title: Anti-allodynic effect of Buja in a rat model of oxaliplatin-induced peripheral neuropathy via spinal astrocytes and pro-inflammatory cytokines suppression.
abstract: BACKGROUND
  Oxaliplatin, a widely used anticancer drug against metastatic colorectal cancer, can induce acute peripheral neuropathy, which is characterized by cold and mechanical allodynia. Activation of glial cells (e.g. astrocytes and microglia) and increase of pro-inflammatory cytokines (e.g. IL-1β and TNF-α) in the spinal cord play a crucial role in the pathogenesis of neuropathic pain. Our previous study demonstrated that Gyejigachulbu-Tang (GBT), a herbal complex formula, alleviates oxaliplatin-induced neuropathic pain in rats by suppressing spinal glial activation. However, it remains to be elucidated whether and how Buja (Aconiti Tuber), a major ingredient of GBT, is involved in the efficacy of GBT.
  
  
  METHODS
  Cold and mechanical allodynia induced by an oxaliplatin injection (6 mg/kg, i.p.) in Sprauge-Dawley rats were evaluated by a tail immersion test in cold water (4 °C) and a von Frey hair test, respectively. Buja (300 mg/kg) was orally administrated for five consecutive days after the oxaliplatin injection. Glial activation in the spinal cord was quantified by immunohistochemical staining using GFAP (for astrocytes) and Iba-1 (for microglia) antibodies. The amount of spinal pro-inflammatory cytokines, IL-1β and TNF-α, were measured by ELISA.
  
  
  RESULTS
  Significant behavioral signs of cold and mechanical allodynia were observed 3 days after an oxaliplatin injection. Oral administration of Buja significantly alleviated oxaliplatin-induced cold and mechanical allodynia by increasing the tail withdrawal latency to cold stimuli and mechanical threshold. Immunohistochemical analysis showed the activation of astrocytes and microglia and the increase of the IL-1β and TNF-α levels in the spinal cord after an oxaliplatin injection. Administration of Buja suppressed the activation of spinal astrocytes without affecting microglial activation and down-regulated both IL-1β and TNF-α levels in the spinal cord.
  
  
  CONCLUSIONS
  Our results indicate that Buja has a potent anti-allodynic effect in a rat model of oxaliplatin-induced neuropathic pain, which is associated with the inhibition of activation of astrocytes and release of pro-inflammatory cytokines in the spinal cord. Thus, our findings suggest that administration of Buja could be an alternative therapeutic option for the management of peripheral neuropathy, a common side-effect of oxaliplatin.
authors.affiliation: Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea.
authors.forename: Yongjae
authors.initials: Y
authors.lastname: Jung
authors.affiliation: Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea.
authors.forename: Ji Hwan
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea.
authors.forename: Woojin
authors.initials: W
authors.lastname: Kim
authors.affiliation: Department of Digestive system of Internal Medicine, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea.
authors.forename: Sang Hyub
authors.initials: SH
authors.lastname: Yoon
authors.affiliation: Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea. skkim77@khu.ac.kr.|Department of Physiology, College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea. skkim77@khu.ac.kr.
authors.forename: Sun Kwang
authors.identifier: http://orcid.org/0000-0002-2649-6652
authors.initials: SK
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001253:Astrocytes / Q000187:drug effects* / Q000276:immunology; D016207:Cytokines / Q000235:genetics* / Q000276:immunology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D008297:Male; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D009944:Organoplatinum Compounds / Q000009:adverse effects*; D000077150:Oxaliplatin; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D053583:Interleukin-1beta; D009944:Organoplatinum Compounds; D014409:Tumor Necrosis Factor-alpha; D000077150:Oxaliplatin
keywords: Astrocytes; Buja; Cold allodynia; Oxaliplatin; Pro-inflammatory cytokines; Spinal cord