The activity of adenosine deaminase and the level of nitric oxide in spinal cord of methotrexate administered rats: protective effect of caffeic acid phenethyl ester

Toxicology. 2006 Feb 1;218(2-3):125-33. doi: 10.1016/j.tox.2005.10.014. Epub 2005 Dec 2.


The aim of this experimental study was to investigate the possible role of nitric oxide (NO) levels and activity of adenosine deaminase (ADA) in the pathogenesis of methotrexate (MTX)-induced neurotoxicity, to demonstrate the effect of caffeic acid phenethyl ester (CAPE), the potent antioxidant, in decreasing the toxicity. A total of 19 adult male rats were divided into three experimental groups, as follows: group I, control group; group II, MTX-treated group; group III, MTX+CAPE-treated group. In the second day of experiment, MTX was administered intraperitoneally (i.p.) with a single dose of 20mg/kg to group II and group III. CAPE was administered i.p. with a dose of 10 micromol/kg once daily for 7 days to group III. Histopathological findings of the inflammatory reaction were observed in spinal cord of MTX administered rats, compared with control rats. All parameters of inflammatory reaction were significantly decreased in MTX plus CAPE administered rats, compared with MTX administered rats. The injection of MTX caused significant increase in the activity of ADA and in levels NO levels in spinal cord of rats (p=0.007 and p=0.0001, respectively). Co-treatment with CAPE caused a significant decrease in activity of ADA and the levels of NO in spinal cord (p=0.024 and p=0.0001, respectively). Study indicate that NO and ADA may play an important role in the pathogenesis of MTX-induced oxidative spinal cord damage. CAPE may have protective aspects in this process by antioxidant and anti-inflammatory effect and it will become a promising drug in the prevention of undesired side effect of MTX.

MeSH terms

  • Adenosine Deaminase / metabolism
  • Animals
  • Antimetabolites, Antineoplastic / toxicity
  • Antioxidants / pharmacology
  • Antirheumatic Agents / toxicity
  • Caffeic Acids / pharmacology*
  • Male
  • Methotrexate / toxicity*
  • Nitric Oxide / metabolism
  • Oxidative Stress
  • Phenylethyl Alcohol / analogs & derivatives*
  • Phenylethyl Alcohol / pharmacology
  • Protective Agents / pharmacology*
  • Rats
  • Rats, Wistar
  • Spinal Cord / drug effects*
  • Spinal Cord / metabolism
  • Spinal Cord / pathology


  • Antimetabolites, Antineoplastic
  • Antioxidants
  • Antirheumatic Agents
  • Caffeic Acids
  • Protective Agents
  • Nitric Oxide
  • Adenosine Deaminase
  • caffeic acid phenethyl ester
  • Phenylethyl Alcohol
  • Methotrexate