Abstract:
:Ketamine is widely used both as anesthetic and abuse drug. In this study, we investigated the effects of a wide range of ketamine concentrations (100-500-1000 μM) on calcium mobilization and the induction of cell death in undifferentiated PC12 cells, 24 h after treatment. Calcium mobilization was measured as the percentage of fluorescence one minute after depolarization by flow cytometry. For the kinetic changes in [Ca2+]c, fluorescence microscopy with Live Imaging was used with a resolution time of 0.87 s (exposure time: 20 ms). Fluo-4 AM was used for both methods. Flow cytometry using TMRE, NAO, and Annexin V-FITC/PI probes were employed for the evaluation of mitochondrial membrane potential (ΔΨm), cardiolipin content and type of cell death respectively. Fluorescence microscopy was used for the evaluation of DNA fragmentation by TUNEL assay with dUTP-conjugated FITC. Results obtained by flow cytometry showed a clear increment in cell response to depolarization after addition of 50 mM and 70 mM KCl in PC12 cells. Simultaneously, cells treated with 100 μM and 500 μM ketamine during 24 h, induced a decreased response to depolarization as compared with control cells. In addition, 1000 μM ketamine induced a similar increase in Fluo4AM fluorescence either after addition of 50 or 70 mM KCl. The kinetic assays showed that after 100 mM KCl, cells pre-treated with ketamine showed a marked decrease in [Ca2+]c as compared with control cells. In the case of 1000 μM ketamine treatment, an increased and sustained [Ca2+]c was observed along the whole assay, indicating a cell disability to maintain calcium homeostasis. Associated with these cytosolic calcium alterations, mitochondrial depolarization, cardiolipin depletion and alteration in Bax protein expression were observed after ketamine treatment. Our data demonstrate that ketamine action in these cells seems to be independent from NMDAR, as observed by the absence of glutamate‑calcium response. Acute disturbance in [Ca2+]c could be mediated by the inhibition of VDCCs as part of the molecular mechanism of ketamine cytotoxicity leading to mitochondrial dysfunction and cell death by apoptosis and necrosis.
journal_name
Exp Mol Patholjournal_title
Experimental and molecular pathologyauthors
Bustamante J,Acosta L,Karadayian AG,Lores-Arnaiz Sdoi
10.1016/j.yexmp.2019.104318subject
Has Abstractpub_date
2019-12-01 00:00:00pages
104318eissn
0014-4800issn
1096-0945pii
S0014-4800(18)30605-1journal_volume
111pub_type
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