Inhibitory Effects of Valproic Acid in Oxaliplatin-Induced Neuropathy in Rat Model

Ke Ren, Kai Yi, Yidan Dai, Motoi Fujiwara, Tetsuo Ohta, Hayato Terayama, Kou Sakabe, Shuang-Qin Yi

Abstract


AIM: Oxaliplatin is a third-generation platinum-based chemotherapy drug, introduced for management of the advanced stages of metastatic colorectal cancer. However, repeated administration of oxaliplatin induced acute and chronic peripheral neuropathy. Valproic acid (VPA) is a neurotherapeutic drug used widespread and worldwide as therapy for seizures, bipolar disorder, and migraine, including children, adult and women of reproductive age.

MATERIALS AND METHODS: In the present study, we investigated the effect of VPA in prevention of oxaliplatin-induced periphery neuropathy in the rat model. We demonstrated that VPA (300 mg/kg) relieved the oxaliplatin (4mg/kg)-induced peripheral neuropathy using behavioral tests, biochemical tests, and histopathological and immunohistochemical evaluations.

RESULTS: VPA administration significantly attenuated the mechanical hyperalgesia by oxaliplatin-induced in rats. VPA exerted a significant protective effect by reducing the occurrence of multinucleolated neurons and the nucleolar eccentricity caused on lumbar dorsal root ganglion from oxaliplatin-treated rats. It revealed an inhibitory effect of VPA on the number and activation of microglia and astrocytes in the dorsal horn of the spinal cord. However, VPA was unable to prevent demyelination and degeneration of nerve fibers from oxaliplatin-induced peripheral neurotoxicity.

COLUSION: The present results demonstrated for the first time that VPA administration ameliorated the oxaliplatin-induced behavioral, biochemical and histopathological changes in rats. The VPA-mediated effects in this study may be attributed to neuroprotection properties and ameliorating oxaliplatin-induced astrocytes and microglial activation. VPA may offer a dual protective approach against etiological factors and resulting maladaptative plasticity.


Keywords


Oxaliplatin; Peripheral neuropathy; Mechanical allodynia; Valproic acid; Astrocyte and Microglia; Nucleolar eccentricity

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