NGP1-01 is a Brain-permeable Dual Blocker of Neuronal Voltage- and Ligand-operated Calcium Channels |
| |
Authors: | Cornelia Kiewert Joachim Hartmann James Stoll Thomas J Thekkumkara Cornelis J Van der Schyf Jochen Klein |
| |
Institution: | (1) Department of Pharmaceutical Sciences, Texas Tech School of Pharmacy, Amarillo, TX 79106, USA;(2) Department of Pharmaceutical Sciences, Texas Tech School of Pharmacy, 1300 Coulter Drive, Amarillo, TX 79106, USA |
| |
Abstract: | Calcium overload of neurons leads to cell death and is a key feature in neurodegenerative diseases. The polycyclic amine NGP1-01 blocks L-type voltage operated calcium channels in cardiomyocytes. Here, we tested whether NGP1-01 blocks neuronal calcium channels. NGP1-01 (1 μM) inhibited depolarization-induced calcium influx by 78% in cortical neurons preloaded with fura-2 AM, with a potency similar to nimodipine. NGP1-01 (1 μM) also inhibited N-methyl-d-aspartate (NMDA)-induced (1 mM) calcium influx by 52%, only slightly less potent than memantine. Using in vivo-microdialysis, we monitored choline release during NMDA infusion as a measure of excitotoxic membrane breakdown. Intraperitoneal injection of NGP1-01 (40 mg/kg) reduced NMDA-induced membrane breakdown by 31% (P<0.01) while memantine (10 mg/kg) reduced choline release by 40%. Our results demonstrate that NGP1-01 simultaneously blocks both major neuronal calcium channels and is sufficiently brain-permeable. We conclude that NGP1-01 is a promising lead structure for a new class of dual-mechanism neuroprotective agents. |
| |
Keywords: | Dual-mechanism drug NGP1-01 Polycyclic amine Memantine Fura-2 NMDA Calcium channels Microdialysis Choline |
本文献已被 PubMed SpringerLink 等数据库收录! |
|