Analysis of the protective effects of a neuronal Cav2.1 calcium channel in brain injury.

Abstract

We previously reported that rolling Nagoya mice carrying a mutation in the α1 subunit of the Cav2.1 channel protective from ischemia- and kainate-induced neuronal damage. However, the protective effect of this mutation and its relationship to brain injury recovery have not been examined. To examine the relationship between Cav2.1 channel function and brain injury, we induced cryogenic brain damage in homozygous rolling Nagoya (rol/rol), control wild-type (+/+), ω-agatoxin IVA-pretreated +/+ (ω-aga +/+), and ω-agatoxin IVA-post-treated +/+ (ω-aga-post-treated +/+) mice. We measured the lesion area, blood brain-barrier permeability and performed immunohistochemistry and western blot analysis. The lesions of rol/rol and ω-aga +/+ mice were significantly smaller than those observed in +/+ mice at both day 1 and day 7 after injury. Similar results were shown in blood-brain barrier permeability. We observed more reactive astrogliosis in +/+ mice than in rol/rol or ω-aga +/+ mice. rol/rol and ω-aga +/+ mice had fewer degenerating cells due to cryogenic injury than did +/+ mice at both day 1 and day 7. ω-Aga-post-treated +/+ mice 24h after injury were sacrificed on day 7. The lesions were smaller in ω-aga-post-treated +/+ mice than those in vehicle-treated +/+ mice. We also examined phosphorylated p38 (pp38) at the injured site. ω-Aga-post-treated +/+ mouse brain slices showed weak pp38 signal; vehicle-treated +/+ mouse brain slices were pp38-positive. These findings demonstrate that the mutant Cav2.1 channel exerts a protective effect against cryogenic brain injury in rolling Nagoya mice. Our results indicate that inhibitors of the Cav2.1-dependent p38 signaling cascade would be useful as therapeutic agents in the treatment of brain injury.

• Authors: T Y Kim, T Yoshimoto, Y Aoyama, K Niimi, E Takahashi
• Journal: Neuroscience (Neuroscience) Vol. 313 Pg. 110-21 (Jan 28 2016) ISSN: 1873-7544 [Electronic] United States
• PMID: 26616403 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Calcium Channel Blockers
• Calcium Channels, N-Type
• Neuroprotective Agents
• voltage-dependent calcium channel (P-Q type)
• p38 Mitogen-Activated Protein Kinases

Topics

• Animals
• Astrocytes (drug effects, metabolism, pathology)
• Blood-Brain Barrier (drug effects, metabolism, pathology)
• Brain Injuries (complications, drug therapy, metabolism, pathology)
• Calcium Channel Blockers (pharmacology)
• Calcium Channels, N-Type (metabolism)
• Capillary Permeability (drug effects, physiology)
• Cold Temperature
• Disease Models, Animal
• Male
• Mice, Transgenic
• Mutation
• Nerve Degeneration (drug therapy, etiology, metabolism, pathology)
• Neurons (drug effects, metabolism, pathology)
• Neuroprotective Agents (pharmacology)
• Phosphorylation
• p38 Mitogen-Activated Protein Kinases (metabolism)