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Published on: October 18, 2018
Neuroprotective effects of blockers for T-type calcium channels
Norelle C Wildburger1, Avary Lin-Ye, Michelle A Baird
1Department of Otolaryngology, Center for Aging, Washington University, 4560 Clayton Avenue, St Louis, MO 63110, USA. jbao@wustl.edu.
Abstract:
Cognitive and functional decline with age is correlated with deregulation of intracellular calcium, which can lead to neuronal death in the brain. Previous studies have found protective effects of various calcium channel blockers in pathological conditions. However, little has been done to explore possible protective effects of blockers for T-type calcium channels, which forms a family of FDA approved anti-epileptic drugs. In this study, we found that neurons showed an increase in viability after treatment with either L-type or T-type calcium channel antagonists. The family of low-voltage activated, or T-type calcium channels, comprise of three members (Cav3.1, Cav3.2, and Cav3.3) based on their respective main pore-forming alpha subunits: alpha1G, alpha1H, and alpha1I. Among these three subunits, alpha1H is highly expressed in hippocampus and certain cortical regions. However, T-type calcium channel blockers can protect neurons derived from alpha1H-/- mice, suggesting that neuroprotection demonstrated by these drugs is not through the alpha1H subunit. In addition, blockers for T-type calcium channels were not able to confer any protection to neurons in long-term cultures, while blockers of L-type calcium channels could protect neurons. These data indicate a new function of blockers for T-type calcium channels, and also suggest different mechanisms to regulate neuronal survival by calcium signaling pathways. Thus, our findings have important implications in the development of new treatment for age-related neurodegenerative disorders.
Insights
Calcium channel blockers show promise for treating age-related cognitive decline. T-type calcium channel blockers protect neurons, suggesting new therapeutic avenues for neurodegenerative disorders.
Area of Science:
- Neuroscience
- Pharmacology
- Calcium Signaling
Background:
- Age-related cognitive decline is linked to disrupted intracellular calcium levels and neuronal death.
- Calcium channel blockers are known to have protective effects in various diseases.
- T-type calcium channels, targeted by FDA-approved anti-epileptic drugs, have not been extensively studied for neuroprotection.
Purpose of the Study:
- To investigate the neuroprotective effects of T-type calcium channel blockers.
- To explore the role of specific T-type calcium channel subunits (alpha1H) in neuroprotection.
- To compare the neuroprotective mechanisms of T-type and L-type calcium channel blockers.
Main Methods:
- Treatment of neurons with L-type and T-type calcium channel antagonists.
- Assessment of neuronal viability after drug treatment.
- Experiments using neurons derived from alpha1H-/- mice.
- Long-term neuronal cultures to evaluate sustained protective effects.
Main Results:
- Both L-type and T-type calcium channel antagonists increased neuronal viability.
- T-type calcium channel blockers protected neurons from alpha1H-/- mice, indicating the effect is not mediated by the alpha1H subunit.
- T-type calcium channel blockers did not provide protection in long-term cultures, unlike L-type calcium channel blockers.
Conclusions:
- T-type calcium channel blockers possess neuroprotective properties independent of the alpha1H subunit.
- Different calcium channel blockers may utilize distinct pathways to regulate neuronal survival.
- Findings suggest potential for T-type calcium channel blockers in treating age-related neurodegenerative diseases.
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