The toxic effects of s(+)-ketamine on differentiating neurons in vitro as a consequence of suppressed neuronal Ca2+ oscillations.
Sinner B, Friedrich O, Zink W, Zausig Y, Graf B (2011)
Publication Language: English
Publication Status: Published
Publication Type: Journal article, Original article
Publication year: 2011
Journal
Book Volume: 113
Pages Range: 1161-9
Journal Issue: 5
DOI: 10.1213/ANE.0b013e31822747df
Open Access Link: http://journals.lww.com/anesthesia-analgesia/Fulltext/2011/11000/The_Toxic_Effects_of_S____Ketamine_on.33.aspx
Abstract
BACKGROUND\nIn 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.\nMETHODS\nHippocampal neurons were incubated at day 15 in culture with the specific NMDA receptor antagonists dizocilpine (MK 801, 100 μM) or S(+)-ketamine (3 μM to 25 μM) 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.\nRESULTS\nBlocking the NMDA receptor with MK 801 or 25 μM 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.\nCONCLUSION\nNeuronal 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.
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APA:
Sinner, B., Friedrich, O., Zink, W., Zausig, Y., & Graf, B. (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), 1161-9. https://doi.org/10.1213/ANE.0b013e31822747df
MLA:
Sinner, Barbara, et al. "The toxic effects of s(+)-ketamine on differentiating neurons in vitro as a consequence of suppressed neuronal Ca2+ oscillations." Anesthesia and analgesia 113.5 (2011): 1161-9.
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