Alleviative Effect of Alpha-Lipoic Acid on Cognitive Impairment in High-Fat Diet and Streptozotocin-Induced Type 2 Diabetic Rats

Ko, Chih‐Yuan; Xu, Jianhua; Lo, Y. Martin; Tu, Rong-Syuan; Wu, James Swi‐Bea; Huang, Wen‐Chung; Shen, Szu‐Chuan

doi:10.3389/fnagi.2021.774477

Cited by 15 publications

(11 citation statements)

References 34 publications

(51 reference statements)

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“…Further research is required; however, as we show here, ALA improves the glutathione system in both analyzed brain structures of HFD-fed rats. Recent studies also confirm that ALA improves cognitive function by normalizing brain glucose metabolism and the expression of synaptic plasticity proteins [ 53 , 112 ].…”

Section: Discussionmentioning

confidence: 91%

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α-Lipoic Acid Strengthens the Antioxidant Barrier and Reduces Oxidative, Nitrosative, and Glycative Damage, as well as Inhibits Inflammation and Apoptosis in the Hypothalamus but Not in the Cerebral Cortex of Insulin-Resistant Rats

Maciejczyk

Żebrowska

Nesterowicz

et al. 2022

Oxidative Medicine and Cellular Longevity

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The research determined the role of α-lipoic acid (ALA) in reducing the brain manifestations of insulin resistance. The mechanism of ALA action is mainly based on its ability to “scavenge” oxygen free radicals and stimulate biosynthesis of reduced glutathione (GSH), considered the most critical brain antioxidant. Although the protective effect of ALA is widely documented in various diseases, there are still no studies assessing the influence of ALA on brain metabolism in the context of insulin resistance and type 2 diabetes. The experiment was conducted on male Wistar rats fed a high-fat diet for ten weeks with intragastric administration of ALA for four weeks. We are the first to demonstrate that ALA improves the function of enzymatic and nonenzymatic brain antioxidant systems, but the protective effects of ALA were mainly observed in the hypothalamus of insulin-resistant rats. Indeed, ALA caused a significant increase in superoxide dismutase, catalase, peroxidase, and glutathione reductase activities, as well as GSH concentration and redox potential ( GSH 2 / GSSG ) in the hypothalamus of HFD-fed rats. A consequence of antioxidant barrier enhancement by ALA is the reduction of oxidation, glycation, and nitration of brain proteins, lipids, and DNA. The protective effects of ALA result from hypothalamic activation of the transcription factor Nrf2 and inhibition of NF-κB. In the hypothalamus of insulin-resistant rats, we demonstrated reduced levels of oxidation (AOPP) and glycation (AGE) protein products, 4-hydroxynoneal, 8-isoprostanes, and 3-nitrotyrosine and, in the cerebral cortex, lower levels of 8-hydroxydeoxyguanosine and peroxynitrite. In addition, we demonstrated that ALA decreases levels of proinflammatory TNF-α but also increases the synthesis of anti-inflammatory IL-10 in the hypothalamus of insulin-resistant rats. ALA also prevents neuronal apoptosis, confirming its multidirectional effects within the brain. Interestingly, we have shown no correlation between brain and serum/plasma oxidative stress biomarkers, indicating the different nature of redox imbalance at the central and systemic levels. To summarize, ALA improves antioxidant balance and diminishes oxidative/glycative stress, protein nitrosative damage, inflammation, and apoptosis, mainly in the hypothalamus of insulin-resistant rats. Further studies are needed to determine the molecular mechanism of ALA action within the brain.

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Section: Discussionmentioning

confidence: 91%

“…Recent studies indicate that ALA improves cognitive function in insulin-resistant rats. ALA normalizes insulin signaling, brain glucose metabolism, and synaptic plasticity in the cerebral cortex and hippocampus of diabetic rats [ 53 ]. However, little is known about the effects of ALA on brain redox homeostasis.…”

Section: Introductionmentioning

confidence: 99%

α-Lipoic Acid Strengthens the Antioxidant Barrier and Reduces Oxidative, Nitrosative, and Glycative Damage, as well as Inhibits Inflammation and Apoptosis in the Hypothalamus but Not in the Cerebral Cortex of Insulin-Resistant Rats

Maciejczyk

Żebrowska

Nesterowicz

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…ALA enhanced the protein expression of PI3K/AKT in the soleus muscle and reduced IR in rats with T2DM in the present study. Our previous study also found that ALA enhanced PI3K/AKT protein expression in the liver and brain tissues of rats with T2DM (Ko, Lo, et al, 2021; Ko, Xu, et al, 2021). ALA increases IRS‐1 protein expression in muscles and increases the binding of IRS‐1 to regulatory subunit p85 of PI3K in obese Zucker rats (Shay et al, 2009).…”

Section: Discussionmentioning

confidence: 60%

Alleviative effects of α‐lipoic acid on muscle atrophy via the modulation of TNF‐α/JNK and PI3K/AKT pathways in high‐fat diet and streptozotocin‐induced type 2 diabetic rats

Huang

et al. 2023

Food Science & Nutrition

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Diabetes mellitus (DM) is often accompanied by clinical complications such as sarcopenia. Previous studies have indicated that oxidative stress and insulin resistance (IR) are highly associated with the pathogenesis of diabetic myopathy. α‐lipoic acid (ALA), a potent biological antioxidant, exists abundantly in a variety of plants and vegetables. This study aimed to investigate the ameliorative effect of ALA on muscle atrophy in type 2 diabetic rats induced by high‐fat diet feeding (HFD) plus streptozotocin (STZ) injection. The HFD/STZ‐induced diabetic rats were orally administered 50, 100, or 200 mg/kg body weight ALA once a day for 13 weeks. The results showed that ALA at the tested concentrations significantly increased the soleus muscle mass and muscle fibers in diabetic rats. Proinflammatory cytokines, such as tumor necrosis factor (TNF)‐α, were found to decrease in both the serum and muscle of ALA‐treated diabetic rats. ALA significantly reduced the protein‐expression levels of phosphorylated c‐Jun N‐terminal kinase (pJNK)/JNK, forkhead box O3 (FOXO3), and muscle ring‐finger protein‐1 (Murf1); whereas, it enhanced the protein‐expression levels of phosphoinositide 3‐kinase (PI3K), phosphorylated protein kinase B (pAKT)/AKT, myogenin determination gene D (MyoD), the mechanistic target of rapamycin (mTOR), and myosin heavy chain (MyHC) in the soleus muscle of diabetic rats. The results from this study suggested that ALA treatment may preserve soleus muscle mass, alleviate muscle atrophy by suppressing the TNF‐α/JNK pathway, and ameliorate the PI3K/AKT pathway in HFD/STZ‐induced type 2 diabetic rats.

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“…In this model, the lipoic acid intervention was associated with increased GLUT1 expression in the hippocampus and improved cognitive function and memory [ 194 ]. In a high-fat-fed STZ induced rat model of T2D, the 13-week lipoic acid intervention increased the expression of IRS1, PI3K, the pAKT/AKT ratio and the pGSK3β/GSK3β ratio in the hippocampus and promoted increased levels of IDE and improved cognitive function compared to the untreated diabetic mouse model [ 195 ]. In humans, a placebo-controlled clinical trial investigated the effectiveness of differing oral lipoic acid doses in T2D participants, and lipoic acid was associated with an enhanced metabolic clearance rate (MCR) of glucose, indicating increased insulin sensitivity.…”

Section: Is There Potential In Evaluating Insulin Mimetics For Ad Tre...mentioning

confidence: 99%

Current Insights on the Use of Insulin and the Potential Use of Insulin Mimetics in Targeting Insulin Signalling in Alzheimer’s Disease

Woodfield

Gonzales

Helmerhorst

et al. 2022

IJMS

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Alzheimer’s disease (AD) and type 2 diabetes (T2D) are chronic diseases that share several pathological mechanisms, including insulin resistance and impaired insulin signalling. Their shared features have prompted the evaluation of the drugs used to manage diabetes for the treatment of AD. Insulin delivery itself has been utilized, with promising effects, in improving cognition and reducing AD related neuropathology. The most recent clinical trial involving intranasal insulin reported no slowing of cognitive decline; however, several factors may have impacted the trial outcomes. Long-acting and rapid-acting insulin analogues have also been evaluated within the context of AD with a lack of consistent outcomes. This narrative review provided insight into how targeting insulin signalling in the brain has potential as a therapeutic target for AD and provided a detailed update on the efficacy of insulin, its analogues and the outcomes of human clinical trials. We also discussed the current evidence that warrants the further investigation of the use of the mimetics of insulin for AD. These small molecules may provide a modifiable alternative to insulin, aiding in developing drugs that selectively target insulin signalling in the brain with the aim to attenuate cognitive dysfunction and AD pathologies.

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Alleviative Effect of Alpha-Lipoic Acid on Cognitive Impairment in High-Fat Diet and Streptozotocin-Induced Type 2 Diabetic Rats

Cited by 15 publications

References 34 publications

α-Lipoic Acid Strengthens the Antioxidant Barrier and Reduces Oxidative, Nitrosative, and Glycative Damage, as well as Inhibits Inflammation and Apoptosis in the Hypothalamus but Not in the Cerebral Cortex of Insulin-Resistant Rats

α-Lipoic Acid Strengthens the Antioxidant Barrier and Reduces Oxidative, Nitrosative, and Glycative Damage, as well as Inhibits Inflammation and Apoptosis in the Hypothalamus but Not in the Cerebral Cortex of Insulin-Resistant Rats

Alleviative effects of α‐lipoic acid on muscle atrophy via the modulation of TNF‐α/JNK and PI3K/AKT pathways in high‐fat diet and streptozotocin‐induced type 2 diabetic rats

Current Insights on the Use of Insulin and the Potential Use of Insulin Mimetics in Targeting Insulin Signalling in Alzheimer’s Disease

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