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 Dl-3-n-Butylphthalide Alleviates Hippocampal Neuron Damage in Chronic Cerebral Hypoperfusion via Regulation of the CNTF/CNTFRα/JAK2/STAT3 Signaling Pathways

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenxian Li ◽  
Di Wei ◽  
Zheng Zhu ◽  
Xiaomei Xie ◽  
Shuqin Zhan ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Signaling Pathways ◽  
Neuronal Death ◽  
Neuronal Apoptosis ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Stat3 Pathway ◽  
Stat3 Signaling

Chronic cerebral hypoperfusion (CCH) contributes to cognitive impairments, and hippocampal neuronal death is one of the key factors involved in this process. Dl-3-n-butylphthalide (D3NB) is a synthetic compound originally isolated from the seeds of Apium graveolens, which exhibits neuroprotective effects against some neurological diseases. However, the protective mechanisms of D3NB in a CCH model mimicking vascular cognitive impairment remains to be explored. We induced CCH in rats by a bilateral common carotid artery occlusion (BCCAO) operation. Animals were randomly divided into a sham-operated group, CCH 4-week group, CCH 8-week group, and the corresponding D3NB-treatment groups. Cultured primary hippocampal neurons were exposed to oxygen-glucose deprivation/reperfusion (OGD/R) to mimic CCH in vitro. We aimed to explore the effects of D3NB treatment on hippocampal neuronal death after CCH as well as its underlying molecular mechanism. We observed memory impairment and increased hippocampal neuronal apoptosis in the CCH groups, combined with inhibition of CNTF/CNTFRα/JAK2/STAT3 signaling, as compared with that of sham control rats. D3NB significantly attenuated cognitive impairment in CCH rats and decreased hippocampal neuronal apoptosis after BCCAO in vivo or OGD/R in vitro. More importantly, D3NB reversed the inhibition of CNTF/CNTFRα expression and activated the JAK2/STAT3 pathway. Additionally, JAK2/STAT3 pathway inhibitor AG490 counteracted the protective effects of D3NB in vitro. Our results suggest that D3NB could improve cognitive function after CCH and that this neuroprotective effect may be associated with reduced hippocampal neuronal apoptosis via modulation of CNTF/CNTFRα/JAK2/STAT3 signaling pathways. D3NB may be a promising therapeutic strategy for vascular cognitive impairment induced by CCH.

scholarly journals Tripchlorolide May Improve Spatial Cognition Dysfunction and Synaptic Plasticity after Chronic Cerebral Hypoperfusion

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Zhao-Hui Yao ◽  
Xiao-li Yao ◽  
Shao-feng Zhang ◽  
Ji-chang Hu ◽  
Yong Zhang
Keyword(s):  
Cognitive Impairment ◽  
Synaptic Plasticity ◽  
Learning And Memory ◽  
Spatial Learning ◽  
Long Term Potentiation ◽  
Chronic Cerebral Hypoperfusion ◽  
Synaptic Proteins ◽  
Cerebral Hypoperfusion ◽  
Spatial Learning And Memory ◽  
Pathophysiological Mechanism

Chronic cerebral hypoperfusion (CCH) is a common pathophysiological mechanism that underlies cognitive decline and degenerative processes in dementia and other neurodegenerative diseases. Low cerebral blood flow (CBF) during CCH leads to disturbances in the homeostasis of hemodynamics and energy metabolism, which in turn results in oxidative stress, astroglia overactivation, and synaptic protein downregulation. These events contribute to synaptic plasticity and cognitive dysfunction after CCH. Tripchlorolide (TRC) is an herbal compound with potent neuroprotective effects. The potential of TRC to improve CCH-induced cognitive impairment has not yet been determined. In the current study, we employed behavioral techniques, electrophysiology, Western blotting, immunofluorescence, and Golgi staining to investigate the effect of TRC on spatial learning and memory impairment and on synaptic plasticity changes in rats after CCH. Our findings showed that TRC could rescue CCH-induced spatial learning and memory dysfunction and improve long-term potentiation (LTP) disorders. We also found that TRC could prevent CCH-induced reductions in N-methyl-D-aspartic acid receptor 2B, synapsin I, and postsynaptic density protein 95 levels. Moreover, TRC upregulated cAMP-response element binding protein, which is an important transcription factor for synaptic proteins. TRC also prevented the reduction in dendritic spine density that is caused by CCH. However, sham rats treated with TRC did not show any improvement in cognition. Because CCH causes disturbances in brain energy homeostasis, TRC therapy may resolve this instability by correcting a variety of cognitive-related signaling pathways. However, for the normal brain, TRC treatment led to neither disturbance nor improvement in neural plasticity. Additionally, this treatment neither impaired nor further improved cognition. In conclusion, we found that TRC can improve spatial learning and memory, enhance synaptic plasticity, upregulate the expression of some synaptic proteins, and increase the density of dendritic spines. Our findings suggest that TRC may be beneficial in the treatment of cognitive impairment induced by CCH.

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 Attenuating vascular stenosis-induced astrogliosis preserves white matter integrity and cognitive function

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Qian Liu ◽  
Mohammad Iqbal H. Bhuiyan ◽  
Ruijia Liu ◽  
Shanshan Song ◽  
Gulnaz Begum ◽  
...  
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Cognitive Impairment ◽  
Cognitive Function ◽  
White Matter ◽  
Spatial Working Memory ◽  
Ex Vivo ◽  
Cerebral Hypoperfusion ◽  
Cellular Mechanisms ◽  
Bilateral Carotid

Abstract Background Chronic cerebral hypoperfusion (CCH) causes white matter damage and cognitive impairment, in which astrogliosis is the major pathology. However, underlying cellular mechanisms are not well defined. Activation of Na+/H+ exchanger-1 (NHE1) in reactive astrocytes causes astrocytic hypertrophy and swelling. In this study, we examined the role of NHE1 protein in astrogliosis, white matter demyelination, and cognitive function in a murine CCH model with bilateral carotid artery stenosis (BCAS). Methods Sham, BCAS, or BCAS mice receiving vehicle or a selective NHE1 inhibitor HOE642 were monitored for changes of the regional cerebral blood flow and behavioral performance for 28 days. Ex vivo MRI-DTI was subsequently conducted to detect brain injury and demyelination. Astrogliosis and demyelination were further examined by immunofluorescence staining. Astrocytic transcriptional profiles were analyzed with bulk RNA-sequencing and RT-qPCR. Results Chronic cerebral blood flow reduction and spatial working memory deficits were detected in the BCAS mice, along with significantly reduced mean fractional anisotropy (FA) values in the corpus callosum, external capsule, and hippocampus in MRI DTI analysis. Compared with the sham control mice, the BCAS mice displayed demyelination and axonal damage and increased GFAP+ astrocytes and Iba1+ microglia. Pharmacological inhibition of NHE1 protein with its inhibitor HOE642 prevented the BCAS-induced gliosis, damage of white matter tracts and hippocampus, and significantly improved cognitive performance. Transcriptome and immunostaining analysis further revealed that NHE1 inhibition specifically attenuated pro-inflammatory pathways and NADPH oxidase activation. Conclusion Our study demonstrates that NHE1 protein is involved in astrogliosis with pro-inflammatory transformation induced by CCH, and its blockade has potentials for reducing astrogliosis, demyelination, and cognitive impairment.

scholarly journals Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive impairment and dementia

2017 ◽  
Vol 131 (19) ◽  
pp. 2451-2468 ◽  
Author(s):  
Jessica Duncombe ◽  
Akihiro Kitamura ◽  
Yoshiki Hase ◽  
Masafumi Ihara ◽  
Raj N. Kalaria ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
White Matter ◽  
Small Vessel Disease ◽  
Amyloid Β ◽  
Vascular Cognitive Impairment ◽  
Chronic Cerebral Hypoperfusion ◽  
Cerebral Hypoperfusion ◽  
Pathophysiological Mechanism ◽  
Rodent Models ◽  
Recent Refinement

Increasing evidence suggests that vascular risk factors contribute to neurodegeneration, cognitive impairment and dementia. While there is considerable overlap between features of vascular cognitive impairment and dementia (VCID) and Alzheimer’s disease (AD), it appears that cerebral hypoperfusion is the common underlying pathophysiological mechanism which is a major contributor to cognitive decline and degenerative processes leading to dementia. Sustained cerebral hypoperfusion is suggested to be the cause of white matter attenuation, a key feature common to both AD and dementia associated with cerebral small vessel disease (SVD). White matter changes increase the risk for stroke, dementia and disability. A major gap has been the lack of mechanistic insights into the evolution and progress of VCID. However, this gap is closing with the recent refinement of rodent models which replicate chronic cerebral hypoperfusion. In this review, we discuss the relevance and advantages of these models in elucidating the pathogenesis of VCID and explore the interplay between hypoperfusion and the deposition of amyloid β (Aβ) protein, as it relates to AD. We use examples of our recent investigations to illustrate the utility of the model in preclinical testing of candidate drugs and lifestyle factors. We propose that the use of such models is necessary for tackling the urgently needed translational gap from preclinical models to clinical treatments.

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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