Protective effects of the ROCK inhibitor fasudil against cognitive dysfunction following status epilepticus in male rats.

Abstract

Despite remarkable advances in epilepsy research, prevention and reversal of cognitive deficits following epilepsy remain a challenge. It was reported that the Rho kinase (ROCK) inhibitor fasudil hydrochloride (FH) could improve cognitive deficits in animal models of Alzheimer's disease (AD). Thus, the aim of the present study was to determine whether FH-mediated inhibition of the effects of ROCK signaling could improve cognitive deficits in male rats (postnatal 21-day old) following status epilepticus (SE) induced by lithium-pilocarpin, the therapeutic window of opportunity and to elucidate the underlying mechanisms. Western blotting analysis showed upregulation of phosphorylated RhoA (p-RhoA) expression, and indicated activation of Rho/ROCK signaling after SE. The Morris water maze (MWM) test was used to analyze learning-memory ability. HE staining, immunofluorescence staining with antineuronal nuclei (NeuN) and anti-neurofilament proteins 200 kD (NF200), transmission electron microscopy, and quantitative analysis of NeuN and synaptophysin by western blotting were performed to observe alterations in neurons, axons, and synapses in the hippocampi. Electroencephalogram (EEG) monitoring was used to record electrophysiological activities after SE. Our results indicated that treatment with FH at the first day following SE or 5 days later both could ameliorate cognitive dysfunction by reducing neuron, axon, and synapse damage, and mitigating EEG discharges, suggesting various roles for the Rho/ROCK signaling pathway in the pathological processes of brain damages following SE induced by lithium-pilocarpine. The Rho/ROCK signaling pathway is, therefore, a potential therapeutic target for the prevention or reversal of epilepsy induced brain damages.

• Authors: Xiaojie Song, Rong He, Wei Han, Tianyi Li, Lingling Xie, Li Cheng, Hengsheng Chen, Mingdan Xie, Li Jiang
• Journal: Journal of neuroscience research (J Neurosci Res) Vol. 97 Issue 4 Pg. 506-519 (04 2019) ISSN: 1097-4547 [Electronic] United States
• PMID: 30421453 (Publication Type: Journal Article)
• Copyright: © 2018 Wiley Periodicals, Inc.

Chemical References

• Protein Kinase Inhibitors
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
• ROCK1 protein, rat
• rho-Associated Kinases
• fasudil

Topics

• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (analogs & derivatives, pharmacology)
• Animals
• Axons
• Brain (physiopathology)
• CA1 Region, Hippocampal (metabolism, pathology, ultrastructure)
• Cognitive Dysfunction (drug therapy, enzymology, physiopathology)
• Male
• Protein Kinase Inhibitors (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Spatial Learning (drug effects)
• Status Epilepticus (chemically induced)
• rho-Associated Kinases (antagonists & inhibitors, metabolism)