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.