title: Aqueous extract of Lithospermi radix attenuates oxaliplatin-induced neurotoxicity in both in vitro and in vivo models.
abstract: BACKGROUND
  Oxaliplatin can induce peripheral neuropathy (OXIPN) as an adverse side effect in cancer patients. Until now, no effective preventive or therapeutic drug has been developed; therefore, the dose-limiting factor of OXIPN is still an obstacle in the use of oxaliplatin to treat cancer patients. In the present study, we report for the first time that the aqueous extract of Lithospermi radix (WLR) can attenuate the OXIPN in both in vitro and in vivo neuropathic models.
  
  
  METHODS
  The protective effect of WLR on OXIPN was evaluated in vitro by quantifying nerve growth factor (NGF)-stimulated neurite outgrowth in PC12 cells treated with a combination of oxaliplatin and WLR. The neuroprotective potential of WLR was further confirmed by measuring the changes in nociceptive sensitivities to external mechanical stimuli in neuropathic animals induced by oxaliplatin. Histological and immunohistochemical studies were further done to examine the effect of WLR in mouse spinal cords and footpads.
  
  
  RESULTS
  Oxaliplatin-induced neurotoxicity in NGF-stimulated PC12 cells. It could reduce the lengths and branching numbers of neuritis in NGF-stimulated PC12 cells. Co-treatment of WLR rescued the differentiated PC12 cells from the neurotoxicity of oxaliplatin. In a chronic OXIPN animal model, administration of oxaliplatin i.p. induced enhanced nociceptive sensitivity to mechanical stimuli (25.0 to 72.5 % of response rate) along with spinal activation of microglias and astrocytes and loss of intraepidermal nerve fibers in footpads, which is remarkably suppressed by oral administration of WLR (67.5 to 35 % of response rate at the end of experiment). Cytotoxicity of oxaliplatin determined in human cancer cells was not affected irrespective of the presence of WLR.
  
  
  CONCLUSIONS
  In conclusion, we demonstrated that WLR can attenuate OXIPN in both in vitro and in vivo experimental models, which may be in part attributed to its anti-inflammatory activity in the spinal cord and its neuroprotective potential in the peripheral nerve system without affecting the anti-tumor potential of oxaliplatin. Therefore, WLR could be considered as a good starting material to develop a novel therapeutic agent targeting OXIPN. However, further studies should be done to elucidate the underlying mechanism such as molecular targets and active constituent(s) in WLR with neuroprotective potential.
authors: KM-Convergence Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon, 34054, Republic of Korea.|Current address: Department of Pathology, Chronic Inhalation Toxicity Research Center, Chemicals Toxicity Research Bureau, Occupational Safety and Health Research Institute, Korea Occupational Safety and Health Agency, Daejeon, Republic of Korea.
authors: Eun-Sang
authors: ES
authors: Cho
authors: KM-Convergence Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon, 34054, Republic of Korea.
authors: Jin-Mu
authors: JM
authors: Yi
authors: KM-Convergence Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon, 34054, Republic of Korea.|Current address: New Drug Development Center, K-BIO Osong Medical Innovation Foundation, Cheongju, Republic of Korea.
authors: Jong-Shik
authors: JS
authors: Park
authors: KM-Convergence Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon, 34054, Republic of Korea.
authors: You Jin
authors: YJ
authors: Lee
authors: KM-Convergence Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon, 34054, Republic of Korea.
authors: Chae Jun
authors: CJ
authors: Lim
authors: KM-Convergence Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon, 34054, Republic of Korea.
authors: Ok-Sun
authors: OS
authors: Bang
authors: KM-Convergence Research Division, Korea Institute of Oriental Medicine, 1672 Yuseong-daero, Yuseong-gu, Daejeon, 34054, Republic of Korea. nosookim@kiom.re.kr.|Department of Korean Medicine, Life Science and Technology, Korea University of Science and Technology, Daejeon, Republic of Korea. nosookim@kiom.re.kr.
authors: No Soo
authors: NS
authors: Kim
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005727:Ganglia, Spinal / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D029684:Lithospermum / Q000737:chemistry*; D008297:Male; D008810:Mice, Inbred C57BL; D009412:Nerve Fibers / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000633:toxicity*; D000077150:Oxaliplatin; D016716:PC12 Cells; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000188:drug therapy; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats
chemical_list: D009944:Organoplatinum Compounds; D010936:Plant Extracts; D020011:Protective Agents; D000077150:Oxaliplatin
keywords: Inflammation; Lithospermi radix; Mechanical hypersensitivity; Oxaliplatin; Peripheral neuropathy