Dehydrozingerone Improves Mood and Memory in Diabetic Mice via Modulating Core Neuroimmune Genes and Their Associated Proteins

Patients with poorly managed diabetes are at a greater risk of developing dementia and experiencing accelerated brain aging due to elevated blood glucose levels. Furthermore, patients with diabetes frequently encounter challenges with memory, recall, and concentration while carrying out their daily activities. The goal of this study was to investigate whether dehydrozingerone, a structural half-analog of curcumin, might improve mood and cognition in diabetics using a well-established mouse model of type 2 diabetes (T2DM) induced by a high-fat diet (HFD) and low streptozotocin (STZ) doses. Dehydrozingerone (DH) at 50 mg/kg orally for 2 weeks improved hippocampal and medial prefrontal cortex (mPFC)-dependent mood and memory in diabetic mice. An integrated transcriptome and proteome analysis revealed that 26 genes encoding mitochondrial energetics (Cox6), insulin resistance (Etnppl), lipid metabolism (Apod, Plin4), accelerated brain aging (Gm11639), and inflammation (Ighg2c) are differentially expressed in the diabetic mouse brain at both the mRNA and protein levels. Further, bioinformatic analysis revealed that these differentially expressed genes (DEGs) and proteins (DEPs) play a critical role in a variety of biological functions, including ion transport, calcium signaling, cellular senescence, mitochondrial energy, autophagy, neuronal plasticity, and cognition. Additionally, anomalies in the glutamine-glutamate/GABA cycle could exacerbate diabetes-related cognitive deficits. Treatment with DH had a variety of advantages, including decreased neuroinflammation and neuronal cell death as well as the promotion of critical genes and proteins necessary to promote cognitive performance. As a consequence, DH may be a potential treatment option for diabetics with persistent neuroinflammation and cognitive impairments.