Masanobu Tsubaki, Taira Matsuo, Rie Komori, Tomoya Takeda, Noriaki Nagai, Toshio Morikawa, Shozo Nishida
Chemotherapy-induced peripheral neuropathy (CIPN) is an adverse event caused by drugs such as bortezomib, vincristine, paclitaxel, and oxaliplatin (L-OHP). This condition can lead to the discontinuation of anticancer drug administration and a diminished quality of life, posing a significant clinical problem. However, the only currently recognized effective treatment is duloxetine, and new therapeutic options are urgently required. Lentinula edodes mycelia extract (LEM) has been reported to improve CIPN in mouse models and alleviate numbness in patients with persistent neuropathy following L-OHP treatment. However, the active ingredients responsible for the attenuation of neuropathy remain unknown. We extracted the fractions from LEM, and an L-OHP-evoked allodynia mouse model was used to investigate which fraction contained the active ingredient. LEM was separated into an ethanol-soluble fraction (LES), an ethanol-insoluble fraction (LEP), and LEM(-), a hot water extract from the LEM-free medium. LEP abolished L-OHP-evoked allodynia, whereas LES and LEM(-) did not. In addition, fractionation of LEP based on molecular weight sieving yielded fractions LEP-1 (molecular weight ≥ 100,000) and LEP-2 (molecular weight < 100,000), the latter of which was found to inhibit L-OHP-evoked allodynia. Similarly, fractionation of LEP-2 gave rise to LEP-3 (molecular weight 3500-50,000) and LEP-4 (molecular weight ≤ 3500), the former of which had no inhibitory effects on L-OHP-evoked allodynia, whereas an inhibitory effect was observed in response to the administration of LEP-4. In addition, LEP-4 was found to abrogate the expression of NR2A and Cav3.2 mRNAs in the dorsal root ganglion (DRG), and inhibited the activation of extracellular regulated-protein kinase 1/2 (ERK1/2) in both the spinal cord and DRG. Moreover, oral administration of 0.25 g/kg LEP-4 ameliorated allodynia, which had developed following L-OHP administration. These findings indicate that the active component preventing CIPN in LEM resides in LEP-4. This compound has prophylactic and therapeutic potential for L-OHP-evoked allodynia by abrogating NR2A and Cav3.2 mRNA expression and activating ERK1/2.