**Ketamine Induces Neuroapoptosis in Stem Cell– Derived Developing Human Neurons Possibly through Intracellular Calcium/Mitochondria/microRNA Signaling Pathway Derived Developing Human Neurons Possibly through Intracellular Calcium/Mitochondria/microRNA Signaling Pathway**

**Ketamine Induces Neuroapoptosis in Stem Cell–**

DOI: 10.5772/intechopen.72939

Danielle Twaroski, Yasheng Yan, Congshan Jiang, Sarah Logan, Zeljko J. Bosnjak and Xiaowen Bai Sarah Logan, Zeljko J. Bosnjak and Xiaowen Bai Additional information is available at the end of the chapter

Danielle Twaroski, Yasheng Yan, Congshan Jiang,

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72939

#### **Abstract**

Ketamine, one of the commonly used agents in pediatric anesthesia, has been linked to neurodegeneration and cognitive dysfunction in developing animal models. Previous studies on developing neurons derived from human embryonic stem cells (hESCs) indicate that ketamine induces neuroapoptosis and the mechanisms remain largely unknown. This study aims to investigate the effect of ketamine on intracellular calcium, mitochondrial signaling, and microRNA profiles in hESCs-derived 2-week-old neurons. The neurons were exposed to ketamine for 6 or 24 hours. Neuroapoptosis was assessed by TUNEL staining. Intracellular calcium level was analyzed using Fluo-4 AM staining. The mitochondria-related neuroapoptosis pathway including mitochondrial membrane potential, cytochrome c release from mitochondria to cytosol, and mitochondrial fission was also investigated. miScript miRNA arrays were used in microRNA target identification studies. The results showed that ketamine exposure induced neuroapoptosis and alterations in intracellular calcium levels. In addition, ketamine decreased mitochondrial membrane potential, resulted in cytochrome c release from mitochondria into cytosol, and increased mitochondrial fission. Among 88 microRNAs investigated, let-7a/e, miR-21, miR-23b, miR-28-5p, and miR-423-5p were found downregulated, while miR-96 was upregulated in the neurons treated with ketamine. Collectively, our findings indicate that ketamine induces neuroapoptosis possibly through the dysregulated intracellular calcium, mitochondria, and microRNA pathway.

**Keywords:** ketamine, calcium, mitochondria, microRNAs, neuroapoptosis

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© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons
