxel (6 mg/kg i.p., once a week for 4 weeks) or oxaliplatin (4 mg/kg i.p., twice a week for 4 weeks) induced both mechanical allodynia and cold hyperalgesia. Paclitaxel-induced peripheral neuropathy was reversed primarily by the acute administration of pemirolast (0.1 and 1 mg/kg p.o.). Moreover, coadministration of the receptor antagonists neurokinin 1 [N-acetyl-l-tryptophan 3,5-bis(trifluoromethyl)benzylester (L-732,138), 100 μg/body i.t.] and neurokinin 2 [5-fluoro-3-[2-[4-methoxy-4-[[(R)-phenylsulphinyl]methyl]-1-piperidinyl]ethyl]-1H-indole (GR159897), 100 μg/body i.t.] strongly reversed paclitaxel-induced neuropathy. On the other hand, oxaliplatin-induced peripheral neuropathy was not reversed by pemirolast. In the in vitro study using cultured adult rat dorsal root ganglion neurons paclitaxel (1000 ng/ml) significantly increased the release of substance P, and pemirolast (100 and 1000 nM) significantly inhibited this increase of substance P release. Oxaliplatin, by contrast, did not increase the release of substance P. These results suggest that substance P is involved in paclitaxel-induced neuropathy, and the mechanism of its action is clearly different from that of oxaliplatin.