Unilateral Carotid Artery Occlusion Research Articles

Observation of blood flow characteristics of collateral circulation of ipsilateral ophthalmic artery in patients with internal carotid artery occlusion

Objective To observe the characteristics of collateral circulation blood flow of ipsilateral ophthalmic artery in patients with internal carotid artery occlusion. Methods The imaging data of 20 patients with internal carotid artery occlusion were analyzed retrospectively. There were 11 males and 9 females, aged from 30 to 65 years, with an average age of (45±3) years. All the patients underwent digital subtraction angiography and transcranial Doppler examination, and 6 patients underwent simultaneous magnetic resonance angiography. The blood supply and collateral circulation of the ipsilateral ophthalmic artery were observed . Results All the patients had unilateral internal carotid artery occlusion. The blood supply of the ipsilateral internal carotid artery and ophthalmic artery comes from the collateral circulation between the middle meningeal artery branches of the external carotid artery and the ophthalmic artery in 18 patients (90.0%); it also comes from the anterior communicating artery of the contralateral internal carotid artery in 16 patients (80.0%); and the posterior communicating artery of the contralateral internal carotid artery in 12 patients (60.0%), respectively. Conclusion The blood flow of the ipsilateral ophthalmic artery mainly comes from the middle meningeal artery branch of the ipsilateral external carotid artery, also comes from the anterior and posterior communicating arteries of the contralateral internal carotid artery. Key words: Arterial occlusive diseases; Ophthalmic artery; Collateral circulation; Angiography, digital subtraction; Ultrasonography, Doppler, transcranial

Iterative analysis of cerebrovascular reactivity dynamic response by temporal decomposition.

ObjectiveTo improve quantitative cerebrovascular reactivity (CVR) measurements and CO 2 arrival times, we present an iterative analysis capable of decomposing different temporal components of the dynamic carbon dioxide‐ Blood Oxygen‐Level Dependent (CO 2‐BOLD) relationship.Experimental DesignDecomposition of the dynamic parameters included a redefinition of the voxel‐wise CO 2 arrival time, and a separation from the vascular response to a stepwise increase in CO 2 (Delay to signal Plateau – DTP) and a decrease in CO 2 (Delay to signal Baseline –DTB). Twenty‐five (normal) datasets, obtained from BOLD MRI combined with a standardized pseudo‐square wave CO 2 change, were co‐registered to generate reference atlases for the aforementioned dynamic processes to score the voxel‐by‐voxel deviation probability from normal range. This analysis is further illustrated in two subjects with unilateral carotid artery occlusion using these reference atlases.Principal ObservationsWe have found that our redefined CO 2 arrival time resulted in the best data fit. Additionally, excluding both dynamic BOLD phases (DTP and DTB) resulted in a static CVR, that is maximal response, defined as CVR calculated only over a normocapnic and hypercapnic calibrated plateau.ConclusionDecomposition and novel iterative modeling of different temporal components of the dynamic CO 2‐BOLD relationship improves quantitative CVR measurements.

Hypoxic postconditioning improves behavioural deficits at 6 weeks following hypoxic-ischemic brain injury in neonatal rats

Hypoxic-ischemic (HI) brain injury in newborns is associated with high morbidity and mortality, with many babies suffering neurological deficits. Recently, we showed that hypoxic postconditioning (PostC) immediately post injury can protect against HI up to one week in neonatal rats. Here, we aimed to examine whether long term functional deficits were also improved by PostC. Sprague-Dawley rats were assigned to control (C) or HI group on postnatal day 7 (P7). The HI group underwent unilateral carotid artery occlusion followed by hypoxia (7% oxygen, 3h). Half of each group were randomly assigned to the PostC group (8% oxygen, 1h/day for 5days post-injury), or normoxic group, where animals were kept under ambient conditions. Righting reflex and negative geotaxis tests were performed on P8 and P14. On P42, rats underwent further behavioural tests of motor function and memory (forelimb grip strength, grid walking and novel object recognition tasks). Brain injury was assessed using histological scoring of brain sections. At P14, PostC reduced the righting reflex deficit compared to HI alone. Long-term (6 weeks) behavioural deficits were observed in grid walking and novel object recognition tests after HI alone, with both functions improved following PostC. Following HI, there was an increase in brain injury assessed by histological scoring compared to control, and this damage was reduced by PostC. This novel finding of long-term histological neuroprotection accompanied by functional improvements by PostC further demonstrates the clinical potential of mild hypoxia for the treatment of HI brain injury.

Astrocyte-derived lipocalin-2 mediates hippocampal damage and cognitive deficits in experimental models of vascular dementia.

Lipocalin-2 (LCN2) has diverse functions in multiple pathophysiological conditions; however, its pathogenic role in vascular dementia (VaD) is unknown. Here, we investigated the role of LCN2 in VaD using rodent models of global cerebral ischemia and hypoperfusion with cognitive impairment and neuroinflammation. Mice subjected to transient bilateral common carotid artery occlusion (tBCCAo) for 50 min showed neuronal death and gliosis in the hippocampus at 7 days post-tBCCAo. LCN2 expression was observed predominantly in the hippocampal astrocytes, whereas its receptor was mainly detected in neurons, microglia, and astrocytes. Furthermore, Lcn2-deficient mice, compared with wild-type animals, showed significantly weaker CA1 neuronal loss, cognitive decline, white matter damage, blood-brain barrier permeability, glial activation, and proinflammatory cytokine production in the hippocampus after tBCCAo. Lcn2 deficiency also attenuated hippocampal neuronal death and cognitive decline at 30 days after unilateral common carotid artery occlusion (UCCAo). Furthermore, intracerebroventricular (i.c.v) injection of recombinant LCN2 protein elicited CA1-neuronal death and a cognitive deficit. Our studies using cultured glia and hippocampal neurons supported the decisive role of LCN2 in hippocampal neurotoxicity and microglial activation, and the role of the HIF-1α-LCN2-VEGFA axis of astrocytes in vascular injury. Additionally, plasma levels of LCN2 were significantly higher in patients with VaD than in the healthy control subjects. These results indicate that hippocampal damage and cognitive impairment are mediated by LCN2 secreted from reactive astrocytes in VaD.

Abstract WP436: Reduced Blood Flow in the Pial Collaterals and Penetrating Arterioles During Chronic Hypoperfusion in Type 2 Diabetic Mice

Introduction: The degree of cortical hypoperfusion following carotid steno-occlusion depends on the dynamic compensation from the collateral circulation. The presence of collaterals is associated with a reduced risk of stroke and transient ischemic attack (TIA) in patients with steno-occlusive carotid artery disease. Although metabolic syndrome negatively impacts collateral status among patients with ischemic stroke, it is unclear whether type 2 diabetes (T2DM) specifically affects leptomeningeal collateral flow regulation and the adaptation of collateral vessels at the circle of Willis during hypoperfusion. Methods: Spatial and temporal changes of the leptomeningeal collateral flow and the flow dynamics of the penetrating arterioles in the distal MCA and ACA branches over two weeks following unilateral common carotid artery occlusion (CCAO) were determined by optical coherent tomography in db/+ and db/db mice, a mouse model for obesity and type 2 diabetes. The temporal adaptation of the circle of Willis (CW) following CCAO was assessed by measuring CW vessel diameters. Results: Following unilateral CCAO, db/db mice exhibited diminished leptomeningeal collateral flow compensation compared to db /+ mice, which coincided with a reduced dilation of distal ACA branches, leading to reduced flow not only in pial vessels, but also in penetrating arterioles bordering the distal MCA and ACA. However, no apparent cell death was detected in either strain of mice during the first week after CCAO. db/db mice also experienced a more severe early reduction in the vessel diameters of several ipsilateral main feeding arteries in the CW, in addition to a delayed post-CCAO adaptive response by one to two weeks compared to db/+ mice. Conclusions: T2DM is an additional risk factor for hemodynamic compromise during cerebral hypoperfusion, which may increase the severity and the risk of stroke or TIA.

Abstract TMP96: Neuroinflammatory Mechanism of Vascular Cognitive Impairment

Introduction: The mechanisms of vascular cognitive impairment (VCI) are poorly understood. We previously demonstrated increased expression and activity of soluble epoxide hydrolase (sEH) in microvascular endothelium of human brain tissue from deceased patients with pre-mortem VCI. sEH is a key enzyme in the inactivation of endogenous lipid signaling mediators, epoxyeicosatrienoic acids (EETs), known to have vasodilator and anti-inflammatory properties. Hypothesis: Upregulation of endothelial sEH impairs cognition, by mechanisms involving reduced cerebral blood flow (CBF) and enhanced inflammation. Methods: Mice constitutively expressing human sEH in endothelium (Tie2-hsEH) and wild-type (WT) underwent unilateral common carotid artery occlusion (UCCAO) or sham surgery, then analyzed 4 months later for cognitive performance using the Morris water maze (MWM), CBF by perfusion MRI, immune cell profiling in brain, blood and spleen using fluorescence-activated cell sorting (FACS) and immunohistochemistry (IHC). Additionally, immune profiling was performed on WT mice 28 days following surgery, with and without pretreatment with immune modulator DRa1-hMOG-35-55 (HLA-DR a1 moiety linked to human MOG-35-55 peptide). Results: Tie2-hsEH mice showed impaired spatial memory retention in the MWM. No differences were observed in CBF between genotypes. IHC demonstrated a higher density of CD45-positive cells in Tie2-hsEH brain compared to WT. FACS analysis revealed a higher frequency of CD11b + CD45 hi cells in Tie2-hsEH vs. WT mice. Furthermore, these cells express higher levels of CD74, the receptor for macrophage migration inhibitory factor (MIF). Similarly, following UCCAO, the frequency of antigen-presenting dendritic cells and CD74 expression on CD11b + CD45 hi cells were increased in brain, but reduced in spleen and blood compared to naïve mice; both changes were reversed by treatment with DRa1-MOG-35-55, resulting in a decreased frequency and activation state of these cells. Conclusions: Our data suggest that infiltration of monocyte-derived macrophages may contribute to cognitive impairment in VCI. Our findings suggest that CD74 expression could serve as a biomarker for VCI, and that DRa1-MOG-35-55 may be effective in treating VCI.

A Mouse Model for Chronic Cerebral Hypoperfusion-induced Cognitive Dysfunction

Background: Chronic cerebral hypoperfusion potentially contributes to the initiation and progression of vascular dementia (VD). Bilateral common carotid artery occlusion (two-vessel occlusion) is the most commonly used animal model to replicate this pathological condition but with high mortality and severe histological cerebral damage. Unilateral common carotid artery occlusion (one-vessel occlusion) was introduced to simulate clinical conditions. Our study was designed to further characterize this model.Methods: In this study, eight-week old CD-1 mice were subjected to left common carotid artery occlusion (LCCAO). Two weeks after the occlusion, their learning and memory were assessed by Barnes maze and fear conditioning. Histo-morphological changes were evaluated by Hematoxylin-Eosin staining. Neuronal and axonal degenerative changes were examined by amino-cupric sliver staining.Results: LCCAO increased the time to find the target box in the Barnes maze test during the 4-day training sessions and one day after the training sessions compared with sham group mice. There was no difference in context-related or tone-related freezing behavior between these two groups. No significant histological neuronal cell damage or degeneration was observed in brain sections of hippocampus and corpus callosum in these two groups.Conclusions: Our results suggest that LCCAO can be used to mimic the vascular dementia. Citation: Jun Li, Zhi-Yi Zuo. A mouse model for chronic cerebral hypoperfusion-induced cognitive dysfunction. J Anesth Perioper Med 2017; 4: 60-66. doi:10.24015/JAPM.2017.0015This is an open-access article, published by Evidence Based Communications (EBC). This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium or format for any lawful purpose. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Combined Hemorrhagic Shock and Unilateral Common Carotid Occlusion Induces Neurological Injury in Adult Male Rats.

Background: Clinical assessment reveals that patients after surgery of cardiopulmonary bypass or coronary bypass experience postoperative cognitive dysfunction. This study aimed to investigate whether resuscitation after a hemorrhagic shock (HS) and/or mild cerebral ischemia caused by a unilateral common carotid artery occlusion (UCCAO) can cause brain injury and concomitant neurological dysfunction, and explore the potential mechanisms.Methods: Blood withdrawal (6 mL/100 g body weight) for 60 min through the right jugular vein catheter-induced an HS. Immediately after the termination of HS, we reinfused the initially shed blood volumes to restore and maintain the mean arterial blood pressure (MABP) to the original value during the 30-min resuscitation. A cooling water blanket used to induce whole body cooling for 30 min after the end of resuscitation.Results: An UCCAO caused a slight cerebral ischemia (cerebral blood flow [CBF] 70%) without hypotension (MABP 85 mmHg), systemic inflammation, multiple organs injuries, or neurological injury. An HS caused a moderate cerebral ischemia (52% of the original CBF levels), a moderate hypotension (MABP downed to 22 mmHg), systemic inflammation, and peripheral organs injuries. However, combined an UCCAO and an HS caused a severe cerebral ischemia (18% of the original CBF levels), a moderate hypotension (MABP downed to 17 mmHg), systemic inflammation, peripheral organs damage, and neurological injury, which can be attenuated by whole body cooling.Conclusions: When combined with an HS, an UCCAO is associated with ischemic neuronal injury in the ipsilateral hemisphere of adult rat brain, which can be attenuated by therapeutic hypothermia. A resuscitation from an HS regards as a reperfusion insult which may induce neurological injury in patients with an UCCAO disease.

Impaired Collateral Flow Compensation During Chronic Cerebral Hypoperfusion in the Type 2 Diabetic Mice.

The presence of collaterals is associated with a reduced risk of stroke and transient ischemic attack in patients with steno-occlusive carotid artery disease. Although metabolic syndrome negatively impacts collateral status, it is unclear whether and to what extent type 2 diabetes mellitus affects cerebral collateral flow regulation during hypoperfusion. We examined the spatial and temporal changes of the leptomeningeal collateral flow and the flow dynamics of the penetrating arterioles in the distal middle cerebral artery and anterior cerebral artery branches over 2 weeks after unilateral common carotid artery occlusion (CCAO) using optical coherent tomography in db/+ and db/db mice. We also assessed the temporal adaptation of the circle of Willis after CCAO by measuring circle of Willis vessel diameters. After unilateral CCAO, db/db mice exhibited diminished leptomeningeal collateral flow compensation compared with db/+ mice, which coincided with a reduced dilation of distal anterior cerebral artery branches, leading to reduced flow not only in pial vessels but also in penetrating arterioles bordering the distal middle cerebral artery and anterior cerebral artery. However, no apparent cell death was detected in either strain of mice during the first week after CCAO. db/db mice also experienced a more severe early reduction in the vessel diameters of several ipsilateral main feeding arteries in the circle of Willis, in addition to a delayed post-CCAO adaptive response by 1 to 2 weeks, compared with db/+ mice. Type 2 diabetes mellitus is an additional risk factor for hemodynamic compromise during cerebral hypoperfusion, which may increase the severity and the risk of stroke or transient ischemic attack.

TCT-692 Unilateral carotid artery occlusion is associated with higher stroke rate after TAVI

TCT-692 Unilateral carotid artery occlusion is associated with higher stroke rate after TAVI

Adenosine A1-Receptors Modulate mTOR Signaling to Regulate White Matter Inflammatory Lesions Induced by Chronic Cerebral Hypoperfusion.

We sought to investigate the role of the adenosine A1 receptors (A1ARs) in white matter lesions under chronic cerebral hypoperfusion (CCH) and explore the potential repair mechanisms by activation of the receptors. A right unilateral common carotid artery occlusion (rUCCAO) method was used to construct a CCH model. 2-chloro-N6-cyclopentyladenosine (CCPA), a specific agonist of A1ARs, was used to explore the biological mechanisms of repair in white matter lesions under CCH. The expression of mammalian target of rapamycin (mTOR), phosphorylation of mTOR (P-mTOR), myelin basic protein (MBP, a marker of white matter myelination) were detected by Western-blot. Pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) and anti-inflammatory cytokine interleukin-10 (IL-10) levels were determined by ELISA. Compared with the control groups on week 2, 4 and 6, in CCPA-treated groups, the ratio of P-mTOR/mTOR, expression of MBP and IL-10 increased markedly, while the expression of TNF-α reduced at week 6. In conclusion, A1ARs appears to reduce inflammation in white matter via the mTOR signaling pathway in the rUCCAO mice. Therefore, A1ARs may serve as a therapeutic target during the repair of white matter lesions under CCH.

Influence of rat adipose tissue-derived mesenchymal stem cells on brain tissues following permanent unilateral common carotid artery occlusion in adult male albino rat

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Adaptation of the cerebrocortical circulation to carotid artery occlusion involves blood flow redistribution between cortical regions and is independent of eNOS.

Cerebral circulation is secured by feed-forward and feed-back control pathways to maintain and eventually reestablish the optimal oxygen and nutrient supply of neurons in case of disturbances of the cardiovascular system. Using the high temporal and spatial resolution of laser-speckle imaging we aimed to analyze the pattern of cerebrocortical blood flow (CoBF) changes after unilateral (left) carotid artery occlusion (CAO) in anesthetized mice to evaluate the contribution of macrovascular (circle of Willis) vs. pial collateral vessels as well as that of endothelial nitric oxide synthase (eNOS) to the cerebrovascular adaptation to CAO. In wild-type mice CoBF reduction in the left temporal cortex started immediately after CAO, reaching its maximum (-26%) at 5-10 s. Thereafter, CoBF recovered close to the preocclusion level within 30 s indicating the activation of feed-back pathway(s). Interestingly, the frontoparietal cerebrocortical regions also showed CoBF reduction in the left (-17-19%) but not in the right hemisphere, although these brain areas receive their blood supply from the common azygos anterior cerebral artery in mice. In eNOS-deficient animals the acute CoBF reduction after CAO was unaltered, and the recovery was even accelerated compared with controls. These results indicate that 1) the Willis circle alone is not sufficient to provide an immediate compensation for the loss of one carotid artery, 2) pial collaterals attenuate the ischemia of the temporal cortex ipsilateral to CAO at the expense of the blood supply of the frontoparietal region, and 3) eNOS, surprisingly, does not play an important role in this CoBF redistribution.

In vivo evidence for long-term vascular remodeling resulting from chronic cerebral hypoperfusion in mice

We have characterized both acute and long-term vascular and metabolic effects of unilateral common carotid artery occlusion in mice by in vivo magnetic resonance imaging and positron emission tomography. This common carotid artery occlusion model induces chronic cerebral hypoperfusion and is therefore relevant to both preclinical stroke studies, where it serves as a control condition for a commonly used mouse model of ischemic stroke, and neurodegeneration, as chronic hypoperfusion is causative to cognitive decline. By using perfusion magnetic resonance imaging, we demonstrate that under isoflurane anesthesia, cerebral perfusion levels recover gradually over one month. This recovery is paralleled by an increase in lumen diameter and altered tortuosity of the contralateral internal carotid artery at one year post-ligation as derived from magnetic resonance angiography data. Under urethane/α-chloralose anesthesia, no acute perfusion differences are observed, but the vascular response capacity to hypercapnia is found to be compromised. These hemispheric perfusion alterations are confirmed by water [15O]-H2O positron emission tomography. Glucose metabolism ([18F]-FDG positron emission tomography) or white matter organization (diffusion-weighted magnetic resonance imaging) did not show any significant alterations. In conclusion, permanent unilateral common carotid artery occlusion results in acute and long-term vascular remodeling, which may have immediate consequences for animal models of stroke but also vascular dementia.

Experimental Cannabinoid 2 Receptor Inhibition in CNS Injury-Induced Immunodeficiency Syndrome.

Severe CNS injury, such as stroke, traumatic brain injury, or spinal cord injury, is known to increase susceptibility to infections. The increased susceptibility to infection is due to an impaired immune response and is referred to as CIDS. The CB2 receptor on immune cells presents a potential therapeutic target in CIDS as activation of this receptor has been shown to be involved in immunosuppression. The main purpose of this study was to determine the impact of CB2 receptor inhibition on leukocyte activation within the microcirculation following endotoxin challenge in an experimental stroke model. Five experimental groups (male C57BL/6 mice, age: 6-8 weeks) were subjected to the following treatments: control; endotoxemia (LPS 5 mg/kg, i.v.); transient cerebral hypoxia-ischemia (HI) + endotoxemia; HI + endotoxemia + CB2 receptor antagonist (AM630 2.5 mg/kg, i.v.). HI was induced by unilateral carotid artery occlusion, followed by 50 minute exposure to a low oxygen atmosphere (8% O2 ). The CB2 receptor antagonist was given 15 min prior to LPS administration. Intravital microscopy (IVM) was carried out 2h after LPS administration. Brains were extracted and stained with tetrazolium chloride (TTC) to measure infarct volume. Compared to endotoxemic animals without CNS injury, mice subjected to HI displayed reduced leukocyte activation in intestinal submucosal venules indicative of CIDS. Administration of the CB2 receptor antagonist in animals with CIDS challenged with endotoxin restored peripheral leukocyte recruitment without a detrimental impact on infarct size. We conclude that the ECS is involved in the impaired immune response following CNS injury. Future studies should further explore the CB2 receptor pathway to develop novel therapies for CIDS.

Long-term effects of cerebral hypoperfusion on neural density and function using misery perfusion animal model.

We investigated the chronic effects of cerebral hypoperfusion on neuronal density and functional hyperemia using our misery perfusion mouse model under unilateral common carotid artery occlusion (UCCAO). Neuronal density evaluated 28 days after UCCAO using [11C]flumazenil-PET and histology indicated no neurologic deficit in the hippocampus and neocortex. CBF response to sensory stimulation was assessed using laser-Doppler flowmetry. Percentage changes in CBF response of the ipsilateral hemisphere to UCCAO were 18.4 ± 3.0%, 6.9 ± 2.8%, 6.8 ± 2.3% and 4.9 ± 2.4% before, and 7, 14 and 28 days after UCCAO, respectively. Statistical significance was found at 7, 14 and 28 days after UCCAO (P < 0.01). Contrary to our previous finding (Tajima et al. 2014) showing recovered CBF response to hypercapnia on 28 days after UCCAO using the same model, functional hyperemia was sustained and became worse 28 days after UCCAO.

Stress-responsive heme oxygenase-1 isoenzyme participates in Toll-like receptor 4-induced inflammation during brain ischemia.

Toll-like receptors (TLRs) are involved in the progression of ischemic brain injury and hence vascular dementia; however, the underlying mechanisms are largely unknown. Here, we have investigated the interrelationship between stress-responsive heme oxygenase (HO)-1 isoenzyme and TLR4 during chronic brain hypoperfusion. The right unilateral common carotid artery occlusion was performed by ligation of the right common carotid artery in C57BL/6J mice. The brain cortex or hippocampus was removed for western blotting and confocal immunofluorescence analysis. The link between HO-1 and TLR4 was further examined by silencing TLR4 and pharmacological inhibition of HO-1 in primary cultured cortical neurons. Cognitive dysfunction and decrease in cerebral blood flow in mice were observed 4 weeks after the occlusion. Our data further show that common carotid artery occlusion induced an increase in TLR4 and HO-1 protein levels. Although the administration of CoPP (10 mg/kg), HO-1 agonist, improved the cognitive dysfunction in a mice model of occlusion, western blot analysis in primary cultured cortical neurons showed that HO-1 was upregulated after lipopolysaccharide treatment; this was partially abolished by the TLR4 siRNA interference. The flow cytometry analysis showed that pharmacological inhibition of HO-1 by ZnPP (100 μM) further exaggerated lipopolysaccharide-induced neuronal cell death. Hence, stress-responsive HO-1 isoenzyme participates in TLR4-induced inflammation during chronic brain ischemia. The pharmacological manipulation of TLR4 or the HO-1 antioxidant defense pathway may represent a novel treatment strategy for neuronal protection in vascular dementia.

Chronic cerebral hypoperfusion enhances Tau hyperphosphorylation and reduces autophagy in Alzheimer's disease mice.

Cerebral hypoperfusion and impaired autophagy are two etiological factors that have been identified as being associated with the development of Alzheimer’s disease (AD). Nevertheless, the exact relationships among these pathological processes remain unknown. To elucidate the impact of cerebral hypoperfusion in AD, we created a unilateral common carotid artery occlusion (UCCAO) model by occluding the left common carotid artery in both young and old 3xTg-AD mice. Two months after occlusion, we found that ligation increases phospho-Tau (p-Tau) at Serine 199/202 in the hippocampus of 3-month-old AD mice, compared to sham-operated AD mice; whereas, there is no change in the wild type (WT) mice after ligation. Moreover, cerebral hypoperfusion led to significant increase of p-Tau in both the hippocampus and cortex of 16-month-old AD mice and WT mice. Notably, we did not detect any change in Aβ42 level in either young or old AD and WT mice after ligation. Interestingly, we observed a downregulation of LC3-II in the cortex of aged AD mice and WT mice after ligation. Our results suggest that elevated p-Tau and reduced autophagy are major cellular changes that are associated with hypoperfusion in AD. Therefore, targeting p-Tau and autophagy pathways may ameliorate hypoperfusion-induced brain damage in AD.

Homeostatic changes in neuronal network oscillations in response to continuous hypoperfusion in the mouse forebrain

Neuronal activity is highly sensitive to changes in oxygen tension. In this study, we examined the impact of hypoxic/ischemic conditions on neuronal ensemble activity patterns in the mouse brain using in vivo extracellular electrophysiological recordings from up to 8 sites in the thalamus, dorsal hippocampus, and neocortex, while cerebral hypoperfusion was induced by unilateral carotid artery occlusion. After a few minutes, the occlusion triggered a rapid change in the power of the local field oscillations. In the hippocampus, but not in the neocortex, the absolute power changes at all frequency ranges (relative to the baseline) became less pronounced with time, and no significant changes were observed 30min after the occlusion-induced hypoperfusion. We also tested whether continuous hypoperfusion induced by the occlusion for up to 1 week alters neuronal activity. In the hippocampus and the thalamus, the chronic occlusion did not lead to a reduction in the power of the local field oscillations. These results indicate that certain neuronal populations have the ability to maintain internal neurophysiological homeostasis against continuous hypoperfusion.

Abstract TMP110: Minocycline Reduces Hypoxia-mediated BBB Disruption by Protecting TJP Degradation and Promoting Angiogenesis in SHR/SP With Chronic White-matter Injury

Introduction: Our previous study indicated that blood-brain barrier (BBB) disruption occurred secondary to hypoxia-induced and MMP-mediated neuroinflammatory white matter (WM) damage in spontaneously hypertensive/stroke prone rats (SHR/SP). Tight junction proteins (TJPs) maintain the normal BBB functions. Here, we investigated the effects of hypoxia on TJP degradation and hypoxia-induced angiogenesis, and tested the effect of long-term minocycline treatment on the BBB integrity and repair. Methods: Male SHR/SPs at 12W (weeks) old were subjected to unilateral carotid artery occlusion (UCAO) and fed a Japanese permissive diet (JPD) for 4W. For the treatment study, the SHR/SP/UCAO/JPD were given minocycline (50 mg/kg in DMSO, i.p.) and the vehicle rats received DMSO from 12W to 20W of life. Results: Sham-operated SHR/SP with normal chow had abnormal TJPs in blood vessels (BVs) at 16W compared to Wistar; they showed a slight increase of BBB permeability and NG2-positive microglia in WM. In the UCAO/JDP group, by 4W, multimodal MRI (T2, ADC, FA, and ASL) showed that WM damage of varying degree reflected the extent of injury corresponding to variable BBB leakage by dynamic contrast-enhanced MRI and IgG staining. TJP levels (claudin-5, occludin, and ZO-1) in WM were significantly decreased. Angiogenesis in WM was detected with increased expression of Ki67 and NG2 in vascular endothelial cells and/or pericytes. UCAO/JPD typically causes the death of SHR-SP/JPD/UCAO rats after 4W. However, minocycline treatment extended survival to 9W after UCAO/JPD and significantly reduced lesion size and vascular damage. TJPs, VEGF-A, and GST-π (mature oligodendrocytes) were increased by minocycline at 8W compared to sham and vehicle. Minocycline also increased the expression of factors involved in angiogenesis and WM repair (Ki67, NG2, MMP-2, MMP-3) in vascular endothelial cells, pericytes, astrocytes, and oligodendrocytes compared to controls. Conclusions: Our results support the hypothesis that damage to the BVs by chronic hypertension and UCAO/JPD produces TJP degradation and increases BBB permeability. Minocycline treatment significantly protects WM from damage by preventing BBB disruption and enhances TJP formation and angiogenesis.