Repurposing of Anti-Diabetic Agents as a New Opportunity to Alleviate Cognitive Impairment in Neurodegenerative and Neuropsychiatric Disorders

Chen, Qian; Cao, Ting; Li, Nana; Zeng, Chuan; Zhang, Shuangyang; Wu, Xiangxin; Zhang, Bikui; Cai, Hualin

doi:10.3389/fphar.2021.667874

Cited by 20 publications

(17 citation statements)

References 181 publications

(206 reference statements)

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“…On the contrary, treatment with metformin was associated with a significant increase in BDNF when compared with the D-gal group. Our results were in agreement with previously published reports which demonstrated that metformin up-regulates BDNF via AMPK activation 47 .…”

Section: Discussionsupporting

confidence: 94%

Metformin alleviates neurocognitive impairment in aging via activation of AMPK/BDNF/PI3K pathway

Ameen

Samaka

Abo-Elsoud

2022

Sci Rep

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Slowing down age-related neurocognitive impairment has been a challenge. We evaluated the therapeutic effects of metformin in d-galactose-induced aging. Additionally, we studied the potential molecular mechanisms that could be responsible for metformin's anti-aging effects. Thirty male rats were equally divided into: 1—control group, which received saline solution, 2—d-galactose (D-gal) group, which received d-galactose (100 mg/kg/day) by gastric lavage for eight weeks, and 3—d-galactose + Metformin (D-gal + Met) treated group, which received d-galactose + metformin (200 mg/kg/day) by gastric lavage for eight weeks. Neurocognitive assessment was done. Measurement of inflammatory, oxidative stress, and BDNF biomarkers was performed. AMPK and PI3K genes expression were assessed. Hippocampal tissues were dissected for histopathological and immunohistochemical studies. D-gal resulted in neurocognitive impairments, elevation of inflammatory biomarkers, altered oxidative stress markers, decreased BDNF, decreased expression of synaptophysin and Bcl2 with increased expression of Caspase-3, and down-regulation of AMPK and PI3K genes. Neurodegenerative changes were present in the hippocampus. Metformin restored significantly D-gal induced neurodegenerative changes. We concluded that metformin could alleviate age-induced neurocognitive deficit via amelioration of neuroinflammation, attenuation of oxidative stress, reduction of apoptosis, as well as promotion of synaptic plasticity. These mechanisms could be mediated via the activation of the AMPK/BDNF/PI3K pathway.

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Section: Discussionsupporting

confidence: 94%

Metformin alleviates neurocognitive impairment in aging via activation of AMPK/BDNF/PI3K pathway

Ameen

Samaka

Abo-Elsoud

2022

Sci Rep

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“…5 Newer GLDs have generated significant interest in their neuroprotective effects by improving insulin resistance and reducing oxidative damage and inflammation, which make them promising therapeutic options for the management of PD. 6 The results of this study indicated a potential benefit of SGLT2 inhibitors in reducing the risk of PD, which aligns with previous research findings. 36,37 A recently published population-based cohort study involving people with T2D found a significant association between SGLT2 inhibitors and a lower risk of PD compared to DPP-4 inhibitors (hazard ratio [HR]: 0.28; 95% CI: 0.09-0.91).…”

Section: Discussionsupporting

confidence: 91%

Meta‐analysis of Association between Newer Glucose‐Lowering Drugs and Risk of Parkinson's Disease

Tang,

Lu,

Okun

et al. 2023

Movement Disord Clin Pract

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BackgroundThe association between newer classes of glucose‐lowering drugs (GLDs) and risk of Parkinson's disease (PD) remains unclear.ObjectiveTo examine the effect of newer GLDs on risk of PD through a meta‐analysis of randomized outcome trials.MethodsIncluded were randomized placebo‐controlled outcome trials that reported PD events associated with three newer classes of GLDs (i.e., DPP‐4 inhibitors, GLP‐1RAs, and SGLT2 inhibitors) in participants with or without type 2 diabetes (T2D). The pooled odds ratio (OR) and 95% confidence interval (CI) were estimated using Peto's method.ResultsThe study included 24 trials involving 33 PD cases among 185,305 participants during a median follow‐up of 2.2 years. Newer GLDs were significantly associated with a lower PD risk (OR, 0.50; 95%CI, 0.25–0.98) than placebo.ConclusionNewer GLDs may possibly be associated with a decreased risk of PD however larger datasets are required to confirm or refute this notion.This article is protected by copyright. All rights reserved.

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“…First, because this study was designed to be cross‐sectional, we collected data at a single point in time and, therefore, could not determine the causality of cognitive impairment related to prediabetes. Second, although some anti‐diabetic drugs, particularly metformin and glucagon‐like peptide‐1 receptor agonists, may have beneficial effects on cognitive function in PD patients (Chen et al., 2021 ), we could not access each patient's medications in the diabetes group due to lack of data. Thus, the effect of diabetes on cognition in our dataset may have been underestimated.…”

Section: Discussionmentioning

confidence: 99%

Association between prediabetes and cognitive function in Parkinson's disease

2022

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Introduction It remains largely unknown whether prediabetes is related to cognitive impairment in Parkinson's disease (PD). This study aimed to assess the association between prediabetes and cognitive function in PD patients. Methods In this cross‐sectional study, 262 PD patients (age, 69.8 ± 10.3 years; Hoehn–Yahr stage, 2.3 ± 0.8) were classified into diabetes (glycated hemoglobin [HbA1c] ≥6.5% or previously diagnosed, n = 76), prediabetes (5.7%–6.4%, n = 90), or diabetes free (≤5.6%, n = 96) groups. Cognitive function was measured using the Montreal Cognitive Assessment (MoCA) test. Results Both the diabetes and prediabetes groups had significantly lower MoCA scores (17.0 ± 6.6 and 18.0 ± 6.1, respectively) than the diabetes free group (20.0 ± 5.7), even after adjusting for potential confounders (p = .002 and p = .008, respectively). In the combined group of prediabetes and diabetes free patients, higher HbA1c levels significantly correlated with lower MoCA scores (p = .031). There was a significant interaction of diabetes status with age, but not with the duration of PD, on cognitive function. Conclusion In addition to diabetes, prediabetes may negatively affect cognitive function in PD patients. Further prospective longitudinal studies are necessary to clarify the impact of prediabetes on the cognitive trajectory of these patients.

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Repurposing of Anti-Diabetic Agents as a New Opportunity to Alleviate Cognitive Impairment in Neurodegenerative and Neuropsychiatric Disorders

Cited by 20 publications

References 181 publications

Metformin alleviates neurocognitive impairment in aging via activation of AMPK/BDNF/PI3K pathway

Metformin alleviates neurocognitive impairment in aging via activation of AMPK/BDNF/PI3K pathway

Meta‐analysis of Association between Newer Glucose‐Lowering Drugs and Risk of Parkinson's Disease

Association between prediabetes and cognitive function in Parkinson's disease

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