Chronic cerebral hypoperfusion in male rats results in sustained HPA activation, and hyperinsulinemia

2021 ◽  
Author(s):  
Theresa A. Lansdell ◽  
Anne M Dorrance
Keyword(s):  
Insulin Resistance ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Male Rats ◽  
Lower Blood Glucose ◽  
Insulin Resistant ◽  
Lower Blood ◽  
Bilateral Carotid ◽  
Glucose Tolerance Tests ◽  
Bilateral Carotid Artery

Vascular contributions to cognitive impairment and dementia (VCID) is a spectrum of cognitive deficits caused by cerebrovascular disease, for which insulin resistance is a major risk factor. A major cause of VCID is chronic cerebral hypoperfusion (CCH). Under stress, sustained hypothalamic-pituitary-adrenal axis (HPA) activation can result in insulin resistance. Little is known about the effects of CCH on the HPA axis. We hypothesized that CCH causes sustained HPA activation and insulin resistance. Male rats were subjected to bilateral carotid artery stenosis (BCAS) for 12 weeks to induce CCH and VCID. BCAS reduced cerebral blood flow and caused memory impairment. Plasma adrenocorticotropic hormone was increased in the BCAS rats (117.2 ± 9.6 vs. 88.29 ± 9.1 pg/mL, BCAS vs. sham, p = 0.0236), as was corticosterone (220 ± 21 vs. 146 ± 18 ng/g feces, BCAS vs. sham, p = 0.0083). BCAS rats were hypoglycemic (68.1 ± 6.1 vs. 76.5± 5.9 mg/dL, BCAS vs. sham, p = 0.0072), with increased fasting insulin (481.6 ± 242.6 vs. 97.94± 40.02 pmol/L, BCAS vs. sham, p = 0.0003) indicating BCAS rats were insulin resistant (HOMA-IR:11.71 ± 6.47 vs. 2.62 ± 0.93; BCAS vs. control, p = 0.0008). Glucose tolerance tests revealed that BCAS rats had lower blood glucose AUCs than controls (250 ± 12 vs. 326 ± 20 mg/dL/h, BCAS vs. sham, p = 0.0075). These studies indicate that CCH causes sustained activation of the HPA and results in insulin resistance, a condition that is expected to worsen VCID.

scholarly journals Chronic cerebral hypoperfusion alters amyloid-β peptide pools leading to cerebral amyloid angiopathy, microinfarcts and haemorrhages in Tg-SwDI mice

2017 ◽  
Vol 131 (16) ◽  
pp. 2109-2123 ◽  
Author(s):  
Natalia Salvadores ◽  
James L. Searcy ◽  
Philip R. Holland ◽  
Karen Horsburgh
Keyword(s):  
Amyloid Β ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Amyloid Angiopathy ◽  
Amyloid Β Peptide ◽  
Wild Type ◽  
Aβ Peptides ◽  
Bilateral Carotid ◽  
The Brain ◽  
Bilateral Carotid Artery

Cerebral hypoperfusion is an early feature of Alzheimer’s disease (AD) that influences the progression from mild cognitive impairment to dementia. Understanding the mechanism is of critical importance in the search for new effective therapies. We hypothesized that cerebral hypoperfusion promotes the accumulation of amyloid-β (Aβ) and degenerative changes in the brain and is a potential mechanism contributing to development of dementia. To address this, we studied the effects of chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis on Aβ peptide pools in a transgenic mouse model of AD (transgenic mice with Swedish, Dutch and Iowa mutations in human amyloid precursor protein (APP) (Tg-SwDI)). Cerebrovascular integrity was characterized by quantifying the occurrence of microinfarcts and haemorrhages and compared with wild-type mice without Aβ. A significant increase in soluble Aβ peptides (Aβ40/42) was detected after 1 month of hypoperfusion in the parenchyma in parallel with elevated APP and APP proteolytic products. Following 3 months, a significant increase in insoluble Aβ40/42 was determined in the parenchyma and vasculature. Microinfarct load was significantly increased in the Tg-SwDI as compared with wild-type mice and further exacerbated by hypoperfusion at 1 and 3 months. In addition, the number of Tg-SwDI hypoperfused mice with haemorrhages was increased compared with hypoperfused wild-type mice. Soluble parenchymal Aβ was associated with elevated NADPH oxidase-2 (NOX2) which was exacerbated by 1-month hypoperfusion. We suggest that in response to hypoperfusion, increased Aβ production/deposition may contribute to degenerative processes by triggering oxidative stress promoting cerebrovascular disruption and the development of microinfarcts.

Pioglitazone and exenatide enhance cognition and downregulate hippocampal beta amyloid oligomer and microglia expression in insulin-resistant rats

2016 ◽  
Vol 94 (8) ◽  
pp. 819-828 ◽  
Author(s):  
Enas S. Gad ◽  
Sawsan A. Zaitone ◽  
Yasser M. Moustafa
Keyword(s):  
Insulin Resistance ◽  
Learning And Memory ◽  
Insulin Signaling ◽  
Beta Amyloid ◽  
Male Rats ◽  
Insulin Resistant ◽  
Ppar Γ ◽  
Glucagon Like Peptide 1 ◽  
Underlying Mechanisms ◽  
Amyloid Oligomer

Insulin resistance is known to be a risk factor for cognitive impairment, most likely linked to insulin signaling, microglia overactivation, and beta amyloid (Aβ) deposition in the brain. Exenatide, a long lasting glucagon-like peptide-1 (GLP-1) analogue, enhances insulin signaling and shows neuroprotective properties. Pioglitazone, a peroxisome proliferated-activated receptor-γ (PPAR-γ) agonist, was previously reported to enhance cognition through its effect on Aβ accumulation and clearance. In the present study, insulin resistance was induced in male rats by drinking fructose for 12 weeks. The effect of monotherapy with pioglitazone (10 mg·kg−1) and exenatide or their combination on memory dysfunction was determined and some of the probable underlying mechanisms were studied. The current results confirmed that (1) feeding male rats with fructose syrup for 12 weeks resulted in a decline of learning and memory registered in eight-arm radial maze test; (2) treatment with pioglitazone or exenatide enhanced cognition, reduced hippocampal neurodegeneration, and reduced hippocampal microglia expression and beta amyloid oligomer deposition in a manner that is equal to monotherapies. These results may give promise for the use of pioglitazone or exenatide for ameliorating the learning and memory deficits associated with insulin resistance in clinical setting.

scholarly journals Artery to vein configuration of arteriovenous fistula improves hemodynamics to increase maturation and patency

2020 ◽  
Vol 12 (557) ◽  
pp. eaax7613
Author(s):  
Hualong Bai ◽  
Nirvana Sadaghianloo ◽  
Jolanta Gorecka ◽  
Shirley Liu ◽  
Shun Ono ◽  
...  
Keyword(s):  
Neointimal Hyperplasia ◽  
Peak Systolic Velocity ◽  
Male Rats ◽  
Secondary Patency ◽  
Hemodialysis Access ◽  
Bilateral Carotid ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Bilateral Carotid Artery

Arteriovenous fistulae (AVF) are the preferred mode of hemodialysis access, but 60% of conventional [vein-to-artery (V-A)] AVF fail to mature, and only 50% remain patent at 1 year. We previously showed improved maturation and patency in a pilot study of the radial artery deviation and reimplantation (RADAR) technique that uses an artery-to-vein (A-V) configuration. Here, we show that RADAR exhibits higher rates of maturation, as well as increased primary and secondary long-term patencies. RADAR is also protective in female patients, where it is associated with decreased reintervention rates and improved secondary patency. RADAR and conventional geometries were compared further in a rat bilateral carotid artery-internal jugular vein fistula model. There was decreased cell proliferation and neointimal hyperplasia in the A-V configuration in male and female animals, but no difference in hypoxia between the A-V and V-A configurations. Similar trends were seen in uremic male rats. The A-V configuration also associated with increased peak systolic velocity and expression of Kruppel-like factor 2 and phosphorylated endothelial nitric oxide synthase, consistent with improved hemodynamics. Computed tomography and ultrasound-informed computational modeling showed different hemodynamics in the A-V and V-A configurations, and improving the hemodynamics in the V-A configuration was protective against neointimal hyperplasia. These findings collectively demonstrate that RADAR is a durable surgical option for patients requiring radial-cephalic AVF for hemodialysis access.

scholarly journals Testosterone deprivation accelerates cardiac dysfunction in obese male rats

2016 ◽  
Vol 229 (3) ◽  
pp. 209-220 ◽  
Author(s):  
Wanpitak Pongkan ◽  
Hiranya Pintana ◽  
Sivaporn Sivasinprasasn ◽  
Thidarat Jaiwongkam ◽  
Siriporn C Chattipakorn ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Mitochondrial Function ◽  
Cardiac Dysfunction ◽  
Left Ventricular ◽  
Normal Diet ◽  
Metabolic Parameters ◽  
Male Rats ◽  
Lv Function ◽  
Insulin Resistant ◽  
Aging Men

Low testosterone level is associated with increased risks of cardiovascular diseases. As obese-insulin-resistant condition could impair cardiac function and that the incidence of obesity is increased in aging men, a condition of testosterone deprivation could aggravate the cardiac dysfunction in obese-insulin-resistant subjects. However, the mechanism underlying this adverse effect is unclear. This study investigated the effects of obesity on metabolic parameters, heart rate variability (HRV), left ventricular (LV) function, and cardiac mitochondrial function in testosterone-deprived rats. Orchiectomized or sham-operated male Wistar rats (n=36per group) were randomly divided into groups and were given either a normal diet (ND, 19.77% of energy fat) or a high-fat diet (HFD, 57.60% of energy fat) for 12weeks. Metabolic parameters, HRV, LV function, and cardiac mitochondrial function were determined at 4, 8, and 12weeks after starting each feeding program. We found that insulin resistance was observed after 8weeks of the consumption of a HFD in both sham (HFS) and orchiectomized (HFO) rats. Neither the ND sham (NDS) group nor ND orchiectomized (NDO) rats developed insulin resistance. The development of depressed HRV, LV contractile dysfunction, and increased cardiac mitochondrial reactive oxygen species production was observed earlier in orchiectomized (NDO and HFO) rats at week 4, whereas HFS rats exhibited these impairments later at week 8. These findings suggest that testosterone deprivation accelerates the impairment of cardiac autonomic regulation and LV function via increased oxidative stress and impaired cardiac mitochondrial function in obese-orchiectomized male rats.

scholarly journals Energy restriction combined with dipeptidyl peptidase-4 inhibitor exerts neuroprotection in obese male rats

2016 ◽  
Vol 116 (10) ◽  
pp. 1700-1708 ◽  
Author(s):  
Hiranya Pintana ◽  
Pongpan Tanajak ◽  
Wasana Pratchayasakul ◽  
Piangkwan Sa-nguanmoo ◽  
Titikorn Chunchai ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Synaptic Plasticity ◽  
Cognitive Function ◽  
Insulin Sensitivity ◽  
Mitochondrial Function ◽  
Male Rats ◽  
Insulin Resistant ◽  
Hippocampal Synaptic Plasticity ◽  
Brain Insulin ◽  
Brain Mitochondrial Function

AbstractDipeptidyl peptidase-4 (DDP-4) inhibitors and energy restriction (ER) are widely used to treat insulin resistance and type 2 diabetes mellitus. However, the effects of ER or the combination with vildagliptin on brain insulin sensitivity, brain mitochondrial function, hippocampal synaptic plasticity and cognitive function in obese insulin-resistant rats have never been investigated. We hypothesised that ER with DDP-4 inhibitor exerts better efficacy than ER alone in improving cognition in obese insulin-resistant male rats by restoring brain insulin sensitivity, brain mitochondrial function and hippocampal synaptic plasticity. A total of twenty-four male Wistar rats were divided into two groups and fed either a normal diet or a high-fat diet (HFD) for 12 weeks. At week 13, the HFD rats were divided into three subgroups (n 6/subgroup) to receive one of the following treatments: vehicle, ER (60 % of energy received during the previous 12 weeks) or ER plus vildagliptin (3 mg/kg per d, p.o.) for 4 weeks. At the end of the treatment, cognitive function, metabolic parameters, brain insulin sensitivity, hippocampal synaptic plasticity and brain mitochondrial function were determined. We found that HFD-fed rats demonstrated weight gain with peripheral insulin resistance, dyslipidaemia, oxidative stress, brain insulin resistance, impaired brain mitochondrial function and cognitive dysfunction. Although HFD-fed rats treated with ER and ER plus vildagliptin showed restored peripheral insulin sensitivity and improved lipid profiles, only ER plus vildagliptin rats had restored brain insulin sensitivity, brain mitochondrial function, hippocampal synaptic plasticity and cognitive function. These findings suggest that only a combination of ER with DPP-4 inhibitor provides neuroprotective effects in obese insulin-resistant male rats.

Abstract 11558: Sitagliptin Attenuated Brain Damage and Cognitive Impairment in Mice With Chronic Cerebral Hypo-Perfusion Through Suppressing Oxidative Stress and Inflammatory Reaction

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Tzu -Hsien Tsai ◽  
Sarah Chua ◽  
Jiunn-Jye Sheu ◽  
Steve Leu ◽  
Hon Kan Yip
Keyword(s):  
Oxidative Stress ◽  
Working Memory ◽  
Cognitive Impairment ◽  
Brain Damage ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Receptor Protein ◽  
Opposite Pattern ◽  
Tnf Α ◽  
Bilateral Carotid

Background: Sitagliptin, a new anti-diabetic drug that inhibits dipeptidyl peptidase (DPP)-4 enzyme activity, has been reported to possess neuroprotective property. We tested the protective effect of sitagliptin against chronic cerebral hypoperfusion (CHP) in mice after bilateral carotid artery stenosis (BCAS). Methods: Thirty C57BL/6 mice were divided into three groups: Sham control (SC) (n=10), CHP (n=10), CHP-sitagliptin (orally 600mg/kg/day) (n=10). Working memory was assessed with novel-object recognition test. Magnetic resonance imaging (MRI) was performed at day 0 and day 90 after BCAS procedure prior to sacrifice. Results: Immunohistochemical (IHC) staining showed significantly enhanced microglia activation, astrocytosis, and demyelinating change of white matter in CHP group than in SC but the changes were significantly suppressed after sitagliptin treatment (all p<0.01). The mRNA expressions of inflammatory (TNF-α, MCP-1and MMP-2) and apoptotic (Bax) biomarkers showed an identical pattern, whereas the anti-inflammatory (IL-10) and anti-apoptotic (Bcl-2) biomarkers showed an opposite pattern compared to that of IHC among all groups (all p<0.01). The protein expressions of oxidative stress (NOX-I, NOX-II, nitrotyrosin, oxidized protein), inflammatory (NF-κB, TNF-α and MMP-2), apoptotic (mitochondrial Bax, cleaved PARP), and DNA-damage (γ-H2AX) markers showed an identical pattern, while expression pattern of anti-apoptotic marker (Bcl-2) was opposite to that of IHC (all p<0.01). Glycogen-like peptide-1 receptor protein expression progressively increased from SC to CHP-sitagliptin (p<0.01). The short-term working-memory loss and cortical-matter reduction on MRI-T2 showed a pattern identical to that of IHC in all groups (all p<0.01). Conclusion: Sitagliptin protected against cognitive impairment and brain damage in a murine CHP model. Key words: chronic cerebral hypoperfusion, sitagliptin, oxidative stress inflammation

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