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Ascorbic acid has been reported to enhance differentiation of embryonic stem (ES) cells into neurons, however, the specific functions of ascorbic acid have not been defined yet. To address this issue, gene expression profiling was performed using cDNA microarray. Ascorbic acid increased the expressions of genes involved in neurogenesis, maturation, and neurotransmission. Furthermore, statistical analysis using Fisher's exact test revealed ascorbic acid significantly modulated the genes involved in cell adhesion and development category. These results provide information on the role for ascorbic acid during neuronal differentiation of ES cells and might contribute to large-scale generation of neurons for future clinical treatment.

Synthetic cannabinoids (CBs) such as the JWH series have caused social problems concerning their abuse liability. Because the JWH series produces euphoric and hallucinogenic effects, they have been distributed illegally under street names such as “Spice” and “Smoke”. Many countries including Korea have started to schedule some of the JWH series compounds as controlled substances, but there are a number of JWH series chemicals that remain uncontrolled by law. In this study, three synthetic CBs with different binding affinities to the CB1 receptor (JWH-073, 081, and 210) and Δ9-tetrahydrocannabinol (Δ9-THC) were evaluated for their potential for psychological dependence. The conditioned place preference test (unbiased method) and self-administration test (fixed ratio of 1) using rodents were conducted. Ki values of the three synthetic cannabinoids were calculated as supplementary data using a receptor binding assay and overexpressed CB1 protein membranes to compare dependence potential with CB1 receptor binding affinity. All mice administered JWH-073, 081, or 210 showed significantly increased time spent at unpreferred space in a dose-dependence manner in the conditioned place preference test. In contrast, all tested substances except Δ9-THC showed aversion phenomenon at high doses in the conditioned place preference test. The order of affinity to the CB1 receptor in the receptor binding assay was JWH-210 > JWH-081 >> JWH-073, which was in agreement with the results from the conditioned place preference test. However, no change in self-administration was observed. These findings suggest the possibility to predict dependence potential of synthetic CBs through a receptor binding assay at the screening level.

Neurogenesis is one of the most complex events in embryonic development. However, little information is available regarding the molecular events that occur during neurogenesis. To identify regulatory genes and underlying mechanisms involved in the differentiation of embryonic stem (ES) cells to neurons, gene expression profiling was performed using cDNA microarrays. In mouse ES cells, we compared the gene expression of each differentiated cell stage using a five-stage lineage selection method. Of 10,368 genes, 1633 (16%) known regulatory genes were differentially expressed at least 2-fold or greater at one or more stages. At stage 3, during which ES cells differentiate into neural stem cells, modulation of nearly 1000 genes was observed. Most of transcription factors (Otx2, Ebf-3, Ptx3, Sox4, 13, 18, engrailed, Irx2, Pax8, and Lim3), signaling molecules (Wnt, TGF, and Shh family members), and extracellular matrix/adhesion molecules (collagens, MAPs, and NCAM) were up-regulated. However, some genes which may play important roles in maintaining the pluripotency of ES cells (Kruppel-like factor 2, 4, 5, 9, myeloblast oncogene like2, ZFP 57, and Esg-1) were down-regulated. The many genes identified with this approach that are modulated during neurogenesis will facilitate studies of the mechanisms underlying ES cell differentiation, neural induction, and neurogenesis.

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