Cerebrovascular complications of diabetes: focus on cognitive dysfunction

Hardigan, Trevor; Ward, Rebecca; Ergul, Adviye

doi:10.1042/cs20160397

Cited by 75 publications

(46 citation statements)

References 185 publications

(190 reference statements)

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“…; Hardigan et al . ), although the impact of hyperglycaemia on the spinal cord microvasculature has not been reported previously. The results we present here support the conclusion that there is a widespread vasculopathy in the spinal cord, which is associated with diabetes and nociceptive processing.…”

Section: Discussionmentioning

confidence: 82%

“…), with both of these contributing to neurological complications including increased susceptibility of people with diabetes to cognitive decline, stroke and peripheral ischaemic neuropathies (motor, sensory and autonomic) (Said, ; Hardigan et al . ). Vascular endothelial growth factor‐A (VEGF‐A) is strongly implicated in diabetic vascular disease, including driving aberrant vessel growth and increased permeability in diabetic retinopathy (Cai & Boulton, ) and is therefore a prime target for diabetic retinopathy treatment (Gupta et al .…”

Section: Introductionmentioning

confidence: 97%

“…; Hardigan et al . ) as well as direct glucose toxicity on sensory neurons (Chowdhury et al . ; Hulse et al .…”

Section: Introductionmentioning

confidence: 99%

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Diabetes‐induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain

Ved

Lobo

Bestall

et al. 2018

The Journal of Physiology

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Key points Diabetes is thought to induce neuropathic pain through activation of dorsal horn sensory neurons in the spinal cord.Here we explore the impact of hyperglycaemia on the blood supply supporting the spinal cord and chronic pain development.In streptozotocin‐induced diabetic rats, neuropathic pain is accompanied by a decline in microvascular integrity in the dorsal horn. Hyperglycaemia‐induced degeneration of the endothelium in the dorsal horn was associated with a loss in vascular endothelial growth factor (VEGF)‐A165b expression. VEGF‐A165b treatment prevented diabetic neuropathic pain and degeneration of the endothelium in the spinal cord.Using an endothelial‐specific VEGFR2 knockout transgenic mouse model, the loss of endothelial VEGFR2 signalling led to a decline in vascular integrity in the dorsal horn and the development of hyperalgesia in VEGFR2 knockout mice.This highlights that vascular degeneration in the spinal cord could be a previously unidentified factor in the development of diabetic neuropathic pain. AbstractAbnormalities of neurovascular interactions within the CNS of diabetic patients is associated with the onset of many neurological disease states. However, to date, the link between the neurovascular network within the spinal cord and regulation of nociception has not been investigated despite neuropathic pain being common in diabetes. We hypothesised that hyperglycaemia‐induced endothelial degeneration in the spinal cord, due to suppression of vascular endothelial growth factor (VEGF)‐A/VEGFR2 signalling, induces diabetic neuropathic pain. Nociceptive pain behaviour was investigated in a chemically induced model of type 1 diabetes (streptozotocin induced, insulin supplemented; either vehicle or VEGF‐A165b treated) and an inducible endothelial knockdown of VEGFR2 (tamoxifen induced). Diabetic animals developed mechanical allodynia and heat hyperalgesia. This was associated with a reduction in the number of blood vessels and reduction in Evans blue extravasation in the lumbar spinal cord of diabetic animals versus age‐matched controls. Endothelial markers occludin, CD31 and VE‐cadherin were downregulated in the spinal cord of the diabetic group versus controls, and there was a concurrent reduction of VEGF‐A165b expression. In diabetic animals, VEGF‐A165b treatment (biweekly i.p., 20 ng g−1) restored normal Evans blue extravasation and prevented vascular degeneration, diabetes‐induced central neuron activation and neuropathic pain. Inducible knockdown of VEGFR2 (tamoxifen treated Tie2CreERT2‐vegfr2flfl mice) led to a reduction in blood vessel network volume in the lumbar spinal cord and development of heat hyperalgesia. These findings indicate that hyperglycaemia leads to a reduction in the VEGF‐A/VEGFR2 signalling cascade, resulting in endothelial dysfunction in the spinal cord, which could be an undiscovered contributing factor to diabetic neuropathic pain.

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Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 97%

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Diabetes‐induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain

Ved

Lobo

Bestall

et al. 2018

The Journal of Physiology

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“…This paradox needs further clarification. The impact of T1D and T2D on vascular contributions to cognitive impairment was also recently reviewed (112) and highlighted a role for the innate immunity-mediated inflammation in neurovascular changes in diabetes. Lastly, cerebrovascular complications of diabetes were discussed with a focus on stroke (85).…”

Section: Consequences and Conclusionmentioning

confidence: 99%

Impact of Metabolic Diseases on Cerebral Circulation: Structural and Functional Consequences

Coucha

Abdelsaid

Ward

et al. 2018

Comprehensive Physiology

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Metabolic diseases including obesity, insulin resistance, and diabetes have profound effects on cerebral circulation. These diseases not only affect the architecture of cerebral blood arteries causing adverse remodeling, pathological neovascularization, and vasoregression but also alter the physiology of blood vessels resulting in compromised myogenic reactivity, neurovascular uncoupling, and endothelial dysfunction. Coupled with the disruption of blood brain barrier (BBB) integrity, changes in blood flow and microbleeds into the brain rapidly occur. This overview is organized into sections describing cerebrovascular architecture, physiology, and BBB in these diseases. In each section, we review these properties starting with larger arteries moving into smaller vessels. Where information is available, we review in the order of obesity, insulin resistance, and diabetes. We also tried to include information on biological variables such as the sex of the animal models noted since most of the information summarized was obtained using male animals. © 2018 American Physiological Society. Compr Physiol 8:773-799, 2018.

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“…The structural and functional interaction of neurons with the surrounding vasculature is critical for proper function of the central nervous system, including learning and memory [6]. Thus, diabetic patients may suffer cognitive impairments which affect quality of life.…”

mentioning

confidence: 99%

Antidepressant and anxiolytic-like, sedation and hypnosis

Horowitz

2017

Journal of Basic and Clinical Physiology and Pharmacology

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affecting behavior in rat and mouse experimental models. These studies tell us how hypothesis-driven research can evolve into products that interact with the serotonergic network and how can herbal products assist development of readily available neuroprotective agents.The first two articles by Bhatt et al.[1] "Neuropharmacological and neurochemical evaluation of N-n-propyl-3-ethoxyquinoxaline-2-carboxamide (6n): a novel serotonergic 5-HT3 receptor antagonist for co-morbid antidepressantand anxiolytic-like potential using traumatic brain injury model in rats" and [2] "Neuropharmacological evaluation of a novel 5-HT3 receptor antagonist (4-benzylpiperazin-1-yl) (3-methoxyquinoxalin-2-yl) methanone (6g) on lipopolysaccharide-induced anxiety models in mice" evaluate the properties of a novel drug 6n, a serotonergic 5-HT3 receptor antagonist, as a potential antidepressant and anxiolytic drug. Serotonin is the major neurotransmitter involved in depression, and this compound was designed based on the hypothesis of Rajkumar and Mahesh [3] that postsynaptic 5-HT3 receptor antagonists can facilitate specific binding of 5-HT to other postsynaptic receptors such as 5-HT1B, 5-HT2A, and 5-HT2C, thereby aiding serotonergic transmission. Studies on 5-HT3A knockout mice further confirmed the role of 5-HT3 receptor subtypes in depression and anxiety-related behaviors [4]. Bhatt et al. use a battery of behavioral tests to show the efficiency of 6n during exposure to two stressors. In Lipopolysaccharide-induced anxiety symptoms in mice, three behavioral paradigms were applied to measure the impact of chronic treatment with 6n on anxiety attenuation and serotonin level. The compound affected serotonin signaling, possibly by enhancing serotonergic transmission. The second model used by Bhatt's team was a traumatic brain injury rat model. Behavioral experimental paradigms as well as assays measuring serotonin, norepinephrine and brain-derived neurotrophic factor levels confirmed the efficiency of 6n. This compound has an optimum log P (2.52) and pA2 values (7.6) greater than the standard 5-HT3 receptor antagonist, ondansetron (pA2-6.9).The third paper in this category is by Rajashree et al. "Effect of Salacia reticulata W. and Clitoria ternatea L. on the cognitive and behavioral enhancement in the streptozotocin-induced young diabetic rats" [5]. The structural and functional interaction of neurons with the surrounding vasculature is critical for proper function of the central nervous system, including learning and memory [6]. Thus, diabetic patients may suffer cognitive impairments which affect quality of life. Using a plus maze, and a Morris water maze, Rajashree et al. attempted to elucidate whether the combination of two herbal formulas has a beneficial effect on central cognitive pathologies caused by stretozotocininduced diabetes in young rats. The combined nootropic treatment was found to be beneficial in young rats during-onset diabetes, being preventive but not curative. The authors hypothesize that the memory enhancement mig...

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Cerebrovascular complications of diabetes: focus on cognitive dysfunction

Cited by 75 publications

References 185 publications

Diabetes‐induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain

Diabetes‐induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain

Impact of Metabolic Diseases on Cerebral Circulation: Structural and Functional Consequences

Antidepressant and anxiolytic-like, sedation and hypnosis

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