Sinner, Barbara and Friedrich, Oliver and Zink, Wolfgang and Zausig, York and Graf, Bernhard M. (2011) The Toxic Effects of S(+)-Ketamine on Differentiating Neurons In Vitro as a Consequence of Suppressed Neuronal Ca2+ Oscillations. ANESTHESIA AND ANALGESIA, 113 (5). pp. 1161-1169. ISSN 0003-2999,
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BACKGROUND: In the immature brain, neuronal Ca2+ oscillations are present during a time period of high plasticity and regulate neuronal differentiation and synaptogenesis. In this study we examined the long-term blockade of hippocampal Ca2+ oscillations, the role of the N-methyl-D-aspartate (NMDA) receptors and the effects of S(+)-ketamine on neuronal synapsin expression. METHODS: Hippocampal neurons were incubated at day 15 in culture with the specific NMDA receptor antagonists dizocilpine (MK 801, 100 mu M) or S(+)-ketamine (3 mu M to 25 mu M) for 24 hours. Terminal-deoxynucleotidyl-transferase (TUNEL) and activated caspase3 were used to detect apoptotic neurons. Ca2+ oscillations were detected after loading the neurons with the Ca2+ -sensitive dye fura-2AM, and dual wavelength excitation fluorescence microscopy was performed. Ca2+/calmodulin kinase II (CaMKII) was measured using Western blots. Synapsin was identified with confocal antisynapsin immunofluorescence. RESULTS: Blocking the NMDA receptor with MK 801 or 25 mu M S(+)-ketamine resulted in a significant increase in apoptotic neurons. MK 801 led to a significant increase in cytosolic Ca2+ concentration and reduction of the amplitude and frequency of the Ca2+ oscillations. Similar to MK 801, the long-term application of S(+)-ketamine resulted in a significant increase in cytosolic Ca2+ concentration 24 hours after washout. This was associated with a down-regulation of the CaMKII and a reduction of the synapsin 24 hours after washout. CONCLUSION: Neuronal Ca2+ oscillations mediate neuronal differentiation and synaptogenesis via activating CaMKII. By acting via the NMDA receptor, S(+)-ketamine exerts its toxic effect through the suppression of neuronal Ca2+ oscillations, down-regulation of the CaMKII, and consecutively reduced synaptic integrity. (Anesth Analg 2011; 113: 1161-9)
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | DEVELOPING RAT-BRAIN; NICOTINIC ACETYLCHOLINE-RECEPTORS; CULTURED HIPPOCAMPAL-NEURONS; SPONTANEOUS CA2+-OSCILLATIONS; APOPTOTIC NEURODEGENERATION; NETWORK OSCILLATIONS; GABAERGIC NEURONS; EARLY EXPOSURE; CELL-DEATH; KETAMINE; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Anästhesiologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 27 May 2020 09:58 |
| Last Modified: | 27 May 2020 09:58 |
| URI: | https://pred.uni-regensburg.de/id/eprint/19913 |
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