Antiepileptic effects of two Rho-kinase inhibitors, Y-27632 and fasudil, in mice

Background and purpose:

Rho/Rho-kinase signalling is involved in many cellular events, including some in the CNS. However, the role of this pathway in epilepsy has not yet been assessed. Therefore, we determined the effects of two Rho-kinase inhibitors, Y-27632 and fasudil, on seizures induced by pentylenetetrazole (PTZ) or maximal electroconvulsive shock (MES).

Experimental approach:

Effects of Y-27632 (5–10 mg kg⁻¹) and fasudil (5–25 mg kg⁻¹) on duration of myoclonic jerks, clonic and tonic convulsions, tonic hindlimb extensions and percentage of tonic convulsion index, as well as recovery latency for righting reflex were investigated in mice stimulated with PTZ (65 mg kg⁻¹) or MES (50 Hz, 50 mA and 0.4 s). These inhibitors were also tested on a model of kindling induced by PTZ (35 mg kg⁻¹, for 11 days). Membrane and cytosolic levels of RhoA protein were measured in brain homogenates from kindled mice.

Key results:

Y-27632 and fasudil diminished onset of myoclonic jerks, clonic convulsions and tonic hindlimb extensions in mice given PTZ. These inhibitors suppressed the percentage of tonic convulsion index and recovery latency for righting reflex in the mice excited with MES. Western blotting demonstrated that Rho translocation to plasma membrane increased in the brain homogenates obtained from PTZ-kindled mice. However, the Rho-kinase inhibitors at the given doses did not change motor coordination of the mice.

Conclusions and implications:

Rho/Rho-kinase signalling may play a role in epilepsy induced by PTZ and MES. Furthermore, Rho-kinase inhibitors could be novel important antiepileptic agents.

British Journal of Pharmacology (2008) 155, 44–51; doi:10.1038/bjp.2008.225; published online 9 June 2008