Permanent Bilateral Carotid Artery Occlusion Research Articles

7, 8-dihydroxyflavone Ameliorates Cholinergic Dysfunction, Inflammation, Oxidative Stress, and Apoptosis in a Rat Model of Vascular Dementia.

Vascular dementia (VD) is a degenerative cerebrovascular disorder associated with progressive cognitive decline. Previous reports have shown that 7,8-dihydroxyflavone (7,8-DHF), a well-known TrkB agonist, effectively ameliorates cognitive deficits in several disease models. Therefore, this study investigated the protective effects of 7,8-DHF against 2-VO-induced VD.VD was established in rats using the permanent bilateral carotid arteries occlusion (two-vessel occlusion, 2-VO) model. 7,8-DHF (5, 10, and 20mg/kg) and Donepezil (10mg/kg) were administered for 4 weeks. Memory function was assessed by the novel objective recognition task (NOR) and Morris water maze (MWM) tests. Inflammatory (TNF-α, IL-1β, and NF-kβ), oxidative stress, and apoptotic (BAX, BCL-2, caspase-3) markers, along with the activity of choline acetylcholinesterase (AChE) was assessed. p-AKT, p-CREB, BDNF, and neurotransmitter (NT) (GLU, GABA, and ACh) levels were also analyzed in the hippocampus of 2-VO rats.Our results show that 7,8-DHF effectively improved memory performance and cholinergic dysfunction in 2-VO model rats. Furthermore, 7,8-DHF treatment also increased p-AKT, p-CREB, and BDNF levels, suppressed oxidative, inflammatory, and apoptotic markers, and restored altered NT levels in the hippocampus.These findings imply that 7, 8-DHF may act via multiple mechanisms and as such serve as a promising neuroprotective agent in the context of VD.

Arginine vasopressin attenuates dysfunction of hippocampal theta and gamma oscillations in chronic cerebral hypoperfusion via V1a receptor

Chronic cerebral hypoperfusion (CCH) is associated with cognitive decline in aging, Alzheimer's disease and vascular dementia. Neural oscillations and their interactions support brain communication and involve in cognitive function. Although arginine vasopressin (AVP) has been linked to spatial learning and memory, the effects of AVP on CCH in terms of the hippocampal neural network is unknown. Here we investigated the dynamics of neural oscillations in the hippocampus in a rat model of permanent bilateral carotid arteries occlusion (two-vessel occlusion, 2VO) under urethane-anesthesia. Hypertonic saline (5.3%) was injected intraperitoneally to induce the endogenous AVP, and SR49059 was used as V1a receptor (an AVP receptor) antagonist. The results showed that AVP partly changed CA3 Schaffer collateral (CA3-SC) power distribution in the rat model of 2VO via V1a receptor, increased theta synchrony between CA3-SC and CA1 areas, enhanced CA3-SC theta-middle gamma phase-phase coupling, and improved spatial learning and memory performance. Biochemical fractionation further confirmed the recovery effect on N-methyl-D-aspartate receptor subunit 2B (NR2B) and postsynaptic density protein 95 (PSD-95) surface expressions after hypertonic saline injection, suggesting a possible molecular mechanism in the hippocampus. The findings shed light on a functional role of endogenous AVP from a neural network perspective that AVP improves theta synchronization and accurate coordination of theta-gamma coupling probably through upregulating NR2B and PSD-95 expressions, and further promotes neural communication in the hippocampus to some extent. As a result, the impairment of spatial learning and memory induced by CCH is significantly alleviated.

A Rho-kinase inhibitor reverses learning and memory deficits in a Rat model of chronic cerebral ischemia by altering Bcl-2/Bax-NMDAR signaling in the cerebral cortex

The current study investigated whether a Rho-kinase inhibitor alleviated impairments in a rat model of chronic cerebral ischemia and examined the specific pathological mechanisms by which Rho-kinase impacts neuronal damage and cognitive dysfunction. Adult Sprague–Dawley rats underwent permanent bilateral carotid artery occlusion (BCAO) to establish our chronic cerebral ischemia model. Chronic Y27632 administration reversed the abnormal behaviors of BCAO-treated rats in the Morris water maze. We performed Western blot analyses of the apoptosis-related proteins Bcl-2 and Bax to examine the potential mechanism underlying the beneficial effects of Y27632 on cerebral ischemia and showed for the first time that Y27632 reversed the decrease in the Bcl-2/Bax ratio in BCAO model rats. Y27632 restored the depression of NR2A- and NR2B-containing N-methyl-d-aspartate receptors (NMDARs) in the cerebral cortex of BCAO model rats. We also investigated these effects on middle cerebral artery occlusion (MCAO) model rats and observed some differences between the two models. In summary, our data provide evidence supporting the hypothesis that Rho-kinase inhibitors exert neuroprotective effects on cerebral ischemia. The Bcl-2/Bax-NMDAR signaling pathway in the cerebral cortex may be responsible for the protective effects of the Rho-kinase inhibitor, and this pathway may represent a pharmacological target for curative clinical strategies.

Executive dysfunction and blockage of brain microvessels in a rat model of vascular cognitive impairment

Most research focuses on overt stroke caused by blockage of major blood vessels. Less attention has been paid to small vessel disease which gives rise to covert stroke that often leads to vascular cognitive impairment (VCI). One reason for this may be the relative lack of relevant animal models. Herein, we describe, a model of VCI induced in middle-aged Sprague-Dawley rats exposed to a diet high in saturated fats, salt and refined sugar (HFSS). In Experiment 1, rats were fed HFSS and subjected to a small mediodorsal (MD) thalamic stroke with or without concomitant permanent bilateral carotid artery occlusion. MD lesions produce significant executive dysfunction in an attention set-shift task (p = 0.012). In Experiment 2, rats were exposed to either HFSS or control diet and functional effects assessed. We found significant hypertension (p = 0.013), blockage of brain microvessels (p = 0.018) and white matter atrophy (p = 0.039) in HFSS diet animals. As in Experiment 1, profound, specific set-shifting executive dysfunction was noted (p = 0.003) following both small MD infarcts (0.332 mm3) and the HFSS diet. In summary, these data describe a middle-aged animal model of VCI that includes clinically relevant metabolic disturbances and small vessel disease and as such may be helpful in developing new cognitive therapies.

Arginine vasopressin ameliorates spatial learning impairments in chronic cerebral hypoperfusion via V1a receptor and autophagy signaling partially

Chronic cerebral hypoperfusion (CCH) is a major factor contributing to neurological disorders and cognitive decline. Autophagy activation is believed to provide both beneficial and detrimental roles during hypoxic/ischemic cellular injury. Although arginine vasopressin (AVP) has been strongly involved in many behaviors, especially in learning and memory, the effects of AVP on CCH and their molecular mechanisms remain unclear. Here, to investigate whether there was neuroprotective effects of AVP on CCH through V1a receptor (an AVP receptor) signaling, permanent bilateral carotid arteries occlusion (two vessel occlusion, 2VO) was used to establish a rat model of CCH, and hypertonic saline (5.3%) was injected intraperitoneally to induce the secretion of AVP. Results showed that hypertonic saline effectively alleviated spatial learning and memory deficit, enhanced synaptic plasticity of CA3-CA1 hippocampal synapses, upregulated N-methyl-d-aspartate receptor subunit 2B (NR2B) and postsynaptic density protein 95 (PSD-95) surface expressions, reduced oxidative stress and increased Nissl bodies in 2VO model rats. These phenomena were significantly decreased by V1a receptor antagonist SR49059. Interestingly, hypertonic saline also upregulated autophagy in the hippocampus of 2VO rats partly through V1a receptor. These findings imply that AVP has a beneficial role for the treatment of cognitive impairments partly through V1a receptor signaling in CCH, which is possibly related to improving synaptic plasticity by promoting NR2B and PSD-95 externalization and by enhancing autophagy.

Disrupted Iron Metabolism and Ensuing Oxidative Stress may Mediate Cognitive Dysfunction Induced by Chronic Cerebral Hypoperfusion

Iron is a highly reactive free radical catalyst that has been shown to exacerbate oxidative stress and cell death in many neurodegenerative diseases. In this study, we produced a rat model of chronic cerebral hypoperfusion (CCH) by permanent bilateral carotid artery occlusion to investigate markers of iron and oxidative stress associated with it. We found CCH led to significant spatial memory impairment in the Morris water maze at 4months after bilateral ligation. Iron deposition was observed in both the hippocampal CA1 area and cerebral cortex, and was correlated with localized neuronal death and increased lipid peroxidation. Western blotting revealed that the expression levels of ferritin heavy chain and the transferrin receptor were significantly elevated in hippocampus and cortex after CCH, whereas expression of iron regulatory protein 1 was significantly lower than in sham-treated rats. We conclude that localized neurodegeneration and concomitant cognitive impairments following CCH may result, at least in part, from local disruption of neuronal iron metabolism.

Mice Deficient in Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) are More Susceptible to Retinal Ischemic Injury In Vivo

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuroprotective peptide exerting protective effects in neuronal injuries. We have provided evidence that PACAP is neuroprotective in several models of retinal degeneration in vivo. Our previous studies showed that PACAP treatment ameliorated the damaging effects of chronic hypoperfusion modeled by permanent bilateral carotid artery occlusion. We have also demonstrated in earlier studies that treatment with PACAP antagonists further aggravates retinal lesions. It has been shown that PACAP deficient mice have larger infarct size in cerebral ischemia. The aim of this study was to compare the degree of retinal damage in wild type and PACAP deficient mice in ischemic retinal insult. Mice underwent 10min of bilateral carotid artery occlusion followed by 2-week reperfusion period. Retinas were then processed for histological analysis. It was found that PACAP deficient mice had significantly greater retinal damage, as shown by the thickness of the whole retina, the morphometric analysis of the individual retinal layers, and the cell numbers in the inner nuclear and ganglion cell layers. Exogenous PACAP administration could partially protect against retinal degeneration in PACAP deficient mice. These results clearly show that endogenous PACAP reacts as a stress-response peptide that is necessary for endogenous protection against different retinal insults.

Increased sensitivity of PACAP knockout mice to retinal ischemia

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuroprotective peptide exerting protective effects in neuronal injuries. PACAP is protective in several models of retinal degeneration in vivo. Our previous studies have shown that PACAP treatment ameliorates the damaging effects of chronic hypoperfusion modeled by permanent bilateral carotid artery occlusion. The aim of the present study was to compare the degree of retinal damage in wild type and PACAP deficient mice in ischemic retinal insult. Mice underwent 10 min of carotid artery occlusion followed by 2‐week reperfusion. Retinas were then processed for histological analysis. It was found that PACAP deficient mice had significantly greater retinal damage, as shown by the thickness of the whole retina and the morphometric analysis of the individual retinal layers, such as inner and outer plexiform and inner and outer nuclear layers. The retinal damage in PACAP knockout animals could be attenuated by exogenous intravitreal PACAP. These results clearly show that endogenous PACAP reacts as a stress‐response peptide that is necessary for endogenous protection against different neuronal insults.

Neurochemical investigation of neuronal cell types affected in ischemic retinopathy and in PACAP-mediated retinoprotection in rats

Event Abstract Back to Event Neurochemical investigation of neuronal cell types affected in ischemic retinopathy and in PACAP-mediated retinoprotection in rats Tamas Atlasz1*, Krisztina Szabadfi2, Peter Kiss3, Norbert Babai2, Mónika Griecs2, Zsombor Koszegi2, Andrea Tamás3, Dóra Reglodi3 and Róbert Gábriel2 1 University of Pécs, Department of Sportbiology, Hungary 2 University of Pécs, Department of Experimental Zoology and Neurobiology, Hungary 3 University of Pécs, Department of Anatomy, Hungary PACAP is neuroprotective in animal models of different brain pathologies, including cerebral ischemia and different types of retinal degenerations. We have previously shown that PACAP is protective against glutamate- and ischemia-induced retinal degeneration, where PACAP-treated retinas had more retained structure. We have also identified neurons protected by PACAP using immunohistochemistry in glutamate excitotoxicity. The aim of the present study was to investigate the cell type-specific effects of PACAP in ischemia-induced retinal degeneration. Rats underwent permanent bilateral carotid artery occlusion, and received intravitreal PACAP treatment (100pmol). Retinas were processed for immuncytochemistry after 2 weeks, for immunoreactivity for vesicular glutamate transporter 1, tyrosine hydroxylase, calretinin, calbindin, parvalbumin, PKC and vesicular GABA transporter. In control ischemic retinas, the cell bodies and processes in the inner nuclear, inner plexiform and ganglion cell layers displayed less immunoreactivity for all antisera. After PACAP treatment, staining of retinas was similar to that of normal eyes, with no significant alterations in immunoreactive patterns. These findings further support the neuroprotective function of PACAP in ischemia-induced retinal degeneration. Support: OTKA: K72592; F67830; 78480; T061766; Richter Foundation, GVOP-3.2.1, Bolyai Scholarship, ETT, Pécs University Medical School Research Grant 2009. Conference: IBRO International Workshop 2010, Pécs, Hungary, 21 Jan - 23 Jan, 2010. Presentation Type: Poster Presentation Topic: Disorders of the nervous system Citation: Atlasz T, Szabadfi K, Kiss P, Babai N, Griecs M, Koszegi Z, Tamás A, Reglodi D and Gábriel R (2010). Neurochemical investigation of neuronal cell types affected in ischemic retinopathy and in PACAP-mediated retinoprotection in rats. Front. Neurosci. Conference Abstract: IBRO International Workshop 2010. doi: 10.3389/conf.fnins.2010.10.00019 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 16 Apr 2010; Published Online: 16 Apr 2010. * Correspondence: Tamas Atlasz, University of Pécs, Department of Sportbiology, Pécs, Hungary, attam@gamma.ttk.pte.hu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Tamas Atlasz Krisztina Szabadfi Peter Kiss Norbert Babai Mónika Griecs Zsombor Koszegi Andrea Tamás Dóra Reglodi Róbert Gábriel Google Tamas Atlasz Krisztina Szabadfi Peter Kiss Norbert Babai Mónika Griecs Zsombor Koszegi Andrea Tamás Dóra Reglodi Róbert Gábriel Google Scholar Tamas Atlasz Krisztina Szabadfi Peter Kiss Norbert Babai Mónika Griecs Zsombor Koszegi Andrea Tamás Dóra Reglodi Róbert Gábriel PubMed Tamas Atlasz Krisztina Szabadfi Peter Kiss Norbert Babai Mónika Griecs Zsombor Koszegi Andrea Tamás Dóra Reglodi Róbert Gábriel Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Evolution of apparent diffusion coefficient and transverse relaxation time (T2) in the subchronic stage of global cerebral oligemia in different rat models

Using magnetic resonance imaging techniques, we examined the time course of apparent diffusion coefficient (ADC), T2, and T2* relaxation times in 1-year-old rats after different forms of cerebral oligemia had been induced by (1) transient systemic hypotension, (2) permanent bilateral carotid artery occlusion (BCCAO), and (3) combined hypotension and BCCAO over a time period of 14 days after the oligemic event. These groups were compared with a group of sham-operated adult rats (controls, 4) to rule out a drift of the parameters over time. The animals were examined in a 2.35 T scanner. ADC, T2, and T2* were measured in both hemispheres of rat parietotemporal cerebral cortex, thalamic nuclei, and hippocampus 1 day before as well as on days 1, 3, 7, and 14 after sham operation and in different models of oligemia, respectively. Hypotension alone had no significant effect on MRI parameters in rat brain. After BCCAO, an increase in T2* was observed. If a permanent BCCAO was combined with transient hypotension, however, 84% of 1-year-old animals died within 14 days after surgery. In the surviving animals, significant changes in ADC, T2, and T2* were observed in the hippocampus and parietotemporal cerebral cortex. ADC showed a decrease on day 1 after oligemia, and an increase on days 3, 7, and 14. The T2* and T2 values were markedly increased on days 7 and 14 after surgery. In conclusion, only severe oligemia combining BCCAO and hypotension induces significant changes in tissue integrity (as shown by ADC) and in blood oxygenation levels in the subchronic period, whereas no significant changes were detected if permanent BCCAO or transient hypotension was applied separately.

Rat models of dementia based on reductions in regional glucose metabolism, cerebral blood flow and cytochrome oxidase activity.

Three models are described in rats which attempt to mimic morphological and behavioural pathology of Alzheimer's dementia; intracerebroventricular injection of streptozotocin (STZ), permanent bilateral carotid artery occlusion (2VO) and brain mitochondrial cytochrome oxidase inhibition by sodium azide. Learning and memory are impaired within 4 weeks in all models. This probably involves a reduction in cortical and/or hippocampal cholinergic neurotransmission. STZ causes microglial activation and specific damage to myelinated tracts in the fornix through generation of oxidative stress, thereby disrupting connections between the septum and hippocampus. 2VO results in damage to myelin and CA1 cells in hippocampus and in abnormal processing of APP to beta-amyloid. It is not known if microglial activation and neuronal damage occur after sodium azide administration. Memory and learning can be improved in the STZ and 2VO models by estradiol, melatonin and cholinesterase inhibitors. Antioxidants and neuroprotective agents may also decrease memory deficits by preventing inflammation and neurodegeneration.

Bcl-2, Bax and Bcl-x expression following hypoxia-ischemia in the infant rat brain.

Severe hypoxic-ischemic cerebral damage was produced in 8-day-old rats following permanent bilateral carotid artery occlusion and 15 min of ischemia. Cellular damage consisted of early necrosis and appearance of cells with apoptotic-like morphology (karyorrhectic cells) and cells with granular chromatin degeneration in the cerebral cortex, hippocampus, thalamus, stratum and amygdala. Expression of Bcl-2, Bax and Bcl-x was examined in control and hypoxic-ischemic rats using immunohistochemistry and Western blotting. Members of the Bcl-2 family were expressed in the vast majority of, if not all, neurons in control pups. Bcl-2, Bax and Bcl-x immunoreactivity decreased in necrotic cells, but about 60% of cells with apoptotic-like morphology and cells with granular chromatin degeneration were stained with antibodies to Bcl-2, Bax or Bcl-x. Although the total number of stained cells decreased with time, recruitment of cells with apoptotic morphology and cells with granular chromatin degeneration was still found up to 48 h. Western blots showed a band at about p28 and p21, respectively for Bcl-2 and Bax in control and hypoxic-ischemic pups at 6, 12 and 24 h. Two bands at about p37 and p30, representing Bcl-xL and Bcl-xS, respectively, were found in samples stained with antibodies to Bcl-x. No gross changes in the intensity of these bands were observed in ischemic pups at 6, 12 and 24 h, except for a slight decrease in Bcl-2 at 24 h, and a slight and inconstant increase of the putative Bcl-xS at 12 h. These results suggest that Bcl-2, Bax, Bcl-xL and Bcl-xS do not play a leading role in the fate of damaged nerve cells following a severe hypoxic-ischemic insult of the developing brain.

Effects of buflomedil on survival rate, local cerebral blood flow and glucose utilization after cerebral ischemia in spontaneously hypertensive rats

Cerebral protective effects of oral Buflomedil administration for 7 days were studied in spontaneously hypertensive rats (SHR). After permanent bilateral carotid artery occlusion (BCAO), the survival rates at 24 hr were 38% and 44% in groups treated with Buflomedil at the doses of 30 mg/kg (n = 16) and 90 mg/kg (n = 15), respectively, which were significantly higher than that in the control group (orally given saline for 7 days), 6%. In rats that survived and given Buflomedil, carbon filling of the brain after BCAO was extended to the territories of the internal carotid artery, while it was restricted to the brainstem and cerebellum in rats died within 3 hr and given either saline or Buflomedil. Local cerebral blood flow (LCBF), monitored by [14C]-Iodoantipyrine autoradiography, was determined at 3 hr after the start of BCAO or at 2 hr after reperfusion in rats orally given either saline or Buflomedil 30 mg/kg for 7 days. Local cerebral glucose utilization (LCGU), monitored by [14C]-Deoxyglucose autoradiography, was determined at 2 hr after reperfusion. At 3 hr after the start of BCAO, the LCBF in the Buflomedil group was higher by 71-128% in the cerebral cortex, 61-150% in the amygdala, caudate-putamen, nucleous accumbens and globus pallidus, and 82% in the internal capsule. At 2 hr after reperfusion, LCBF did not differ between groups, but LCGU in the Buflomedil group was significantly higher by 26-49% in the cerebral cortex, cochlear nuclei and vestibular nuclei than that in the control group. From these results, it is concluded that Buflomedil improved survival rate after permanent BCAO and have beneficial effect on local cerebral blood flow distribution after BCAO in SHR.