Abstract
Our previous studies indicated that adapentpronitrile, a new adamantane-based dipeptidyl peptidase-IV (DPP-IV) inhibitor, has a hypoglycemic effect and ameliorates rat pancreatic β cell dysfunction in type 2 diabetes mellitus through inhibiting DPP-IV activity. However, the effect of adapentpronitrile on the neurodegenerative diseases has not been studied. In the present study, we first found that adapentpronitrile significantly ameliorated neuronal injury and decreased amyloid precursor protein (APP) and amyloid beta (Aβ) expression in the hippocampus and cortex in the high fat diet/STZ rat model of diabetes. Furthermore, adapentpronitrile significantly attenuated oxidative stress, downregulated expression of the pro-apoptotic proteins BAX, cytochrome c, caspase-9, and caspase-3, and upregulated expression of the anti-apoptotic protein Bcl-2, although there was no effect on GLP-1R expression. At 30 min post-injection of adapentpronitrile (50 mg/kg) via the tail vein, its concentration in normal rat brain was 0.2034 ± 0.0094 μg/g. Subsequently, we further confirmed the neuroprotective effects and mechanism of adapentpronitrile in HT22 cells treated with high glucose (HG) and aluminum maltolate [Al(mal)3] overload, respectively. Our results showed significant decreases in mitochondrial membrane potential (MTP) and Bcl-2 expression, accompanied by a significant increase in apoptosis, reactive oxygen species (ROS) generation, and the expression of pro-apoptotic proteins in HT22 cells exposed to these stimuli. Adapentpronitrile treatment protected against neuronal injury, suppressed ROS generation, and reduced MTP and mitochondrial apoptosis in HT22 cells; however, DPP-IV activity was not detected. Our results suggest that adapentpronitrile protects against diabetic neuronal injury, at least partially, by inhibiting mitochondrial oxidative stress and the apoptotic pathway in a DPP-IV-independent manner.
Highlights
Diabetes is a multifactorial metabolic disease characterized by hyperglycemia and high morbidity
Effects of Adapentpronitrile on Oxidative Stress in the Hippocampus and Cortex of Rat. Both hippocampal and cortex superoxide dismutase (SOD) activity in high-fat diet (HFD)/STZ group significantly decreased compared with the control group
The dipeptidyl peptidase-IV (DPP-IV) inhibitor adapentpronitrile effectively attenuates the neuronal injury caused by high glucose (HG)/Al(mal)3 overload in vitro and ameliorates both the hippocampal and cortical neuron injury caused by HFD combined with low dose STZ in vivo
Summary
Diabetes is a multifactorial metabolic disease characterized by hyperglycemia and high morbidity. The incidence of diabetes has increased sharply in the last decade. Cognitive impairment induced by neuronal injury is one of the chronic complications of diabetes (Maher and Schubert, 2009; Biessels and Reagan, 2015; Baglietto-Vargas et al, 2016). Epidemiological studies show that diabetes significantly increases the risk of dementia and may develop into Alzheimer’s disease. Numerous studies have demonstrated that oxidative stress and mitochondrial abnormalities are common to the etiologies of both diabetes and Alzheimer’s disease (Bosco et al, 2011; Moreira, 2012). Anti-diabetic agents might have important clinical and social value in the treatment of AD
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