Title: Chronic stimulation of GABAA receptor with muscimol reduces amyloid β protein (25–35)-induced neurotoxicity in cultured rat cortical cells
https://www.sciencedirect.com/science/a ... 0205001082
Abstract: The present study was performed to examine how the stimulation of γ-aminobutyric acid (GABA) receptor affects amyloid β protein (25–35) (Aβ (25–35)), a synthetic 25–35 amyloid peptide, -induced neurotoxicity using cultured rat cortical neurons. Aβ (25–35) produced a concentration-dependent reduction of cell viability, which was significantly reduced by (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine (MK-801), an N-methyl-d-aspartate (NMDA) receptor antagonist, verapamil, an L-type Ca2+ channel blocker, and NG-nitro-l-arginine methyl ester (l-NAME), a nitric oxide synthase inhibitor. Pretreatment with muscimol, a GABAA receptor agonist, over a concentration range of 0.1–10 μM 24 h before the treatment with 10 μM Aβ (25–35) showed concentration-dependent inhibition on the Aβ (25–35)-induced neuronal apoptotic death. However, baclofen (1 and 10 μM), a GABAB receptor agonist, failed to inhibit the Aβ (25–35)-induced neuronal death. In addition, pretreatment with muscimol (1 μM) for 24 h inhibited the Aβ (25–35) (10 μM)-induced elevation of cytosolic Ca2+ concentration ([Ca2+]c) and glutamate release, generation of reactive oxygen species (ROS), and caspase-3 activity in cultured neurons. These neuroprotective effects of muscimol (1 μM) were completely blocked by the simultaneous treatment with 10 μM bicuculline, a GABAA receptor antagonist, indicating that the protective effects of muscimol were due to GABAA receptor stimulation. When, however, treated just 15 min before the treatment with Aβ (25–35), muscimol (1 μM) did not show any protective effect against Aβ (25–35) (10 μM)-induced neurotoxicity in cultured neurons. These results suggest that the chronic activation of GABAA receptor may ameliorate Aβ-induced neurotoxicity by interfering with the increase of [Ca2+]c, and then by inhibiting glutamate release, generation of ROS and caspase-3 activity.
Chronic stimulation of GABAA receptor with muscimol reduces amyloid β protein (25–35)-induced neurotoxicity in cultur...
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