DNA methyltransferases (DNMTs) are promising epigenetic targets for the development of novel drugs, especially for neurodegenerative disorders. In recent years, there has been increased interest in small molecules that can cross the blood-brain barrier for the treatment of neurodegenerative diseases. Therefore, comparing the neuronal differentiative effects of a natural compound curcumin and a synthetic small molecule RG108 was the aim of this study. The effects of curcumin and RG108 on neuronal differentiation and neurite outgrowth were investigated in the PC-12 Adh cell line. First, a nontoxic concentration was determined to be 100nM with WST-1 assay. Subsequently, cells were treated with 100nM curcumin and RG108 alone or in combination with 50nM nerve growth factor (NGF). Cell differentiations were evaluated by a real-time cell analyzer system. Neurite outgrowth was determined and morphologically shown by immunofluorescence staining with anti-beta III tubulin antibody on PC-12 Adh cells. Also, growth-associated protein-43 (GAP-43) and b-tubulin III mRNA expression levels, associated with neurite outgrowth promotion, were determined with real-time polymerase chain reaction (RT-PCR). According to our results, 100nM curcumin and RG108 significantly induced neurite outgrowth of PC-12Adh cells with 50nM NGF. Curcumin + NGF combination further increased cell differentiations and total neurite lengths more than curcumin alone and RG108 + NGF combination groups. Strikingly, curcumin and NGF combination upregulated GAP43 and b-tubulin mRNA expression levels excessively. In conclusion, curcumin was found to be more effective than RG108 on neuronal differentiation and neurite outgrowth of PC-12Adh cells in a combination with NGF. Therefore, natural DNMT1 inhibitors, such as curcumin, can be a novel approach for the neurodegenerative disorders treatment.