Diabetes is a progressive metabolic disease that can severely damage several organs, including the central nervous system. It has been suggested that diabetes can induce cognitive dysfunction due to expression changes of excitatory neurotransmission mediated by N-methyl-D-aspartate (NMDA) receptors. In addition, diabetes is associated with imbalances in the regulation of intracellular Ca2+, which leads to neuronal damage and, ultimately, a decline in cognitive abilities. Moreover, Type 1 diabetes patients have higher glutamate levels in their brains, which can be used as an early marker of diabetes-related neurodegenerative diseases. Melatonin, a hormone with neuroprotective properties, has been shown to play a role in preventing cognitive impairment in various conditions. In this study, the effect of melatonin on the expressions of NMDA receptor subunits (NR2A and NR2B) and Ca2+/calmodulin-dependent kinase II (CaMKII) mRNA in the prefrontal cortex of streptozotocin-induced type 1 diabetic rat were investigated by real-time PCR. The results showed that the prefrontal cortex in diabetic rats showed a significant increase in the expression of NR2A, NR2B, and CaMKII mRNA. In contrast, the levels of these entire genes were decreased significantly in diabetes supplemented with melatonin. It is suggested that NR2A, NR2B, and CaMKII may play a role in neuronal calcium overload caused by diabetes, and melatonin can ameliorate their expression alterations. Moreover, by regulating these molecules, melatonin treatment may also prevent diabetes-related cognitive impairments.Acknowledgement: This study was supported by a research grant from HRH Princess Mahachakri Sirindhorn Medical Center, Faculty of Medicine, Srinakharinwirot University (Contract No.150/2565).