Preventive Effects of Bee Venom Derived Phospholipase A₂ on Oxaliplatin-Induced Neuropathic Pain in Mice.

Dongxing Li,Dasom Shin,Sun Kim,Woojin Kim,Yongjae Jung,Hyunsu Bae

doi:10.3390/toxins8010027

Abstract

Oxaliplatin, a chemotherapy drug used to treat colorectal cancer, induces specific sensory neurotoxicity signs that are aggravated by cold and mechanical stimuli. Here we examined the preventive effects of Bee Venom (BV) derived phospholipase A2 (bvPLA2) on oxaliplatin-induced neuropathic pain in mice and its immunological mechanism. The cold and mechanical allodynia signs were evaluated by acetone and von Frey hair test on the hind paw, respectively. The most significant allodynia signs were observed at three days after an injection of oxaliplatin (6 mg/kg, i.p.) and then decreased gradually to a normal level on days 7–9. The oxaliplatin injection also induced infiltration of macrophages and upregulated levels of the pro-inflammatory cytokine interleukin (IL)-1β in the lumbar dorsal root ganglia (DRG). Daily treatment with bvPLA2 (0.2 mg/kg, i.p.) for five consecutive days prior to the oxaliplatin injection markedly inhibited the development of cold and mechanical allodynia, and suppressed infiltration of macrophages and the increase of IL-1β level in the DRG. Such preventive effects of bvPLA2 were completely blocked by depleting regulatory T cells (Tregs) with CD25 antibody pre-treatments. These results suggest that bvPLA2 may prevent oxaliplatin-induced neuropathic pain by suppressing immune responses in the DRG by Tregs.

Highlights

Oxaliplatin is a third-generation platinum-based chemotherapy drug that has recently gained significant importance for treating advanced metastatic colorectal cancer [1,2]
We evaluated the preventive effects of BV-derived PLA2 (bvPLA2) on oxaliplatin-induced cold and mechanical allodynia
The bvPLA2 pre-treatment significantly reduced mechanical allodynia on day 3 (Figure 1b). These results suggest that bvPLA2 has the potential to prevent oxaliplatin-induced cold and mechanical allodynia

Summary

Introduction

Oxaliplatin is a third-generation platinum-based chemotherapy drug that has recently gained significant importance for treating advanced metastatic colorectal cancer [1,2]. Oxaliplatin is effective against a wide range of other tumors, such as ovarian, breast, and lung cancers [3,4]. Oxaliplatin is structurally similar to cisplatin but contains a 1,2-diaminocyclohexane carrier ligand. This modification enhances its anti-tumor activity and alters the side effect profile from other platinum-based drugs, as it is not nephrologically or hematologically toxic [5,6]. Oxaliplatin can cause peripheral neuropathy characterized by dysesthesia in the hands and feet, which is a major dose-limiting side effect [7]. A number of studies have suggested that preventing chemotherapy-induced peripheral neuropathy (CIPN) is important [8], as the chemotherapy

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