Impairment of neurovascular coupling in the hippocampus due to decreased nitric oxide bioavailability supports early cognitive dysfunction in type 2 diabetic rats

Gonçalves, João; Seiça, Raquel; Laranjinha, João; Lourenço, Cátia F.

doi:10.1016/j.freeradbiomed.2022.11.009

Cited by 11 publications

(7 citation statements)

References 42 publications

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“…Compared to wild‐type littermates, CD‐fed HSL−/− mice showed signs of insulin resistance while maintaining circulating insulin levels, in agreement with what has been previously reported (Mulder et al., 2003). Insulin resistance in the Goto‐Kakizaki rat model has been shown to trigger impaired neurovascular coupling in the dentate gyrus of the hippocampus (Gonçalves et al., 2022), energy metabolism alterations in neurons and astrocytes (Girault et al., 2019), and memory impairment (Duarte et al., 2019; Gonçalves et al., 2022). However, the genotype effect on insulin sensitivity was negligible when compared to that of HFD exposure.…”

Section: Discussionmentioning

confidence: 99%

Genetic deletion of hormone‐sensitive lipase in mice reduces cerebral blood flow but does not aggravate the impact of diet‐induced obesity on memory

Skoug,

Rogova,

Spégel

et al. 2024

Journal of Neurochemistry

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Hormone‐sensitive lipase (HSL) is active throughout the brain and its genetic ablation impacts brain function. Its activity in the brain was proposed to regulate bioactive lipid availability, namely eicosanoids that are inflammatory mediators and regulate cerebral blood flow (CBF). We aimed at testing whether HSL deletion increases susceptibility to neuroinflammation and impaired brain perfusion upon diet‐induced obesity. HSL−/−, HSL+/−, and HSL+/+ mice of either sex were fed high‐fat diet (HFD) or control diet for 8 weeks, and then assessed in behavior tests (object recognition, open field, and elevated plus maze), metabolic tests (insulin and glucose tolerance tests and indirect calorimetry in metabolic cages), and CBF determination by arterial spin labeling (ASL) magnetic resonance imaging (MRI). Immunofluorescence microscopy was used to determine coverage of blood vessels, and morphology of astrocytes and microglia in brain slices. HSL deletion reduced CBF, most prominently in cortex and hippocampus, while HFD feeding only lowered CBF in the hippocampus of wild‐type mice. CBF was positively correlated with lectin‐stained vessel density. HSL deletion did not exacerbate HFD‐induced microgliosis in the hippocampus and hypothalamus. HSL−/− mice showed preserved memory performance when compared to wild‐type mice, and HSL deletion did not significantly aggravate HFD‐induced memory impairment in object recognition tests. In contrast, HSL deletion conferred protection against HFD‐induced obesity, glucose intolerance, and insulin resistance. Altogether, this study points to distinct roles of HSL in periphery and brain during diet‐induced obesity. While HSL−/− mice were protected against metabolic syndrome development, HSL deletion reduced brain perfusion without leading to aggravated HFD‐induced neuroinflammation and memory dysfunction.

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Section: Discussionmentioning

confidence: 99%

Genetic deletion of hormone‐sensitive lipase in mice reduces cerebral blood flow but does not aggravate the impact of diet‐induced obesity on memory

Skoug,

Rogova,

Spégel

et al. 2024

Journal of Neurochemistry

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“…Given the critical role of • NO as the direct mediator of neurovascular coupling (NVC [7], a process critical for brain structure and function [66]), the mechanism of • NO production from nitrite via its reduction to • NO by ascorbate may represent a key physiological mechanism that participates in the regulation of brain homeostasis by improving the NVC and CBF and could acquire a particular relevance in situations where NVC is compromised, such as ischemia, neurodegeneration and aging. Therefore, the nitrite-• NO pathway may open avenues to the development of new and innovative therapies to improve the impaired NVC observed in several conditions, including neurodegenerative diseases, aging and diabetes [55,66,67].…”

Section: Discussionmentioning

confidence: 99%

Nitric Oxide Production from Nitrite plus Ascorbate during Ischemia upon Hippocampal Glutamate NMDA Receptor Stimulation

Nunes

Laranjinha

2023

BioChem

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Nitric oxide (•NO), a diffusible free radical, is an intercellular messenger, playing a crucial role in several key brain physiological processes, including in neurovascular coupling (NVC). In the brain, glutamatergic activation of the neuronal nitric oxide synthase (nNOS) enzyme constitutes its main synthesis pathway. However, when oxygen (O2) supply is compromised, such as in stroke, ischemia, and aging, such •NO production pathway may be seriously impaired. In this context, evidence suggests that, as already observed in the gastric compartment, the reduction of nitrite by dietary compounds (such as ascorbate and polyphenols) or by specific enzymes may occur in the brain, constituting an important rescuing or complementary mechanism of •NO production. Here, using microsensors selective for •NO, we show that nitrite enhanced the •NO production in a concentration-dependent manner and in the presence of ascorbate evoked by N-methyl-D-aspartate (NMDA) and glutamate stimulation of rat hippocampal slices. Additionally, nitrite potentiated the •NO production induced by oxygen-glucose deprivation (OGD). Overall, these observations support the notion of a redox interaction of ascorbate with nitrite yielding •NO upon neuronal glutamatergic activation and given the critical role of NO as the direct mediator of neurovascular coupling may represents a key physiological mechanism by which •NO production for cerebral blood flow (CBF) responses to neuronal activation is sustained under hypoxic/acidic conditions in the brain.

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“…A study employed NO microelectrodes and laser Doppler probes to simultaneously measure changes in NO and CBF in the hippocampus of Goto-Kakizaki(GK) rats (a diabetic rat model), revealing a reduction in the increase of NO following glutamate activation and impairment of NVC ( Gonçalves et al, 2022 ). Another investigation utilized laser Doppler flowmetry to measure CBF in the somatosensory cortex of GK rats after whisker stimulation demonstrating that NVC impairment was accompanied by elevated reactive oxygen and nitrogen species (RONS), nitrotyrosine, and peroxynitrite (a product of the reaction between oxygen free radicals and NO) in both plasma and cerebral arteries ( Kelly-Cobbs et al, 2012 ).…”

Section: Hyperglycemic and Nvc Impairmentmentioning

confidence: 99%

The role of neurovascular coupling dysfunction in cognitive decline of diabetes patients

Feng,

Gao

2024

Front. Neurosci.

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Neurovascular coupling (NVC) is an important mechanism to ensure adequate blood supply to active neurons in the brain. NVC damage can lead to chronic impairment of neuronal function. Diabetes is characterized by high blood sugar and is considered an important risk factor for cognitive impairment. In this review, we provide fMRI evidence of NVC damage in diabetic patients with cognitive decline. Combined with the exploration of the major mechanisms and signaling pathways of NVC, we discuss the effects of chronic hyperglycemia on the cellular structure of NVC signaling, including key receptors, ion channels, and intercellular connections. Studying these diabetes-related changes in cell structure will help us understand the underlying causes behind diabetes-induced NVC damage and early cognitive decline, ultimately helping to identify the most effective drug targets for treatment.

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Impairment of neurovascular coupling in the hippocampus due to decreased nitric oxide bioavailability supports early cognitive dysfunction in type 2 diabetic rats

Cited by 11 publications

References 42 publications

Genetic deletion of hormone‐sensitive lipase in mice reduces cerebral blood flow but does not aggravate the impact of diet‐induced obesity on memory

Genetic deletion of hormone‐sensitive lipase in mice reduces cerebral blood flow but does not aggravate the impact of diet‐induced obesity on memory

Nitric Oxide Production from Nitrite plus Ascorbate during Ischemia upon Hippocampal Glutamate NMDA Receptor Stimulation

The role of neurovascular coupling dysfunction in cognitive decline of diabetes patients

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