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

scholarly journals Role of HMGB1 in an Animal Model of Vascular Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion

2020 ◽  
Vol 21 (6) ◽  
pp. 2176 ◽  
Author(s):  
Amelia Nur Vidyanti ◽  
Jia-Yu Hsieh ◽  
Kun-Ju Lin ◽  
Yao-Ching Fang ◽  
Ismail Setyopranoto ◽  
...  
Keyword(s):  
Animal Model ◽  
Cognitive Impairment ◽  
Cognitive Decline ◽  
Chronic Phase ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Hippocampal Atrophy ◽  
Tnf Α

The pathophysiology of vascular cognitive impairment (VCI) is associated with chronic cerebral hypoperfusion (CCH). Increased high-mobility group box protein 1 (HMGB1), a nonhistone protein involved in injury and inflammation, has been established in the acute phase of CCH. However, the role of HMGB1 in the chronic phase of CCH remains unclear. We developed a novel animal model of CCH with a modified bilateral common carotid artery occlusion (BCCAO) in C57BL/6 mice. Cerebral blood flow (CBF) reduction, the expression of HMGB1 and its proinflammatory cytokines (tumor necrosis factor-alpha [TNF-α], interleukin [IL]-1β, and IL-6), and brain pathology were assessed. Furthermore, we evaluated the effect of HMGB1 suppression through bilateral intrahippocampus injection with the CRISPR/Cas9 knockout plasmid. Three months after CCH induction, CBF decreased to 30–50% with significant cognitive decline in BCCAO mice. The 7T-aMRI showed hippocampal atrophy, but amyloid positron imaging tomography showed nonsignificant amyloid-beta accumulation. Increased levels of HMGB1, TNF-α, IL-1β, and IL-6 were observed 3 months after BCCAO. HMGB1 suppression with CRISPR/Cas9 knockout plasmid restored TNF-α, IL-1β, and IL-6 and attenuated hippocampal atrophy and cognitive decline. We believe that HMGB1 plays a pivotal role in CCH-induced VCI pathophysiology and can be a potential therapeutic target of VCI.

scholarly journals Minocycline attenuates cognitive impairment and restrains oxidative stress in the hippocampus of rats with chronic cerebral hypoperfusion

2008 ◽  
Vol 24 (5) ◽  
pp. 305-313 ◽  
Author(s):  
Zhi-You Cai ◽  
Yong Yan ◽  
Shan-Quan Sun ◽  
Jun Zhang ◽  
Liang-Guo HUANG ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion

scholarly journals Attenuation of Brain Damage and Cognitive Impairment by Direct Renin Inhibition in Mice With Chronic Cerebral Hypoperfusion

Hypertension ◽  
2011 ◽  
Vol 58 (4) ◽  
pp. 635-642 ◽  
Author(s):  
Yi-Fei Dong ◽  
Keiichiro Kataoka ◽  
Kensuke Toyama ◽  
Daisuke Sueta ◽  
Nobutaka Koibuchi ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Brain Damage ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Renin Inhibition

scholarly journals Bilateral common carotid artery stenosis in normotensive rats impairs endothelium-dependent dilation of parenchymal arterioles

2016 ◽  
Vol 310 (10) ◽  
pp. H1321-H1329 ◽  
Author(s):  
Nusrat Matin ◽  
Courtney Fisher ◽  
William F. Jackson ◽  
Anne M. Dorrance
Keyword(s):  
Cognitive Impairment ◽  
Carotid Artery ◽  
Endothelial Function ◽  
Carotid Artery Stenosis ◽  
Short Term Memory ◽  
Artery Stenosis ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Cyclooxygenase Inhibitors ◽  
Bilateral Carotid

Chronic cerebral hypoperfusion is a risk factor for cognitive impairment. Reduced blood flow through the common carotid arteries induced by bilateral carotid artery stenosis (BCAS) is a physiologically relevant model of chronic cerebral hypoperfusion. We hypothesized that BCAS in 20-wk-old Wistar-Kyoto (WKY) rats would impair cognitive function and lead to reduced endothelium-dependent dilation and outward remodeling in the parenchymal arterioles (PAs). After 8 wk of BCAS, both short-term memory and spatial discrimination abilities were impaired. In vivo assessment of cerebrovascular reserve capacity showed a severe impairment after BCAS. PA endothelial function and structure were assessed by pressure myography. BCAS impaired endothelial function in PAs, as evidenced by reduced dilation to carbachol. Addition of nitric oxide synthase and cyclooxygenase inhibitors did not change carbachol-mediated dilation in either group. Inhibiting CYP epoxygenase, the enzyme that produces epoxyeicosatrienoic acid (EETs), a key determinant of endothelium-derived hyperpolarizing factor (EDHF)-mediated dilation, abolished dilation in PAs from Sham rats, but had no effect in PAs from BCAS rats. Expression of TRPV4 channels, a target for EETs, was decreased and maximal dilation to a TRPV4 agonist was attenuated after BCAS. Together these data suggest that EET-mediated dilation is impaired in PAs after BCAS. Thus impaired endothelium-dependent dilation in the PAs may be one of the contributing factors to the cognitive impairment observed after BCAS.

scholarly journals Epigenetic Conditioning Induces Intergenerational Resilience to Dementia in a Mouse Model of Vascular Cognitive Impairment

2021 ◽  
Author(s):  
Krystal Courtney D Belmonte ◽  
Eleanor B Holmgrem ◽  
Tiffany A Wills ◽  
Jeff M Gidday
Keyword(s):  
Cognitive Impairment ◽  
Recognition Memory ◽  
First Generation ◽  
Ex Vivo ◽  
Long Term Potentiation ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Generation Adult ◽  
Bilateral Carotid

Background: Vascular cognitive impairment and dementia (VCID), which occurs immediately or in delayed fashion in 25-30% of stroke survivors, or secondary to chronic cerebral hypoperfusion, is the second leading cause of dementia following Alzheimers disease. To date, efficacious therapies are unavailable. We have shown previously in mice that repetitive hypoxic preconditioning (RHC) induces a long-lasting resilience to acute stroke (Stowe et al., 2011). More recently, we documented that untreated, first-generation adult progeny of mice exposed to RHC prior to mating are protected from retinal ischemic injury (Harman et al., 2020), consistent with accumulating evidence supporting the concept that long-lasting phenotypes induced epigenetically by intermittent stressors may be heritable. We undertook the present study to test the hypothesis that RHC will induce resilience to VCID, and that such RHC-induced resilience can also be inherited. Methods: Chronic cerebral hypoperfusion (CCH) was induced in C57BL/6J mice secondary to bilateral carotid artery stenosis with microcoils in both the parental (F0) generation, and in their untreated first-generation (F1) offspring. Cohorts of F0 mice were directly exposed to either 8 wks of RHC (1 h of systemic hypoxia 11% oxygen, 3x/week) or normoxia prior to CCH. Cohorts of F1 mice were derived from F0 mice treated with RHC prior to mating, and untreated, normoxic controls that were age-matched at the time of stenosis induction. Demyelination in the corpus callosum of F0 mice was assessed following 3 months of CCH by immunohistochemistry. Mice from both generations were assessed for short-term recognition memory in vivo by novel object preference (NOP) testing following 3 months of CCH, and a month thereafter, ex vivo measurements of CA1 hippocampal long-term potentiation (LTP) were recorded from the same animals as a metric of long-lasting changes in synaptic plasticity. Results: Three months of CCH caused demyelination and concomitant impairments in recognition memory in control mice from both generations. However, these CCH-induced memory impairments were prevented in F0 animals directly treated with RHC, as well as in their untreated adult F1 progeny. Similarly, hippocampal LTP was preserved in the 4-month CCH cohorts of mice directly treated with RHC, and in their untreated offspring with CCH. Conclusions: Our findings demonstrate that RHC or other repetitively-presented, epigenetic-based therapeutics may hold promise for inducing a long-lasting resilience to VCID in treated individuals, and in their first-generation adult progeny.

scholarly journals Inhibition of the Immunoproteasome Subunit LMP7 Ameliorates Cerebral White Matter Demyelination Possibly via TGFβ/Smad Signaling

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Xingyong Chen ◽  
Nannan Yao ◽  
Zejing Lin ◽  
Yinzhou Wang
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Function ◽  
White Matter ◽  
Growth Factor ◽  
Ischemic Injury ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Cerebral White Matter ◽  
Smad Signaling ◽  
Bilateral Carotid

Objectives. Chronic cerebral hypoperfusion induces white matter ischemic injury and cognitive impairment, whereas the mechanism remains unclear. Immunoproteasomes have been implicated in the pathogenesis of acute ischemia stroke and multiple sclerosis. However, the expression and role of immunoproteasomes in the brain of chronic cerebral hypoperfusion remain to be clarified. Methods. Chronic white matter ischemic injury mice models were induced by bilateral carotid artery stenosis (BCAS). A selective immunoproteasome subunit low-molecular-mass peptide-7 (LMP7) inhibitor PR957 was administered to mice. Cognitive function, white matter integrity, and potential pathways were assessed after BCAS. Results. The present study found that chronic cerebral hypoperfusion following BCAS induced cerebral white matter demyelination and cognitive impairment, accompanied with elevated expression of the immunoproteasomes LMP2 and LMP7, activation of astrocytes and microglia, and increased production of inflammatory cytokines (e.g., interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), IL-10, transforming growth factor-β1 (TGFβ1), and insulin-like growth factor-1 (IGF-1)). However, inhibition of LMP7 with the specific proteasome inhibitor PR957 significantly mitigated the histological damage of the white matter, suppressed inflammatory response, and paralleled by an improvement of cognitive function. Furthermore, treatment of PR957 significantly upregulated the level of TGFβ1, the total expression level, and the phosphorylation level of Smad2/3 and promoted brain remyelination. Surprisingly, PR957 alone had no effects on the neuroinflammation response and the activation of TGFβ/Smad signaling in the sham-operated (BCAS-nonoperated) mice. Conclusions. The possible mechanism underlying this was attributed to that the immunoproteasome regulates TGFβ/Smad signaling-mediated neuroinflammation and oligodendrocyte remyelination.

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