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ToxSci Advance Access originally published online on May 12, 2004
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Toxicological Sciences 80, 296-303 (2004)
Toxicological Sciences vol. 80 no. 2 © Society of Toxicology 2004; all rights reserved.

Erk1/2 Phosphorylation and Reactive Oxygen Species Formation via Nitric Oxide and Akt-1/Raf-1 Crosstalk in Cultured Rat Cerebellar Granule Cells Exposed to the Organic Solvent 1,2,4-Trimethylcyclohexane

Oddvar Myhre*,{dagger},1, Sigrun Hanne Sterri*, Inger Lise Bogen* and Frode Fonnum*

* Norwegian Defence Research Establishment, Division for Protection and Materiel, P.O. Box 25, N-2027 Kjeller, Norway, and {dagger} VISTA (The Norwegian Academy of Science and Letters/Statoil), P.O. Box 25, N-2027 Kjeller, Norway

Received March 1, 2004; accepted April 13, 2004

Previously, we have shown that exposure of cultured rat cerebellar granule cells to the hydrocarbon solvent 1,2,4-trimethylcyclohexane leads to formation of reactive oxygen species (ROS). However, the cellular mechanisms responsible for formation of ROS in these cells after exposure to organic solvents are poorly understood. Here, we found that 1,2,4-trimethylcyclohexane induced a time and concentration dependent dephosphorylation of Akt-1 at Ser-473 and Raf-1 at Ser-259. An increased level of phosphorylated extracellular signal-regulated kinases (Erk1/2) at Tyr-204 was observed. By use of the nitric oxide synthase inhibitors N{omega}-nitro-L-arginine methylester and diphenyleneiodonium, we found that intracellular formation of nitric oxide was necessary for phosphorylation of Erk1/2 and for the formation of ROS. Furthermore, the ROS formation was inhibited by the Erk1/2 pathway inhibitor U0126. A 1,2,4-trimethylcyclohexane (TMCH)-induced cell death was lowered by U0126 and the free radical scavenger vitamin E. Our results show that Erk1/2 kinases and nitric oxide (NO) may participate in ROS formation induced by 1,2,4-trimethylcyclohexane in cultured rat cerebellar granule cells, and also indicate a crosstalk between Akt and the Raf-Mek-Erk signaling systems.

Key Words: organic solvents; mitogen-activated protein kinases; Akt-1; Raf-1; nitric oxide; reactive oxygen species.


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