GLP-1 receptor nitration contributes to loss of brain pericyte function in a mouse model of diabetes

Bailey, Joseph; Coucha, Maha; Bolduc, Deanna R.; Burnett, Faith N.; Barrett, Amy; Ghaly, Mark; Abdelsaid, Mohammed

doi:10.1007/s00125-022-05730-5

Cited by 12 publications

(11 citation statements)

References 49 publications

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“…Hydrogen peroxide, superoxide derivates, hydroxyl radical or peroxynitrites increase endothelial calcium concentration in time- and dose-dependent manner causing dysregulation in calcium homeostasis, acting as proapoptotic factor in cerebral vascular cells [ 66 , 70 , 72 ]. In addition, oxidative stress has a key role in insulin resistance and progression of diabetes [ 73 , 74 ] and diabetic mice show vascular alterations associated with increased oxidative stress, pericyte dysfunction and cerebrovascular integrity compromise [ 75 ]. Likewise, advanced glycation end products, resulting from hyperglycemia in T2D, alter the structure and function of BBB proteins [ 62 ] and diabetes-induced inflammation leads to astrocytic feet swelling in small vessels, separation of the plasma membrane and accumulation of hypertrophic microglia [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Accelerated amyloid angiopathy and related vascular alterations in a mixed murine model of Alzheimer´s disease and type two diabetes

Vargas-Soria

Ramos-Rodríguez

Marco

et al. 2022

Fluids Barriers CNS

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Background While aging is the main risk factor for Alzheimer´s disease (AD), emerging evidence suggests that metabolic alterations such as type 2 diabetes (T2D) are also major contributors. Indeed, several studies have described a close relationship between AD and T2D with clinical evidence showing that both diseases coexist. A hallmark pathological event in AD is amyloid-β (Aβ) deposition in the brain as either amyloid plaques or around leptomeningeal and cortical arterioles, thus constituting cerebral amyloid angiopathy (CAA). CAA is observed in 85–95% of autopsy cases with AD and it contributes to AD pathology by limiting perivascular drainage of Aβ. Methods To further explore these alterations when AD and T2D coexist, we have used in vivo multiphoton microscopy to analyze over time the Aβ deposition in the form of plaques and CAA in a relevant model of AD (APPswe/PS1dE9) combined with T2D (db/db). We have simultaneously assessed the effects of high-fat diet-induced prediabetes in AD mice. Since both plaques and CAA are implicated in oxidative-stress mediated vascular damage in the brain, as well as in the activation of matrix metalloproteinases (MMP), we have also analyzed oxidative stress by Amplex Red oxidation, MMP activity by DQ™ Gelatin, and vascular functionality. Results We found that prediabetes accelerates amyloid plaque and CAA deposition, suggesting that initial metabolic alterations may directly affect AD pathology. T2D significantly affects vascular pathology and CAA deposition, which is increased in AD-T2D mice, suggesting that T2D favors vascular accumulation of Aβ. Moreover, T2D synergistically contributes to increase CAA mediated oxidative stress and MMP activation, affecting red blood cell velocity. Conclusions Our data support the cross-talk between metabolic disease and Aβ deposition that affects vascular integrity, ultimately contributing to AD pathology and related functional changes in the brain microvasculature.

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Section: Discussionmentioning

confidence: 99%

Accelerated amyloid angiopathy and related vascular alterations in a mixed murine model of Alzheimer´s disease and type two diabetes

Vargas-Soria

Ramos-Rodríguez

Marco

et al. 2022

Fluids Barriers CNS

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“…Activation of GLP-1 receptor is thought to improve brain pericyte function resulting in restoration of vascular integrity and BBB functions. 6 The potential efficacy of GLP-1 receptor agonists specifically dulaglutide and liraglutide toward MS has been shown in studies of experimental autoimmune encephalomyelitis (EAE). Dulaglutide caused a reduction in clinical manifestations and histopathological outcomes, and the incidence of encephalitogenic Th1/Th17 cells in EAE mice.…”

Section: Discussionmentioning

confidence: 99%

Exploring the association between weight loss-inducing medications and multiple sclerosis: insights from the FDA adverse event reporting system database

Shirani,

Cross,

Stuve

2024

Ther Adv Neurol Disord

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Background: Several studies have demonstrated that early childhood and adolescent obesity are risk factors for multiple sclerosis (MS) susceptibility. Obesity is thought to share inflammatory components with MS through overproduction of pro-inflammatory adipokines (e.g., leptin) and reduction of anti-inflammatory adipokines (e.g, adiponectin). Recently, drug repurposing (i.e. identifying new indications for existing drugs) has garnered significant attention. The US Food and Drug Administration Adverse Event Reporting System (FAERS) database serves not only as a resource for mining adverse drug reactions and safety signals but also for identifying inverse associations and potential medication repurposing opportunities. Objective: We aimed to explore the association between weight-loss-inducing drugs and MS using real-world reports from the FAERS database. Design: Secondary analysis of existing data from the FAERS database. Methods: We conducted a disproportionality analysis using the FAERS database between the fourth quarter of 2003 and the second quarter of 2023 to explore associations between MS and weight loss-inducing drugs. Disproportionality was quantified using the reporting odds ratio (ROR). An inverse association was defined when the upper limit of the 95% confidence interval for ROR was <1. Results: We found an inverse association between MS and anti-diabetic weight loss-inducing drugs including semaglutide (ROR: 0.238; 95% CI: 0.132–0.429), dulaglutide (ROR: 0.165; 95% CI: 0.109–0.248), liraglutide (ROR: 0.161; 95% CI: 0.091–0.284), empagliflozin (ROR: 0.234; 95% CI: 0.146–0.377), and metformin (ROR: 0.387; 95% CI: 0.340–0.440). No inverse associations were found for other weight loss-inducing drugs such as phentermine, bupropion, topiramate, zonisamide, and amphetamine. An exception was naltrexone (ROR: 0.556; 95% CI: 0.384–0.806). Conclusion: Our findings suggest a potential consideration for repurposing anti-diabetic weight loss-inducing drugs including semaglutide, dulaglutide, and liraglutide (glucagon-like peptide-1 receptor agonists), empagliflozin (sodium-glucose cotransporter-2 inhibitor), and metformin (biguanide), for MS. This warrants validation through rigorous methodologies and prospective studies.

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“…STZ is a glucosamine-nitrosourea compound derived from soil bacteria originally identified for its antibiotic and anticancer properties. The intraperitoneal injection of STZ is a classic method of developing type 1 diabetes mellitus in rodent model and is widely used in studies of diabetesrelated cognitive dysfunction [38][39][40]. However, it has been shown that the intracerebroventricular administration of STZ can have neurotoxic effects in the brain [41,42].…”

Section: Discussionmentioning

confidence: 99%

Neuronal Hyperactivity in the Hippocampus during the Early Stage of Streptozotocin-Induced Type 1 Diabetes in Mice

Fang,

Xu,

Zhang

et al. 2023

Neuroendocrinology

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Introduction Cognitive dysfunction due to reduced neuronal transmission in the brain is a major emerging complication in diabetes. However, recent neuroimaging studies have demonstrated non-linear changes including hyperactivity in the hippocampus during the early stage of diabetes. This study aimed to determine the changes in neuronal activity at a single-cell level in hippocampal CA1 pyramidal neurons in the early stage of streptozotocin-induced type 1 diabetes in mice. Methods Whole-cell patch-clamp recordings from acute brain slices were performed in mice over 4 consecutive weeks following the induction of hyperglycaemia using streptozotocin. In addition, microdialysate was collected from CA1 area while the mice were in an arousal state. The concentrations of glutamate and GABA in the microdialysate was then measured using ultra-performance liquid chromatography with mass spectrometry. Results CA1 Neurons in streptozotocin-induced diabetic mice exhibited higher membrane potentials (p = 0.0052), higher frequency of action potentials (p = 0.0052), and higher frequency of spontaneous excitatory post-synaptic currents (p = 0.037) compared with controls during the second week after hyperglycaemia was established. No changes in electrophysiological parameters were observed during the first, the third and the fourth week. Moreover, the diabetic mice had higher extracellular glutamate concentration in CA1 area compared with controls (p = 0.021) during the second week after the initiation of diabetes. No change in the extracellular GABA concentration was observed. Conclusion Our study demonstrated a temporary state of neuronal hyperactivity at the single-cell level in the hippocampal CA1 region during the early stage of diabetes. This neuronal hyperactivity might be related to altered glutamate metabolism and provide clues for future brain-target intervention.

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GLP-1 receptor nitration contributes to loss of brain pericyte function in a mouse model of diabetes

Cited by 12 publications

References 49 publications

Accelerated amyloid angiopathy and related vascular alterations in a mixed murine model of Alzheimer´s disease and type two diabetes

Accelerated amyloid angiopathy and related vascular alterations in a mixed murine model of Alzheimer´s disease and type two diabetes

Exploring the association between weight loss-inducing medications and multiple sclerosis: insights from the FDA adverse event reporting system database

Neuronal Hyperactivity in the Hippocampus during the Early Stage of Streptozotocin-Induced Type 1 Diabetes in Mice

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