Prophylactic Administration of Aucubin Inhibits Paclitaxel-Induced Mechanical Allodynia <i>via</i> the Inhibition of Endoplasmic Reticulum Stress in Peripheral Schwann Cells

Abstract

Paclitaxel is a chemotherapeutic agent that causes peripheral neuropathy as its major dose-limiting side effect. However, the peripheral neuropathy is difficult to manage. A study we recently conducted showed that repetitive administration of aucubin as a prophylactic inhibits paclitaxel-induced mechanical allodynia. However, the mechanisms underlying the anti-allodynic activity of aucubin, which is a major component of Plantaginis Semen, was unclear. In addition to mechanical allodynia, aucubin inhibited spontaneous and mechanical stimuli-induced firing in spinal dorsal horn neurons; however, catalpol, a metabolite of aucubin, did not show these effects. Furthermore, paclitaxel induced the expression of CCAAT/enhancer-binding protein homologous protein, a marker of endoplasmic reticulum (ER) stress, in the sciatic nerve and a Schwann cell line (LY-PPB6 cells); however, this effect was inhibited by aucubin. These results suggest that aucubin inhibits paclitaxel-induced mechanical allodynia through the inhibition of ER stress in peripheral Schwann cells. Key words paclitaxel; mechanical allodynia; aucubin; firing; Schwann cell; stressPaclitaxel is an anti-microtubule agent originally isolated from the bark of the Pacific yew tree (Taxus brevifolia) and is wildly used to treat solid neoplasms such as breast, ovarian, and lung cancers.1,2) However, in spite of its useful anticancer effect, paclitaxel causes peripheral neuropathy, which is characterized by mechanical allodynia, spontaneous pain, shooting and burning pain, tingling, and numbness, with a stocking-and-glove distribution.3) The peripheral neuropathy is a major dose-limiting side effect, which disturbs cancer treatment with paclitaxel. Therefore, relief of the neuropathy is very important for improving both the QOL and cancer treatment with paclitaxel. Several drugs, including gabapentin and amifostine, have failed to relieve paclitaxel-induced peripheral neuropathy [4][5][6] ; therefore, alternative therapeutic agents are need.Goshajinkigan is a traditional herbal formulation that consists of 10 herbal medicines (Rehmanniae Radix, Achyranthis Radix, Corni Fructus, Dioscoreae Rhizoma, Plantaginis Semen, Alismatis Rhizoma, Poria, Moutan Cortex, Cinnamoni Cortex, and Processi Aconiti Radix). It has been shown to attenuate the progression of peripheral neuropathy induced by docetaxel and paclitaxel/carboplatin treatments in cancer patients.7,8) Our previous study has been shown that repetitive administration of goshajinkigan extract as a prophylactic inhibits the exacerbation of paclitaxel-induced mechanical allodynia in mice.9) We also showed that aucubin, which is an iridoid glycoside and the main component of Plantaginis Semen, plays an important role in the anti-allodynic action of goshajinkigan.10) However, the mechanisms underlying the anti-allodynic activity of aucubin are not understood completely. It was reported in a previous study that paclitaxel decreased peripheral blood flow and induced mechanical allodynia in mice.11) The study also demonstra...

Endoplasmic reticulum–mitochondria interplay in chronic pain: The calcium connection

“…184 Another study found that a single intraperitoneal injection of Ptx (5 mg/kg) was sufficient to induce CHOP expression in the sciatic nerve, increase the excitability of spinal dorsal horn neurons, and lead to mechanical allodynia in C57BL/6 NCr mice. 40,185 In vitro, Ptx treatment of SK-N-SH neuroblastoma cells increased the phosphorylation of eIF2a and induced the expression of CHOP as well as the pro-apoptotic caspase 3 186,187 Furthermore, pretreatment with fluvoxamine, a Sigma 1 receptor inducer, and BiP-inducer X (BIX) attenuated ER stress and protected the SK-N-SH cells from paclitaxel-associated cytotoxicity. 187 However, whether these drugs can mitigate pain in CIPN remains to be investigated.…”

Search of anti-allodynic compounds from Plantaginis Semen, a crude drug ingredient of Kampo formula “Goshajinkigan”

“…Taken together, it is suggested that the alteration of plasma level of aucubin and inhibition of PTX-induced allodynia do not have direct correlation. Antiallodynic activity by repetitive administration of aucubin may be due to organic protection, such as the protection of demyelination [23].…”

“…We reported that intraperitoneal injection of 1 inhibited firing induced by mechanical stimuli in spinal dorsal horn neurons in PTX-treated mice. Furthermore, an endoplasmic reticulum (ER) stress inhibition mechanism is suggested by the inhibitory effect of 1 on the PTX-induced expression of CCAAT/enhancer-binding protein homologous protein, a protein marker of ER stress, in the mouse sciatic nerve and LY-PPB6 cells (a rat Schwann cell line) [23]. Demyelination associated with chronic pain is induced by PTX in peripheral nerves [25,26], because PTX causes damage in the Schwann cells [25], which form myelin sheaths, via ER stress [27,28].…”

Mechanisms of Chemotherapy-Induced Peripheral Neuropathy

“…The results from experimental studies are still not consistent because the activation of microglial cells has been observed in another study [103]. In a study by Imai et al, it was shown that cisplatin and oxaliplatin may induce mitochondrial dysfunction in cultured Schwann cells, followed by numerous disturbances in molecular function and cellular structure contributing to peripheral neuropathy [64,104].…”