Blockade of 5-HT(3) receptor with MDL7222 and Y25130 reduces hydrogen peroxide-induced neurotoxicity in cultured rat cortical cells

Life Sci. 2005 Dec 5;78(3):294-300. doi: 10.1016/j.lfs.2005.04.043. Epub 2005 Aug 19.

Abstract

The present study was performed to examine the neuroprotective effects of 5-hydroxytryptamine (5-HT)(3) receptor antagonists against hydrogen peroxide (H(2)O(2))-induced neurotoxicity using cultured rat cortical neurons. Pretreatment of 5-HT(3) receptor antagonists, tropanyl-3,5-dichlorobenzoate (MDL72222, 0.1 and 1 microM) and N-(1-azabicyclo[2.2.2.]oct-3-yl)-6-chloro-4-ethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide hydrochloride (Y25130, 0.5 and 5 microM), significantly inhibited the H(2)O(2) (100 microM)-induced neuronal cell death as assessed by a MTT assay and the number of apoptotic nuclei, evidenced by Hoechst 33342 staining. The protective effects of MDL72222 (1 microM) and Y25130 (5 microM) were completely blocked by the simultaneous treatment with 100 microM 1-phenylbiguanide, a 5-HT(3) receptor agonist, indicating that the protective effects of these compounds were due to 5-HT(3) receptor blockade. In addition, MDL72222 (1 microM) and Y25130 (5 microM) inhibited the H(2)O(2) (100 microM)-induced elevation of cytosolic Ca(2+) concentration ([Ca(2+)](c)) and glutamate release, generation of reactive oxygen species (ROS), and caspase-3 activity. These results suggest that the activation of the 5-HT(3) receptor may be partially involved in H(2)O(2)-induced neurotoxicity, by membrane depolarization for Ca(2+) influx. Therefore, the blockade of 5-HT(3) receptor with MDL72222 and Y25130 may ameliorate the H(2)O(2)-induced neurotoxicity by interfering with the increase of [Ca(2+)](c), and then by inhibiting glutamate release, generation of ROS and caspase-3 activity.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Cerebral Cortex / embryology
  • Cerebral Cortex / metabolism
  • Glutamic Acid / metabolism
  • Hydrogen Peroxide / toxicity*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology*
  • Oxazines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Serotonin 5-HT3 Receptor Antagonists*
  • Tropanes / pharmacology*

Substances

  • Bridged Bicyclo Compounds, Heterocyclic
  • Neuroprotective Agents
  • Oxazines
  • Reactive Oxygen Species
  • Serotonin 5-HT3 Receptor Antagonists
  • Tropanes
  • Glutamic Acid
  • azasetron
  • Hydrogen Peroxide
  • bemesetron