An L-type calcium channel agonist, bay K8644, extends the window of intervention against ischemic neuronal injury.

Abstract

Our previous data indicate that the inhibition of L-type calcium channels (LTCCs) might be the cause of post-ischemic neuronal injury and that the activation of LTCCs can give rise to neuroprotection. In the present study, we aimed to profile the intervention window of Bay K8644, an LTCC agonist, and determine the involved mechanisms. The four vessel occlusion and oxygen-glucose deprivation models were employed to mimic ischemia/reperfusion damage in vivo and in vitro. Neuronal injury was analyzed using Nissl and Fluoro-Jade B staining in vivo and Hoechst 33342 and propidium iodide staining in vitro. The behavioral effects were tested using the Morris water maze. The phosphorylation of P38, Jun N-terminal kinase, and extracellular-regulated kinase (ERK) was detected by Western blotting. Our results show that Bay K8644 administered as late as 24 h after reperfusion prevented CA1 neuronal death and ameliorated the deficiencies in spatial learning performance induced by global ischemia. In oxygen-glucose deprivation (OGD), Bay K8644 delivered from 1 to 12 h after re-oxygenation reduced neuronal death. The decrease in p-ERK1/2 that was observed at 1 h after OGD was reversed by Bay K8644, and the effect of Bay K8644 was blocked by treatment with U0126 and MEK kinase dead transfection. Moreover, similar to Bay K8644, FPL 64176, another potent LTCC agonist, extends the window of intervention against neuronal injury in an in vitro model of ischemia. In conclusion, our data suggest that opening LTCCs may be a practicable approach for stroke therapy.

• Authors: Hong-hai Hu, Shu-ji Li, Pu Wang, Hua-cheng Yan, Xiong Cao, Feng-qin Hou, Ying-ying Fang, Xin-hong Zhu, Tian-ming Gao
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 47 Issue 1 Pg. 280-9 (Feb 2013) ISSN: 1559-1182 [Electronic] United States
• PMID: 23054684 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Butadienes
• Calcium Channels, L-Type
• Neuroprotective Agents
• Nitriles
• Pyrroles
• U 0126
• FPL 64176
• 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
• Extracellular Signal-Regulated MAP Kinases

Topics

• 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester (pharmacology, therapeutic use)
• Animals
• Brain Ischemia (drug therapy, enzymology, pathology, physiopathology)
• Butadienes (pharmacology)
• Calcium Channels, L-Type (metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Maze Learning (drug effects)
• Memory (drug effects)
• Neurons (drug effects, metabolism, pathology)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Nitriles (pharmacology)
• Phosphorylation (drug effects)
• Pyrroles (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar