The effect of cordycepin on brain oxidative stress and protein expression in streptozotocin-induced diabetic mice

Abstract

Diabetes mellitus (DM) is characterized by metabolic disorders and psychological deficits, including cognitive decline. Here, we investigated the effect of cordycepin on oxidative stress and protein expression in the brains of diabetic mice. Twenty-four mice were divided into four groups, one comprising untreated healthy mice (N); one comprising healthy mice treated with cordycepin (24 mg/kg body weight) (N+Cor); one comprising untreated DM mice; and one comprising DM mice treated with cordycepin (24 mg/kg body weight) (DM+Cor). After 14 days of treatment, cognitive behavior was assessed using the novel object recognition (NOR) test. The brain levels of oxidative stress markers (glutathione, catalase, and superoxide dismutase) were examined using the respective detection kits. Protein expression in brain tissues was assessed by liquid chromatography with tandem mass spectrometry (LC-MS/MS); the functions of the identified proteins were annotated by PANTHER, while major protein-protein interactions were assessed using STITCH. We found that cordycepin treatment significantly decreased body weight and food and water intake in the DM+Cor group compared with that in the DM group; however, no differences in blood glucose levels were found between the two groups. Cordycepin treatment significantly reversed cognitive decline in diabetic mice in the NOR test and ameliorated antioxidant defenses. Additionally, we identified ULK1 isoform 2, a protein associated with cognitive function via the activated AMPK and autophagic pathways, as being uniquely expressed in the DM+Cor group. Our findings provide novel insights into the cellular mechanisms underlying how cordycepin improves cognitive decline in diabetic mice.

Keywords: brain protein; cognitive function; cordycepin; diabetes mellitus; free radical.

Fig. 1.

The effect of cordycepin on cognition in streptozotocin (STZ)-induced diabetic mice as assessed by the novel object recognition (NOR) test. (A) Recognition index. (B) The total exploration time for both trials combined. Values with a different letter above the bar differ significantly (P<0.05). N, healthy control mice treated with vehicle; N+Cor, healthy mice treated with cordycepin at a dose of 24 mg/kg body weight; DM, diabetic mice treated with vehicle; DM+Cor, diabetic mice treated with cordycepin at a dose of 24 mg/kg body weight.

Fig. 2.

Effect of cordycepin on oxidative stress markers. (A) Reduced glutathione (GSH) levels. (B) Catalase (CAT) levels. (C) Superoxide dismutase (SOD) levels. Values with a different letter above the bar differ significantly (P<0.05). N, healthy control mice treated with vehicle; N+Cor, healthy mice treated with cordycepin at a dose of 24 mg/kg body weight; DM, diabetic mice treated with vehicle; DM+Cor, diabetic mice treated with cordycepin at a dose of 24 mg/kg body weight.

Fig. 3.

Venn diagram of the protein expression profiles among the four groups. N, healthy control mice treated with vehicle; N+Cor, healthy mice treated with cordycepin at a dose of 24 mg/kg body weight; DM, diabetic mice treated with vehicle; DM+Cor, diabetic mice treated with cordycepin at a dose of 24 mg/kg body weight.

Fig. 4.

Distribution of the proteins uniquely expressed in the N+Cor group (healthy mice treated with cordycepin at a dose of 24 mg/kg body weight) in the Biological Process category.

Fig. 5.

The protein interaction network of cordycepin and unique brain protein (ULK1 and Ears2) in the regulation of autophagy and the aminoacyl-tRNA biosynthesis pathway generated using STITCH.