Animal Model Of Vascular Dementia Research Articles

The effect of acupuncture on oxidative stress in animal models of vascular dementia: a systematic review and meta-analysis

BackgroundGrowing evidence showed that acupuncture may improve cognitive function by reducing oxidative stress, key to the pathogenesis in vascular dementia (VaD), but this is yet to be systematically analysed. This study aimed to summarize and evaluate the effect of acupuncture on oxidative stress in animal models of VaD.MethodEight databases including PubMed, Embase, Web of Science, Cochrane library, CNKI, Wan Fang, CBM, and VIP were searched since their establishment until April 2023, for studies that reported the effect of acupuncture on oxidative stress in VaD animal models. Relevant literature was screened, and information was extracted by two reviewers. The primary outcomes were the levels of oxidative stress indicators. The methodological quality was assessed via the SYRCLE Risk of Bias Tool. Statistical analyses were performed using the RevMan and Stata software.ResultsIn total, 22 studies with 747 animals were included. The methodology of most studies had flaws or uncertainties. The meta-analysis indicated that, overall, acupuncture significantly reduced the expression of pro-oxidants including reactive oxygen species (standardized mean differences [SMDs] = -4.29, 95% confidence interval [CI]: -6.26, -2.31), malondialdehyde (SMD = -2.27, 95% CI: -3.07, -1.47), nitric oxide (SMD = -0.85, 95% CI: -1.50, -0.20), and nitric oxide synthase (SMD = -1.01, 95% CI: -1.69, -0.34) and enhanced the levels of anti-oxidants including super oxide dismutase (SMD = 2.80, 95% CI: 1.98, 3.61), glutathione peroxidase (SMD = 1.32, 95% CI: -0.11, 2.76), and catalase (SMD = 1.31, 95% CI: 0.05, 2.58) in VaD animal models. In subgroup analyses, acupuncture showed significant effects on most variables. Only partial modelling methods and treatment duration could interpret the heterogeneity of some outcomes.ConclusionAcupuncture may inhibit oxidative stress to improve cognitive deficits in animal models of VaD. Nevertheless, the methodological quality is unsatisfactory. More high-quality research with a rigorous design and further experimental researches and clinical trials are needed to confirm these findings.Systematic review registrationThis study was registered in PROSPERO (CRD42023411720).

Can acupuncture reverse oxidative stress and neuroinflammatory damage in animal models of vascular dementia?: A preclinical systematic review and meta-analysis.

Vascular dementia is a cognitive dysfunction syndrome caused by cerebral vascular factors such as ischemic stroke and hemorrhagic stroke. The effect of acupuncture on vascular dementia models is ambiguous, and there is controversy about whether acupuncture has a placebo effect. Oxidative stress and inflammation are the most essential mechanisms in preclinical studies of vascular dementia. However, there is no meta-analysis on the mechanism of vascular dementia in animal models. It is necessary to explore the efficacy of acupuncture through Meta-analysis of preclinical studies. Three major databases, PubMed, Embase and Web of Science (including medline), were searched in English until December 2022.The quality of the including literature was assessed using SYRCLE's risk of bias tool. Review Manager 5.3 was used to statistically summarize the included studies and the statistical effect values were expressed by SMD. The outcomes included: behavioral tests (escape latency, number of crossings), pathological sections (Nissl and TUNEL staining), oxidative stress markers (ROS, MDA, SOD, GSH-PX) and neuroinflammatory factors (TNF-α, IL-1β, IL-6). A total of 31 articles were included in this meta-analysis. The results showed that the escape latency, the contents of ROS, MDA, IL-1β, and IL-6 were decreased, and the contents of SOD and Nissl-positive neurons were increased in the acupuncture group as compared with the non-group (P < .05). Compared with the impaired group, the acupuncture group also had the above advantages (P < .05). In addition, the acupuncture group also increased the number of crossings and GSH-PX content, and decreased the expression of TUNEL-positive neurons and TNF-α (P < .05). From behavioral tests to slices and pathological markers in animal models of vascular dementia, it can be proved that acupuncture is effective in targeting oxidative stress and neuroinflammatory damage, and acupuncture is not a placebo effect. Nevertheless, attention needs to be paid to the gap between animal experiments and clinical applications.

Efficacy of Artemisia annua Linné in improving cognitive impairment in a chronic cerebral hypoperfusion-induced vascular dementia animal model

BackgroundVascular dementia (VaD) is the second most common type of dementia after Alzheimer's disease. Currently, no FDA-approved drugs are available for the treatment of VaD. Artemisia annua Linné (AA) is known to have antioxidant properties, but its effects and mechanisms of action on cognitive impairment are still unknown. PurposeIn this study, the improvement in cognitive impairment by AA in terms of protection against oxidative stress, neuroinflammation, and preservation of the integrity of the neurovascular unit (NVU) was assessed in an animal model of VaD with bilateral common carotid artery occlusion (BCCAO). MethodsEight-week-old male Wistar rats were allowed to adapt for four weeks, and BCCAO was induced at 12 weeks of age. The rats were randomly assigned into four groups, with seven rats in each group: sham group without BCCAO, VaD group that received oral administration of distilled water after BCCAO surgery, and two AA groups that received oral administration of 150 mg/kg or 750 mg/kg AA after BCCAO surgery for 8 weeks. Nine weeks after BCCAO surgery, the cognitive function of the rats was evaluated and accumulated oxidative stress was assessed by immunohistochemistry, immunofluorescence, and western blotting. Damage to the components of the NVU was evaluated, and sirtuin (Sirt) 1 and 2 expression and nuclear factor-erythrocyte 2-associated factor 2 (Nrf2)/Kelch-like ECH-associated protein1 (Keap1) activation were investigated to assess the reduction in cell signaling and antioxidant pathways. ResultsBCCAO-induced cerebral perfusion decreased memory function and induced neuroinflammation and oxidative stress. But AA treatment mitigated cognitive impairment and reduced neuroinflammation and oxidative stress caused by chronic cerebral hypoperfusion. AA extracts activated the Nrf2/Keap1/activating antioxidant response elements pathway and maintained Sirt 1 and 2, subsequently leading to the maintenance of neurons, improved construct of microvessels, increased platelet-derived growth factor receptor beta, and platelet-endothelial cell adhesion molecule-1 associated with the blood-brain barrier integrity. ConclusionAA is effective in alleviating BCCAO-induced cognitive decline and its administration may be a useful therapeutic approach for VaD.

Pharmaceutical and pharmacological studies of Shen Ma Yi Zhi granule for prevention of vascular dementia: A review.

Background: With dementia significantly increasing hospitalization and disability rates, worldwide aging of the population presents major challenges to public health. The majority of cases of cognitive dysfunction among the elderly, however, are characterized by an identifiable, preventable and treatable vascular component. As such, increased study of preventative methods in the context of dementia is warranted. Traditional Chinese medicine compounds have been reported to be neuroprotective and improve cognitive function via a variety of mechanisms. Shen Ma Yi Zhi granule (SMYZG) is one such collection of compounds that has been proven clinically effective. Pharmacological mechanisms of action, pharmacokinetics and clinical applications of SMYZG have been previously studied using a variety of vascular dementia animal models. SMYZG activates and regulates four main signaling pathways relevant to vascular dementia including the AMPK/PPARα/PGC-1α/UCP2, Nrf2/HO-1, HIF-1/VEGF/Notch, and VEGF/Flk-1/p8 MAPK pathways. Furthermore, SMYZG influences anti-inflammatory and anti-oxidant stress responses, reverses demyelination of brain white matter and vascular endothelium, regulates pericyte function and normalizes mitochondrial metabolism. Neuroprotective effects of SMYZG, as well as those promoting regeneration of vascular endothelium, have also been reported in studies of rat models of vascular dementia. Future research concerning SMYG is warranted for development of vascular dementia preventative management strategies.

The effect of electroacupuncture on the expression of Sirt1 and STAT3 in hippocampus and amygdala of vascular dementia rats.

Inflammation has long been considered a key factor in learning and memory impairment in patients with vascular dementia (VaD). Studies have confirmed that electroacupuncture can improve the learning and memory impairment of patients with VaD by reducing inflammation, but the specific mechanism of this effect is still unclear. The aim of this study was to explore the underlying mechanism of electroacupuncture in the treatment of VaD. The vascular dementia animal model was established by bilateral occlusion of common carotid arteries, and electroacupuncture treatment was given at Baihui (DU20) and Zusanli (ST36). The morris water maze (MWM) was used to test the spatial learning and memory ability of rats in each group. To evaluate the expression of Sirtuin1 (Sirt1), Signal transducer and activator of transcription 3 (STAT3) and inflammatory cytokine (IL-17) in the hippocampus and amygdala, immunohistochemistry and western blot were performed. The MWM test and Nissl staining results show that electroacupuncture can significantly improve the learning and memory impairment of VaD rats, and can repair damaged neurons. Immunohistochemistry and western blot results showed that electroacupuncture could enhance the expression of sirt1 in VaD rats, on the contrary, the expression of STAT3 and IL-17 was reduced due to electroacupuncture. The result suggests that electroacupuncture can suppress inflammation through the Sirt1/STAT3 pathway and improve spatial learning and memory in VaD rats.

Chronic Renin-Angiotensin System Activation Induced Neuroinflammation: Common Mechanisms Underlying Hypertension and Dementia?

Hypertension is a major risk factor for the pathogenesis of vascular dementia and Alzheimer's disease. Chronic activation of the renin-angiotensin system (RAS) contributes substantially to neuroinflammation. We propose that neuroinflammation arising from chronic RAS activation can initiate and potentiate the onset of hypertension and related dementia. Neuroinflammation induced by chronic activation of the RAS plays a key role in the pathogenesis of dementia. Increased levels of pro-inflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and transforming growth factor (TGF)-β have been reported in brain tissue of vascular dementia patients and animal models of vascular dementia induced by either angiotensin II infusion or transverse aortic coarctation. It is proposed that neuronal cell death and synaptic dysfunction induced by neuroinflammation lead to cognitive impairment in dementia. The neuroprotective RAS pathway, regulated by angiotensin-converting enzyme 2 (ACE2) which converts angiotensin II into angiotensin-(1-7), can attenuate hypertension and dementia. Furthermore, the use of anti-hypertensive medications in preventing dementia or cognitive decline in hypertensive patients and animal models of dementia have mostly been beneficial. Current evidence suggests a strong link between RAS induced neuroinflammation and the onset of hypertension and dementia, which warrants further investigation. Strategies to counteract an overactive RAS and enhance the neuroprotective arm of the RAS may help prevent or improve cognitive impairment associated with hypertension.

AIM2 inflammasome mediates apoptotic and pyroptotic death in the cerebellum following chronic hypoperfusion

Vascular dementia (VaD) is the second most common form of dementia and is caused by vascular pathologies resulting in chronic cerebral hypoperfusion (CCH)- induced brain injury, and ultimately cognitive impairment and memory loss. Several lines of evidence have demonstrated chronic inflammation may be involved in VaD disease progression. It is now recognized that a major contributor to cerebral and systemic chronic inflammation involves the activation of innate immune molecular complexes termed inflammasomes. Whilst previous studies on animal models of VaD have focused on the cortex, hippocampus and striatum, few studies have investigated the effect of CCH on the cerebellum. Emerging studies have found new roles of the cerebellum in cognition, based on its structural interconnectivity with other brain regions and clinical relevance in neuropsychological deficits. In the present study, we conducted our investigation on the cerebellum using a CCH mouse model of VaD following bilateral common carotid artery stenosis (BCAS). This study is the first to characterize an increased expression of inflammasome receptors, adaptor and effector proteins, markers of inflammasome activation, proinflammatory cytokines, and apoptotic and pyroptotic cell death proteins in the cerebellum following CCH. Furthermore, in AIM2 knockout mice, we observed attenuated inflammasome-mediated production of proinflammatory cytokines, apoptosis, and pyroptosis in the cerebellum following CCH. Collectively, our findings provide novel evidence that AIM2 inflammasome activation promotes apoptosis and pyroptosis in the cerebellum following chronic hypoperfusion in a mouse model of VaD.

Preservation of spatial memory and neuroprotection by the fatty acid amide hydrolase inhibitor URB597 in a rat model of vascular dementia.

BackgroundChronic cerebral hypoperfusion (CCH) is a major risk factor for vascular dementia (VaD). There are currently no broadly effective prevention or treatment strategies for VaD, but recent studies have reported promising results following vascular bypass surgery and pharmacomodulation of the brain endocannabinoid system (ECS). In this study, early effects of encephalomyosynangiosis (EMS) bypass surgery and augmented endocannabinoid signaling on CCH-induced cognitive dysfunction and neuronal damage were investigated.MethodsAn animal model of VaD was established by bilateral common carotid artery occlusion (BCCAO). Cannabinoid signaling was upregulated by treatment with the fatty acid amide hydrolase inhibitor URB597 (URB). Spatial learning and memory, cerebral blood flow (CBF), revascularization, brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling, and apoptosis were compared among Sham, BCCAO, BCCAO + EMS, BCCAO + URB, and BCCAO + URB + EMS groups. Spatial learning and memory were evaluated using the Morris water maze (MWM). The CBF in cortex and hippocampus was evaluated by 3-dimensional arterial spin labeling. The neovascularization was visualized by CD34 immunofluorescence staining, and BDNF-TrkB signaling protein expression levels were assessed by Western blotting.ResultsTreatment with URB597 but not EMS alone reversed the spatial learning and memory deficits induced by BCCAO. Neovascularization was enhanced after EMS surgery but not by URB597. Alternatively, there were no significant differences in CBF among treatment groups. Expression levels of BDNF and TrkB were significantly reduced by CCH compared to Sham treatment, and downregulation of both proteins was reversed by URB597 treatment but not EMS. BCCAO enhanced neuronal apoptosis, which was also reversed by URB597.ConclusionsAugmentation of endogenous cannabinoid signaling but not EMS protects against CCH-induced neurodegeneration and preserves spatial learning and memory, possibly by activating BDNF-TrkB signaling.

Donepezil down-regulates propionylation, 2-hydroxyisobutyrylation, butyrylation, succinylation, and crotonylation in the brain of bilateral common carotid artery occlusion-induced vascular dementia rats.

Vascular dementia (VaD), caused by stroke or small vessel disease, is the second-most common type of dementia after Alzheimer's disease (AD). Donepezil is an acetylcholinesterase inhibitor that is currently used in patients with mild to moderate AD, and has recently been shown to improve cognitive performance in patients with VaD. In this study, we evaluated the effects of donepezil on VaD, and investigated the underlying molecular mechanisms of action. VaD was established by ligation of the bilateral common carotid artery occlusion (BCCAO). Executive function was tested by the Morris water maze (MWM) test and the attentional set shifting task (ASST). Our results showed that donepezil improved executive dysfunction and cognitive flexibility in BCCAO rats. In addition, we showed that donepezil treatment decreased the level of Aβ1-42 in BCCAO rats by enzyme-linked immunosorbent assay. Post-translational modifications (PTMs) are known to be critical mechanisms in the regulation of various cellular processes. Furthermore, PTMs have been linked to the central nervous system, which highlights the importance of PTMs in neurodegenerative diseases. In this study, we used western blot analysis to identify several novel PTMs in the hippocampus of BCCAO rats that were treated with or without donepezil. The data revealed that lysine propionylation, 2-hydroxyisobutyrylation, butyrylation, succinylation, and crotonylation were elevated in the hippocampus of BCCAO rats when compared to sham rats. This increase was abolished by donepezil treatment. Taken together, we speculate that donepezil treatment improves cognitive function in our animal model of VaD, possibly by reducing aberrant acyl-PTMs.

Dl-3-n-butylphthalide promotes remyelination process in cerebral white matter in rats subjected to ischemic stroke

Remyelination has been widely noticed as an important repair mechanism triggered after a stroke-induced white matter injury, but it often fails due to the lack of recruitment of the oligodendrocyte progenitor cells (OPCs) to the demyelinated area and the inadequate differentiation of OPCs. Racemic dl-3-n-butylphthalide (dl-NBP) has been reported to improve the functional recovery in animal models of vascular dementia, Alzheimer’s disease (AD) and ischemic stroke. Dl-NBP (70 mg/kg) by oral gavage for two weeks from day 7 after a stroke was administered in the study, the treatment promoted differentiation and maturation of OPCs in perilesional white matter and enhanced the length of crossing corticospinal tract (CST) fibers into the denervated hemispheres. These effects could be linked to increased expression levels of brain-derived neurotrophic factor (BDNF) and the reduced expression of neurite outgrowth inhibitor (NogoA) in the perilesional area in dl-NBP group. However, dl-NBP did not increase the numbers of neuron/glia type 2 (NG2)-positive and oligodendrocyte lineage transcription factor 2 (Olig2)-positive cells in the subventricular zone. Our data highlight the effects of dl-NBP in the remyelination process and reveal the therapeutic potential of this approach in cerebral ischemia.

Effects of α-lipoic acid on chronic cerebrovascular hypoperfusion in an animal model of vascular dementia.

Given the aging population, the treatment of vascular dementia (VaD) is becoming increasingly important. The antioxidant α-lipoic acid (α-LA) protects against neurodegeneration in VaD, but the underlying mechanisms remain unclear. Hence, we aimed to identify the effects of α-LA on cognitive function following chronic cerebrovascular hypoperfusion in a VaD animal model. Mice were categorized into the sham, bilateral common carotid artery stenosis (BCAS), or BCAS + α-LA group. The BCAS + α-LA group was intraperitoneally injected (100 mg/kg) once daily with α-LA for 4 weeks after BCAS surgery, while the BCAS and sham groups were injected with saline. After the last injection, we examined cognitive function and exploration behavior using the Morris water maze. Mice brains were then harvested for Western blot analyses. The BCAS group, but not the BCAS + α-LA group, showed cognitive dysfunction in the Morris water maze. Apoptosis pathways involving poly (ADP-ribose) polymerase (PARP) cleavage, phosphorylated-mammalian target of rapamycin (p-mTOR), phosphorylated-3-phosphoinositide-dependent protein kinase-1, and phosphorylated-protein kinase B (p-AKT) were enhanced in the BCAS group than the α-LA group. The BCAS + α-LA group demonstrated less PARP cleavage and p-mTOR function than did the BCAS group. The activity of autophagy pathways involving LC3B was higher in the BCAS and BCAS + α-LA groups than the sham group, but there were no significant differences between the BCAS and BCAS + α-LA groups. In the BCAS rodent model, cognitive dysfunction and apoptosis mediated by the phosphatase and tensin homolog/AKT/mTOR pathway were observed in the hippocampus. However, acting on the mTOR pathway, α-LA improved cognitive function and led to hippocampal cell survival. Thus, α-LA may be useful for treating VaD.

Effect of Ghrelin on Memory Impairment in a Rat Model of Vascular Dementia

The purpose of this study was to identify the effect of ghrelin on memory impairment in a rat model of vascular dementia induced by chronic cerebral hypoperfusion. Randomized controlled groups and the posttest design were used. We established the representative animal model of vascular dementia caused by bilateral common carotid artery occlusion and administered 80 μg/kg ghrelin intraperitoneally for 4 weeks. First, behavioral studies were performed to evaluate spatial memory. Second, we used molecular biology techniques to determine whether ghrelin ameliorates the damage to the structure and function of the white matter and hippocampus, which are crucial to learning and memory. Ghrelin improved the spatial memory impairment in the Y-maze and Morris water maze test. In the white matter, demyelination and atrophy of the corpus callosum were significantly decreased in the ghrelin-treated group. In the hippocampus, ghrelin increased the length of hippocampal microvessels and reduced the microvessels pathology. Further, we confirmed angiogenesis enhancement through the fact that ghrelin treatment increased vascular endothelial growth factor (VEGF)-related protein levels, which are the most powerful mediators of angiogenesis in the hippocampus. We found that ghrelin affected the damaged myelin sheaths and microvessels by increasing angiogenesis, which then led to neuroprotection and improved memory function. We suggest that further studies continue to accumulate evidence of the effect of ghrelin. Further, we believe that the development of therapeutic interventions that increase ghrelin may contribute to memory improvement in patients with vascular dementia.

Chotosan ameliorates cognitive impairment and hippocampus neuronal loss in experimental vascular dementia via activating the Nrf2-mediated antioxidant pathway

Recent studies suggested that Chotosan has ameliorative effects on vascular dementia through antioxidative pathways. Nevertheless, no systematic pharmacological research was conducted to evaluate the contribution of nuclear factor-E2-related factor 2 (Nrf2), a crucial regulator of antioxidative system, on Chotosan-induced neuroprotection invascular dementia. The present study aimed to investigate the neuroprotective effect of Chotosan on vascular dementia and reveal the possible molecular mechanism involving Nrf2. We found that Chotosan treatment could ameliorate memory impairment and reduce neuron cell loss induced by common carotid artery occlusion surgery. Furthermore, Chotosan could significantly reverse reactive oxygen species production, neuronal apoptosis and microglia over-activation in hippocampus. In addition, Chotosan enhanced Nrf2 expression and its nuclear translocation as well as its downstream antioxidant protein expression, NAD(P)H/quinone oxidoreductase 1 and heme oxygenase-1. These findings suggest that Chotosan exert neuroprotection in an animal model of vascular dementia via activating Nrf2-mediated antioxidant pathway. Chotosan may serve as a potential candidate and promising Nrf2 activator for treating vascular dementia.

L-3-n-butylphthalide attenuates cognitive deficits in db/db diabetic mice.

Numerous epidemiological studies have shown that diabetes mellitus (DM) is associated with dementia and cognition decline. However, there is currently no effective treatment for diabetes-induced cognitive dysfunction. The neuroprotective effect of L-3-n-butylphthalide (L-NBP) has been demonstrated in vascular dementia animal models. The purpose of this study was to determine whether L-NBP can ameliorate cognitive deficits in db/db mice, a model of obesity and type 2 diabetes. The mice were administered with vehicle or L-NBP (120mg/kg) by gavage daily for 6weeks. Then, Morris water maze tasks were performed, and hippocampal LTP was recorded in vivo. Next, the synaptic structure of the CA1 hippocampus region was investigated via electron microscopy. Finally, the expression levels of MDA, SOD, 8-OHdG, and NADPH oxidase subunits gp91 and p67, as well as the expression of NF-κB p65, TNF-α, IL-1β and caspase-3 were measured by Western blot, RT-PCR and ELISA. Treatment with L-NBP significantly attenuated the learning and memory deficits in db/db mice. Concomitantly, L-NBP also increased hippocampus synaptic plasticity, characterized by an enhanced in vivo LTP, and suppressed oxidative stress, as indicated by increased SOD activity and decreased MDA, 8-OHdG, and NADPH oxidase subunits p67 and gp91. L-NBP also significantly decreased NF-κB p65, TNF-α, IL-1βand caspase-3 levels in the hippocampus. L-NBP significantly ameliorated cognitive decline in type 2 diabetic mice, and this effect was accompanied by an improvement in hippocampal plasticity and an amelioration of oxidative stress, inflammation and apoptosis cascades. Thus, L-NBP may be a promising therapeutic agent against DM-mediated cognitive dysfunction.

Effects of acupuncture on vascular dementia (VD) animal models: a systematic review and meta-analysis

BackgroundVascular dementia is the second most common type of dementia that causes cognitive dysfunction. Acupuncture, an ancient therapy, has been mentioned for the treatment of vascular dementia in previous studies. This study aimed to evaluate the effects of acupuncture in animal models of vascular dementia.MethodsExperimental animal studies of treating vascular dementia with acupuncture were gathered from Embase, PubMed and Ovid Medline (R) from the dates of the databases’ creation to December 2016. We adopted the CAMARADES 10-item checklist to evaluate the quality of the included studies. The Morris water maze test was considered as an outcome measure. The software Stata12.0 was used for the meta-analysis. Heterogeneity was examined using I2 statistics, and we conducted subgroup analyses to determine the causes of heterogeneity for escape latency and duration in original platform.ResultsSixteen studies involving 363 animals met the inclusion criteria. The included studies scored between 4 and 8 points, and the mean was 5.44. The results of the meta-analysis indicated remarkable differences with acupuncture on increasing the duration in the former platform quadrant both in EO models (SMD = 1.56, 95% CI: 1.02 ~ 2.11; p < 0.00001) and 2-VO models (SMD 4.29, 95% CI 3.23 ~ 5.35; p < 0.00001) compared with the control groups.ConclusionsAcupuncture may be effective in improving cognitive function in vascular dementia animal models. The mechanisms of acupuncture for vascular dementia are multiple such as anti-apoptosis, antioxidative stress reaction, and metabolism enhancing of glucose and oxygen.

Gadolinium presence, MRI hyperintensities, and glucose uptake in the hypoperfused rat brain after repeated administrations of gadodiamide

The discussed topic about gadolinium-based contrast agents (GBCA) safety has recently been revived due to the evidence of hyperintensities observed in the dentate nucleus (DN) and globus pallidus (GP) in the brain of patients with normal kidney function. Several preclinical studies have been conducted to understanding how the use of GBCAs can promote the gadolinium deposition in the brain. Here, we evaluate the impact of chronic cerebral hypoperfusion on gadolinium presence. T1 hyperintensities and BBB integrity were evaluated by MRI in chronically hypoperfused and healthy rats injected with either gadodiamide or hypertonic saline. Additionally, the assessment of glucose metabolism by PET imaging and the gadolinium content by ICP-MS was performed after the last MR scan. Chronically hypoperfused rats displayed a greater MRI T1w signal in the DCN and hippocampus compared to Sham-operated animals, suggesting gadolinium accumulation. Dynamic contrast-enhanced (DCE) MRI assessment of BBB permeability revealed loss of integrity (high Ktrans) after rat injury in the dentate nuclei and hippocampus. Ex vivo tissue analysis showed greater gadolinium retention in the cerebellum and subcortical regions, supporting the imaging finding. FDG-PET imaging of the cerebellum did not reveal abnormal uptake in the DCN after chronic cerebral hypoperfusion. Higher signal intensity followed by higher Gd concentration observed in DCN and hippocampus of animals subjected to cerebral injury can be associated with an increase in BBB permeability due to the applied vascular dementia animal model. Nonetheless, no glucose metabolism abnormalities were detected in chronically hypoperfused cerebellum.

Stepwise occlusion of the carotid arteries of the rat: MRI assessment of the effect of donepezil and hypoperfusion-induced brain atrophy and white matter microstructural changes.

Bilateral common carotid artery occlusion (BCCAo) in the rat is a widely used animal model of vascular dementia and a valuable tool for preclinical pharmacological drug testing, although the varying degrees of acute focal ischemic lesions it induces could interfere with its translational value. Recently, a modification to the BCCAo model, the stepwise occlusion of the two carotid arteries, has been introduced. To acquire objective translatable measures, we used longitudinal multimodal magnetic resonance imaging (MRI) to assess the effects of semi-chronic (8 days) donepezil treatment in this model, with half of the Wistar rats receiving the treatment one week after the stepwise BCCAo. With an ultrahigh field MRI, we measured high-resolution anatomy, diffusion tensor imaging, cerebral blood flow measurements and functional MRI in response to whisker stimulation, to evaluate both the structural and functional effects of the donepezil treatment and stepwise BCCAo up to 5 weeks post-occlusion. While no large ischemic lesions were detected, atrophy in the striatum and in the neocortex, along with widespread white matter microstructural changes, were found. Donepezil ameliorated the transient drop in the somatosensory BOLD response in distant cortical areas, as detected 2 weeks after the occlusion but the drug had no effect on the long term structural changes. Our results demonstrate a measurable functional MRI effect of the donepezil treatment and the importance of diffusion MRI and voxel based morphometry (VBM) analysis in the translational evaluation of the rat BCCAo model.

Effects of safflower yellow on beta-amyloid deposition and activation of astrocytes in the brain of APP/PS1 transgenic mice

Safflower yellow (SY), one of traditional Chinese medicine extracted from safflower, has been shown to have neuroprotective effects on animal models of vascular dementia and Alzheimer’s diseases (AD), by inhibiting oxidative injury, neuronal apoptosis and tau hyperphosphorylation. In this study, we investigated whether safflower yellow (SY) can improve cognitive function, decrease Amyloid β (Aβ) accumulation and overactivation of astrocytes in AD mouse model. We found that SY treatment significantly ameliorated the learning and memory deficits of APP/PS1 mice. By hematoxylin-eosin staining, we found that the neuronal loss and death in APP/PS1 mice was decreased by SY treatment. Immunohistochemical staining showed that SY treatment dramatically down-regulated Aβ1-42 deposition and glial fibrillary acidic protein (GFAP) level in APP/PS1 mice. Biochemical analysis also showed that SY treatment reduced soluble and insoluble Aβ1-42 level in the cortex and soluble Aβ1-42 level in the hippocampus of APP/PS1 mice. Moreover, we found that SY treatment decreased the expression of proteins related to generation of Aβ, and markedly increased expression of enzymes associated with clearance of Aβ in the brain of APP/PS1 mice. These results indicate that the SY can serve as a promising therapeutic approach for the treatment of AD.

A Mini-Review of the NADPH oxidases in Vascular Dementia: Correlation with NOXs and Risk Factors for VaD.

Oxidative stress (OS) is one of the factors that cause dementia conditions such as Alzheimer’s disease and vascular dementia (VaD). In the pathogenesis of VaD, OS is associated with risk factors that include increased age, hypertension, and stroke. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) are a molecular source of reactive oxygen species (ROS). According to recent studies, inhibition of NOX activity can reduce cognitive impairment in animal models of VaD. In this article, we review the evidence linking cognitive impairment with NOX-dependent OS, including the vascular NOX and non-vascular NOX systems, in VaD.

Pregnancy improves cognitive deficit and neuronal morphology atrophy in the prefrontal cortex and hippocampus of aging spontaneously hypertensive rats.

It is well known that the survival is higher in women compared to men and women have a better survival prognosis than men in some pathologies such as vascular dementia (VD). Our previous reports showed that the spontaneously hypertensive (SH) rat, an animal model of VD, exhibited dendritic atrophy of pyramidal neurons of the dorsal hippocampus (DH) and the prefrontal cortex (PFC) at 8 months of age. Cerebrolysin (CBL), a neurotrophic peptide mixture, reduces dendritic atrophy and improves the memory process in aged rats. Here, we investigated whether one pregnancy or/and CBL was capable of improving cognitive behavior and neuronal alterations in old female SH rats. Diastolic and systolic blood pressure were assessed before pregnancy (3 months old) and CBL administration (6 months old), and after CBL administration (12 months old). Immediately after of 6 months of CBL treatment, locomotor activity in novel environments and memory and learning by the Morris Water Maze test were evaluated. By the Golgi-Cox staining method, dendritic parameters were assessed in PFC and DH. Our results suggest that rats with one pregnancy showed better memory with an enhancement in dendritic length and dendritic spine density in the aforementioned regions.