Role of miR‐34c in ketamine‐induced neurotoxicity in neonatal mice hippocampus

Abstract

Ketamine is a commonly used pediatric anesthetic, but it might affect development, or even induce neurotoxicity in the neonatal brain. We have used an in vivo neonatal mouse model to induce ketamine-related neurotoxicity in the hippocampus, and found that miR-34c, a microRNA associated with pathogenesis of Alzheimer's disease, was significantly upregulated during ketamine-induced hippocampal neurodegeneration. Functional assay of silencing miR-34c demonstrated that downregulation of miR-34c activated PKC-ERK pathway, upregulated anti-apoptotic protein BCL2, and ameliorated ketamine-induced apoptosis in the hippocampus. Cognitive examination with the Morris water maze test showed that ketamine-induced memory impairment was significantly improved by miR-34c downregulation. Thus, miR-34c is important in regulating ketamine-induced neurotoxicity in hippocampus.

Long noncoding RNA BDNF-AS regulates ketamine-induced neurotoxicity in neural stem cell derived neurons

“…In the study of in vivo model of rat, Zuo and colleagues showed that PI3K/Akt and CREB/BDNF signaling pathways were involved in the attenuation of baicalin on ketamine-induced neurotoxicity [19]. In another study of using both in vivo and in vitro model of mouse hippocampus, Cao and colleagues demonstrated that epigenetic regulation of microRNA-34c had protective effect on reducing ketamine-induced apoptosis on hippocampal neurons through ERK signaling pathway [12]. In both cases, it seems like signaling pathways involving tyrosine kinase receptors (BDNF/Akt in formal case and ERK in later case) were active regulators in modulating ketamine-induced neurotoxicity both in vivo and in vitro.…”

“…In recent years, emerging evidence has demonstrated that high dosage of ketamine induced neurotoxicity in developing brains in both humans and animals [9][10][11]. While various candidate genes and signaling pathways were suggested to be involved [12,13], the exact mechanisms underling the regulation of ketamine-induced neurotoxicity are still poorly understood. Also, it is difficult to assess ketamineinduced neurotoxicity with prolonged exposure and higher dosages on human subjects, especially on infants or children.…”

MicroRNAs: New Players in Anesthetic-Induced Developmental Neurotoxicity

“…However, the potential functions of microRNAs in anesthetic-induced neurotoxicity are just starting to be investigated. More recently, five studies from our and other laboratories pointed to important roles of several microRNAs (e.g., miR-21, miR-34a, miR-34c, miR-124, and miR-137) in anesthetic-induced developmental neurotoxicity using various experimental models [45, 72-75]. These studies have been summarized and are shown in Table 2.…”

MiR-34c induces apoptosis and inhibits the viability of M4e cells by targeting BCL2

“…It was previously reported that B cell lymphoma 2 (BCL2), a central genetic apoptotic regulator (9), which is crucial for cell apoptosis, migration and invasion (3), is involved in the pathogenesis of laryngeal cancer (10)(11)(12). In addition, research into other diseases has reported on the association between miR-34c and BCL2 (13)(14)(15); there is an inverse association between levels of miR-34c and expression of BCL2. Knockdown of miR-34c upregulated anti-apoptotic protein BCL2 to ameliorate apoptosis in the hippocampus or promote embryonic stem cell (ESC) differentiation (13)(14)(15).…”

“…In addition, research into other diseases has reported on the association between miR-34c and BCL2 (13)(14)(15); there is an inverse association between levels of miR-34c and expression of BCL2. Knockdown of miR-34c upregulated anti-apoptotic protein BCL2 to ameliorate apoptosis in the hippocampus or promote embryonic stem cell (ESC) differentiation (13)(14)(15). Based on these reports, the authors of the present study hypothesized that there may be an association between miR-34c and BCL2, which is involved in the pathogenesis of laryngeal cancer.…”