Abstract
Diabetes mellitus (DM) is an independent risk factor for cognitive impairment. Although the etiology of diabetic cognitive impairment is complex and multifactorial, the hippocampus neuronal apoptosis is recognized as a main cause of diabetes-induced cognitive impairment. 2-Dodecyl-6-methoxycyclohexa-2,5-diene-1,4-dione (DMDD) was purified from the roots of Averrhoa carambola L. Previous research demonstrated that DMDD was safe and effective in delaying some diabetic complications. However, the efficacy of DMDD to ameliorate diabetic cognitive impairment in type 2 diabetes mice has not been reported. In the present study, the behavioral evaluation was performed by Y maze and novel object recognition in db/db mice. Gene expression profiles were detected using mouse lncRNA microarray analysis in the hippocampi of db/db mice. Changes in the neurodegeneration-associated proteins and the apoptosis-related proteins were determined in both db/db mice and high glucose-treated HT22 cells by Western blotting. We observed that DMDD treatment significantly ameliorated the spatial working memory and object recognition memory impairment in db/db mice. Further study showed that neurodegeneration-associated protein tau was decreased after DMDD treatment in the hippocampi of db/db mice. Eleven lncRNAs and four mRNAs including pro-apoptotic gene Hif3a were significantly differently expressed after DMDD treatment in the hippocampi of db/db mice. The expression of Hif3a, cleaved parp, and caspase 3 proteins was significantly increased in the hippocampi of diabetic db/db mice compared with db/m control mice and then decreased after DMDD treatment. Similar beneficial effects of DMDD were observed in HG-treated HT22 cells. These data indicate that DMDD can alleviate cognitive impairment by inhibiting neuronal apoptosis through decreasing the expression of pro-apoptotic protein Hif3a. In conclusion, our study suggests that DMDD has great potential to be a new preventive and therapeutic compound for diabetic cognitive impairment.
Highlights
Diabetes mellitus (DM) is a complex metabolic disturbances characterized by chronic hyperglycemia
The percentage of duration in the novel arm was significantly higher in DMDD-treated db/db mice than in the vehicletreated db/db mice (p < 0.05) (Figure 2B). These results suggested that DMDD treatment had significant positive effects on the spontaneous alternation and improved spatial working memory in db/db mice
The expression levels of Hif3a, cleaved Parp, caspase 3, and Bax were significantly reduced in DMDD-treated db/db group compared with db/db-vehicle group (p < 0.05). These results indicated that DMDD treatment decreased pro-apoptotic factor Hif3a expression and protected neurons from high glucose-induced apoptosis in vivo and in vitro
Summary
Diabetes mellitus (DM) is a complex metabolic disturbances characterized by chronic hyperglycemia. The pathophysiology of cognitive dysfunction in diabetes is multifactorial, including insulin signaling defect, inflammatory pathways, oxidative stress, mitochondrial abnormalities, and Tau signaling (Zilliox et al, 2016; Bharadwaj et al, 2017). The link between diabetes and neurodegenerative disease has been well established, but the underlying mechanisms of pathological development remains unclear. Previous studies focused on tauopathies, α-synuclein accumulation (Ashraf et al, 2014), mitochondrial dysfunction, and apoptosis (Cheng et al, 2019). Multiple studies showed that diabetes-related metabolic dysfunction affected tau phosphorylation and resulted in hyperphosphorylated tau accumulates to form neurofibrillary tangles (NFTs) and lead to neuronal death (Zhang et al, 2018; Ho et al, 2020). Α-synuclein accumulation plays a key role in diabetic cognitive impairment. Recent studies have shown that compared with normal controls, patients with diabetes had higher CSF tau and α-synuclein levels (Pagano et al, 2018)
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