Ketamine Impairs Neural Cell Functions by Altering the BDNF Pathway and Glial Cell Polarization

Document Type

Conference Proceeding

Publication Date

5-1-2020

Publication Title

Anesth Analg

Abstract

INTRODUCTION: Recent pre-clinical and clinical studies demonstrated that long-term exposure to general anesthetic medications interferes with brain development and may lead to permanent cognitive impairments.(1,2) Thus, blockade of NMDA receptors by ketamine in the developing rodent brain causes excessive apoptosis.(3) In addition, ketamine inhibits the proliferation of neural stem cells and disturbs normal neurogenesis. However, the effects of anesthetics on glial cells and the pathways affected by anesthetics are not yet understood. METHODS: Here, we employed human cultured neural cells and analyzed the effects of ketamine on the functions of human neuronal and glial cells and delineated the cellular and molecular mechanisms that mediate their effects. We analyzed effects of ketamine and on the expression of BDNF using RT-PCR and on the polarization of astrocytes and microglia. The role of the p38 and JNK map kinases was also explored. RESULTS: We found that ketamine inhibited the proliferation of neural stem cells and increased apoptosis of human neurons. This anesthetic also decreased the expression of BDNF and increased that of pro-BDNF that has been recently reported to increase in various neurological disorders. Ketamine also affected the phenotype of both astrocytes and microglia. It promoted the polarization of M1 microglia and A1 astrocytes that exhibit pro-inflammatory functions and are characteristic of neurodegenerative diseases and the aging brain. Moreover, the treated microglia cells also expressed lower levels of BDNF and the treated astrocytes, lower levels of the glutamate transporters EAAT1 and EAAT2. Ketamine increased the phosphorylation of p38 and JNK and inhibition of these pathways abrogated the effects of these agents on the M1 microglia polarization. CONCLUSION: We found that ketamine impaired human neuronal and glial cell functions. Inhibition of BDNF and increased pro-BDNF expression were associated with the neurotoxic effects of ketamine. Moreover, the promotion of M1 and A1 phenotypes of microglia and astrocyte, respectively, demonstrate that in addition to the direct effects of ketamine on neural stem cells and neurons, it may also exert neurotoxic effects by increasing neuroinflammation and dysregulated glial cell functions via activation of the p38 and JNK pathways. (Figure Presented).

Volume

130

Issue

5

First Page

468

Last Page

470

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