Metformin Protects Against Diabetes-Induced Cognitive Dysfunction by Inhibiting Mitochondrial Fission Protein DRP1

Abstract

Objectives: Diabetes is an independent risk factor for dementia. Mitochondrial dysfunction is a critical player in diabetes and diabetic complications. The present study aimed to investigate the role of mitochondrial dynamic changes in diabetes-associated cognitive impairment.Methods: Cognitive functions were examined by novel object recognition and T-maze tests. Mice hippocampi were collected for electron microscopy and immunofluorescence examination. Neuron cell line HT22 and primary hippocampal neurons were challenged with high glucose in vitro. Mitotracker-Red CM-H2X ROS was used to detect mitochondrial-derived free radicals.Results: Diabetic mice exhibited memory loss and spatial disorientation. Electron microscopy revealed that diabetic mice had larger synaptic gaps, attenuated postsynaptic density and fewer dendritic spines in the hippocampus. More round-shape mitochondria were observed in hippocampal neurons in diabetic mice than those in control mice. In cultured neurons, high glucose induced a high phosphorylated level of dynamin-related protein 1 (DRP1) and increased oxidative stress, resulting in cell apoptosis. Inhibition of mitochondrial fission by Mdivi-1 and metformin significantly decreased oxidative stress and prevented cell apoptosis in cultured cells. Treatment of Mdivi-1 and metformin restored cognitive function in diabetic mice.Conclusion: Metformin restores cognitive function by inhibiting mitochondrial fission, reducing mitochondrial-derived oxidative stress, and mitigating neuron loss in hippocampi of diabetic mice. The protective effects of metformin shed light on the therapeutic strategy of cognitive impairment.

Relative Molecular Similarity in Compound Structures Modulating Neurodegenerative Apoptosis

“…Compound structures with neurotoxic potential, given in Figure 1, fit to the 4) with fitting-points on both purine and furan rings. Streptozotocin (7) a glucosamine-nitrosourea structure, provides the same fits as glucose (5,6) and these fitting-points are shared by ethidium (12). In contrast to the fits of glucose, those of pentylenetetrazole (8,9) do not overlap.…”

“…MPTP (1-methyl-4phenyl-1,2,3,6-tetrahydropyridine) [26], paraquat [26], rotenone [26], ethidium bromide [27], cuprizone [28], 3-nitro-L-tyrosine [29], streptozotocin [30], pentylenetetrazole (PTZ) [31], metamphetamine [32], lysophosphatidylcholine [33], sphingosine [34]. Compounds providing protection against experimentally induced diabetes and β-cell apoptosis: loganin [1], taurine [2], silibinin [3], 17β-estradiol [6], vitamin D3 [7], mdivi-1 [12], metformin [12], gliclazide [35], nicotinamide [36], telmisartan [37]. Compounds providing protection against apoptosis in animal models of Parkinson's and MS respectively: ursolic acid [26], astilbin [26], β-lapachone [26], papaverine [26], embelin [26], dexrazoxane [26], schisandrin A [26], 20-hydroxyecdysone [38], NE52-QQ57 [39]; magnol [40], cannabidiol [41], monomethylfumarate [42], glucosylceramide [43].…”

“…Mitochondrial dysfunction and neuroinflammation feature markedly in the neuron degeneration of MS, Parkinson's and Alzheimer's diseases [8] [11]. The hippocampal neurons of patients with Parkinson's and Alzheimer's demonstrate excessive mitochondrial fragmentation [12]. Reports that identify type-2 diabetes as a risk factor for both diseases may implicate a shared mechanism of glucose dysregulation [13] [14].…”

“…impact mitochondrial function.Reduced endoplasmic reticulum stress and oxidative stress mechanisms are responsible for the protective effects of estradiol, vitamin D, loganin, taurine and silibinin on β-cell and Schwann cell apoptosis induced by glucose, streptozotocin and palmitic acid[1] [2] [3][6]. There is evidence for an abnormality in the regulation of mitochondrial fission by dynamic-related protein 1 (DRP1) in Alzheimer's, Parkinson's and diabetes[12]. Oxidative stress and apoptosis in hippocampal cell cultures are ameliorated by the DRP1 inhibitor mdivi-1 and the diabetic drug metformin[12].…”

Mulberry-Derived 1-Deoxynojirimycin Prevents Type 2 Diabetes Mellitus Progression via Modulation of Retinol-Binding Protein 4 and Haptoglobin

“…Dynamin 1-like protein (drp1) was also found in this group; its function is to regulate mitochondrial fission [ 40 ]. It was reported that metformin can suppress excessive mitochondrial fission by inhibiting drp1 protein activity and restoring mitochondrial homeostasis in diabetic mice [ 41 ]. Son of sevenless protein 1 (SOS1) is involved in the tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) in the insulin signaling pathway [ 42 ].…”