Neuroprotective activities of carvedilol and a hydroxylated derivative: Role of membrane biophysical interactions

• Published in: Biochemical pharmacology Vol. 56; no. 12; pp. 1645 - 1656
• Main Authors: Lysko, Paul G, Lysko, Kathryn A, Webb, Christine L, Feuerstein, Giora, Mason, Pamela E, Walter, Mary F, Mason, R.Preston
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 15.12.1998; Elsevier Science
• Subjects: Animals; antioxidant; Antioxidants - pharmacology; Biological and medical sciences; Calcium Channel Blockers - chemistry; Carbazoles - chemistry; Carbazoles - pharmacology; Carvedilol; Cell Membrane - chemistry; Cell Membrane - drug effects; Cells, Cultured; cerebellar neuron; Cerebellum - chemistry; dihydropyridine; Dihydropyridines - antagonists & inhibitors; Free Radical Scavengers - pharmacology; Lipid Bilayers - chemistry; Medical sciences; Models, Molecular; Neurons - chemistry; Neurons - drug effects; Neuropharmacology; Neuroprotective agent; Neuroprotective Agents - pharmacology; NMDA; Pharmacology. Drug treatments; Propanolamines - chemistry; Propanolamines - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - drug effects; sodium channel; Sodium Channel Blockers; Veratridine - toxicity; X-Ray Diffraction; x-ray scatter; NMDA; antioxidant; x-ray scatter; sodium channel; cerebellar neuron; dihydropyridine; Cell culture; Vasodilator agent; Membrane interaction; α1-Adrenergic receptor; Neuroprotective agent; Antioxidant; In vitro; β-Adrenergic receptor; Alpha blocking agent; Neuron; Analog; Carvedilol; Antihypertensive agent; Antagonist; Biological effect; Mechanism of action; Beta blocking agent
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(98)00275-5

Carvedilol is a vasodilating β-blocker and antioxidant approved for treatment of mild to moderate hypertension, angina, and congestive heart failure. SB 211475 (4-[2-hydroxyl-3-[[2-(2-methoxy-phenoxy)ethyl]amino]propoxyl]-9 H-carbazol-3-ol), a hydroxylated carvedilol analogue, is an even more potent antioxidant in several assay systems. Carvedilol also has neuroprotective capacity with modulatory actions at N-methyl- d-aspartate (NMDA) receptors and Na + channels. In the present study, we demonstrated that in cultured rat cerebellar neurons, SB 211475 has 28-fold greater antioxidant activity than carvedilol, but is 2- to 6-fold less potent, respectively, at inhibiting neurotoxic activities at Na + channels and at NMDA receptor channels. To determine a biophysical rationale for these differential activities, small angle x-ray scattering data were obtained from model lipid and brain membrane bilayers containing either carvedilol, SB 211475, or dihydropyridine calcium channel blockers. Electron density profiles revealed that the location of SB 211475 was restricted to the glycerol backbone/hydrocarbon interface and significantly reduced membrane width by 5%, whereas the time-averaged location for carvedilol and flunarizine also extended to the hydrated surface of the bilayer. Comparison of carvedilol with several dihydropyridines showed a correlation between high ClogP values (lipophilicity), Na + channel inhibitory potency, and bilayer localization. The antioxidant activity of SB 211475 could be explained by restricted intercalation into the glycerol phosphate/hydrocarbon interface, creating an increase in volume associated with the phospholipid acyl chains, which would then become resistant to lipid peroxidation. Differential channel modulation may also be explained by these membrane structural results, which indicate that carvedilol and the less spatially restricted dihydropyridine molecules are more likely to inhibit transmembrane receptor channels.