Common Carotid Artery Occlusion Research Articles

Neuroprotective Potential of Indian Propolis and in Combination with Curcumin against Bilateral Common Carotid Artery Occlusion Induced Vascular Dementia in Rats

Vascular dementia (VaD) is associated with chronic brain ischemia and gradual memory loss which is increasing gradually but limited treatments are available as therapeutic moieties to combat the VaD. Hence in this study Indian propolis alone or in combination with curcumin was explored as a treatment modality to alleviate the VaD. VaD model was induced by bilateral common carotid artery occlusion (BCCAO). Indian propolis (200 mg/kg), curcumin (200 mg/kg) individually, and the combination of Indian propolis (100 mg/kg) with curcumin (100 mg/kg) were administered in BCCAO model followed by an estimation of behavioral (neurological score, hanging and open field test) and biochemical parameters (reduced glutathione, catalase, malondialdehyde, and acetylcholine esterase). In this study it was found that there were no changes in the locomotor activity while the neurological score was reduced and the hanging time was increased in the drug treated group which clearly depicts the neuroprotective potential of curcumin, Indian propolis individually and the combination of Indian propolis with curcumin. The combination of Indian propolis with curcumin was much better in terms of neuroprotective activity than Indian propolis and curcumin treated group as depicted by the results of behavioural and biochemical parameters. Moreover, haematoxylin and eosin (H and E) staining was performed, and was found that a combination of Indian propolis(100 mg/kg) with curcumin (100 mg/kg) attenuated better histological alterations of the hippocampus in BCCAO model group than in other treated groups. Hence these findings provided that Indian propolis in combination with curcumin has great potential as a neuroprotective agent on the cognitive deficits of VaD rats.

Preclinical Evaluation of Neuroprotective Activity of Piper nigrum L. in Cerebral Ischemic Reperfusion Induced Oxidative Stress

Introduction: Stroke is a potentially fatal condition that is defined by the fast development of clinical symptoms of ischemia. Numerous flavonoids have been demonstrated in animal models to ameliorate brain ischemia-reperfusion damage. Piperine is a flavonoid derived from Piper nigrum L. that exhibits a variety of pharmacological effects. The purpose of this research was to determine if Piper nigrum L. has a protective effect against the brain damage caused by bilateral common carotid artery occlusion (BCCAO) in rats. Materials and Methods: The animal study was certified by Institutional Animal Ethics Committee (IAEC) under research project no. RKCP/COI/RP/12/28. Numerous parameters were evaluated to ascertain the extent of oxidative stress and eventual protection of Piper nigrumL. including glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), lipid peroxidation (LPO), brain protein, and calcium levels in brain homogenate. The preventive effect of P. nigrum was evaluated and compared with quercetin as a standard using histopathology and the region of cerebral infarction. Results: In our research, we observed a substantial rise in superoxide dismutase (SOD), catalase, glutathione, and brain protein levels and a fall in lipid peroxidation and calcium levels in the P. nigrum and quercetin treated groups with the level of significance (p value) less than 0.05, confirming the protective effect against brain injury. Additionally, P. nigrum was shown to provide less protection compared to quercetin. Conclusion: As a result of these data, we hypothesise that P. nigrummay have a considerable neuroprotective effect in the brain against ischemic/ reperfusion-induced oxidative damage.

Retinal Oxygen Delivery and Metabolism Response to Hyperoxia During Bilateral Common Carotid Artery Occlusion in Rats.

PurposeThe purpose of the current study was to test the hypothesis that responses of total retinal blood flow (TRBF), inner retinal oxygen delivery (DO2), metabolism (MO2), and extraction fraction (OEF) to hyperoxia are higher after minutes of bilateral common carotid artery occlusion (BCCAO) as compared to days of BCCAO.MethodsTwenty-eight rats were subjected to BCCAO for 30 minutes (n = 12), 1 day (n = 8), or 3 days (n = 8). Eight of the 12 rats were also evaluated at baseline, prior to BCCAO. During room air breathing (RA) and 100% O2 inspiration (hyperoxia), blood flow and phosphorescence lifetime imaging were performed to measure TRBF and vascular O2 contents, respectively. DO2, MO2, and OEF were calculated from these measurements.ResultsAfter 30 minutes or 3 days of BCCAO, TRBF did not differ between RA and hyperoxia conditions (P ≥ 0.14) but decreased under hyperoxia after 1 day (P = 0.01). Compared to RA, DO2 and MO2 were increased under hyperoxia after 30 minutes of BCCAO (P ≤ 0.02). Additionally, MO2 was decreased under hyperoxia after 1 day of BCCAO (P = 0.04). OEF was decreased under hyperoxia compared to RA (P < 0.001). Under hyperoxia, TRBF and DO2 were reduced after all BCCAO durations compared to baseline (P ≤ 0.04), whereas MO2 did not differ from baseline after 30 minutes of BCCAO (P = 1.00).ConclusionsThe findings indicate that hyperoxia introduced minutes after ischemia can reduce DO2 impairments and potentially return MO2 to approximately normal values. This information contributes to the knowledge of the effect of supplemental oxygen intervention on TRBF, DO2, MO2, and OEF outcomes after variable durations of ischemia.

P38 MAPK Endogenous Inhibition Improves Neurological Deficits in Global Cerebral Ischemia/Reperfusion Mice.

Cerebral ischemia/reperfusion (I/R) injury is a complex pathophysiological process that can lead to neurological function damage and the formation of cerebral infarction. The p38 MAPK pathway has attracted considerable attention in cerebral I/R injury (IRI), but little research has been carried out on its direct role in vivo. In this study, to observe the effects of p38 MAPK endogenous inhibition on cerebral IRI, p38 heterozygous knockdown (p38KI/+) mice were used. We hypothesized that p38 signaling might be involved in I/R injury and neurological damage reduction and that neurological behavioral deficits improve when p38 MAPK is inhibited. First, we examined the neurological damage and neurological behavioral deficit effects of I/R injury in WT mice. Cerebral I/R injury was induced by the bilateral common carotid artery occlusion (BCCAO) method. The cerebral infarction area and volume were assessed and analyzed by 2,3,5-triphenyltetrazolium chloride (TTC) staining. p38 MAPK and caspase-3 were detected by western blotting. Neuronal apoptosis was measured using TUNEL staining. Neurological deficits were detected by behavioral testing. Furthermore, to assess whether these neuroprotective effects occurred when p38 MAPK was inhibited, p38 heterozygous knockdown (p38KI/+) mice were used. We found that p38 MAPK endogenous inhibition rescued hippocampal cell apoptosis, reduced ischemic penumbra, and improved neurological behavioral deficits. These findings showed that p38 MAPK endogenous inhibition had a neuroprotective effect on IRI and that p38 MAPK may be a potential therapeutic target for cerebral IRI.

Single-stage repair for ascending aortic aneurysm, artery stenosis and occlusion of neck vessels caused by Takayasu arteritis

Takayasu arteritis results in a variety of vascular symptoms, and there are some cases in which progressive vascular lesions require surgical intervention. We present a case with ascending aortic aneurysm, right common carotid artery stenosis, left common carotid artery occlusion and left subclavian artery stenosis caused by Takayasu arteritis that was successfully treated with total arch replacement and ascending aorta to right internal carotid artery bypass.

Depressive-like behaviors induced by chronic cerebral hypoperfusion associate with a dynamic change of GABAB1/B2 receptors expression in hippocampal CA1 region

Cerebral ischemia could induce depressive-like behaviors; however, the alteration of gamma-aminobutyric acid receptors type B (GABAB) receptors in these pathological processes has not been extensively investigated. The aim of the current study was to document the behavioral change and the alteration of GABAB receptors in chronic cerebral hypoperfusion. The permanent occlusion of the bilateral common carotid arteries (two-vessel occlusion, 2VO) was performed to induce chronic cerebral ischemia (CCH). The depressive-like behaviors were evaluated with sucrose preference test, novelty suppress feeding test as well as forced swim test at 4, 8, and 12 weeks after the 2VO surgery. The total, surface and intracellular expressions of GABAB subunit 1 (GABAB1) and subunit 2 (GABAB2) in hippocampal CA1 were quantified by western blot. The depressive-like behaviors were observed in rats suffered from 4, 8, and 12 weeks 2VO in sucrose preference test, novelty suppress feeding test and forced swim test. In addition, the surface and total expression of GABAB1 in CA1 was reduced at 4 weeks after 2VO rather than 8 or 12 weeks. While the surface and total expression of GABAB2 in CA1 was decreased throughout the ischemia timeline (4, 8, and 12 weeks). Taken together, our findings suggested the potential roles of GABAB1 and GABAB2 subunits involved in depressive-like behaviors caused by chronic cerebral hypoperfusion.

Metformin, Rapamycin, or Nicotinamide Mononucleotide Pretreatment Attenuate Cognitive Impairment After Cerebral Hypoperfusion by Inhibiting Microglial Phagocytosis.

Vascular cognitive impairment (VCI) is the second leading form of dementia after Alzheimer's disease (AD) plaguing the elder population. Despite the enormous prevalence of VCI, the biological basis of this disease has been much less well-studied than that of AD, with no specific therapy currently existing to prevent or treat VCI. As VCI mainly occurs in the elderly, the role of anti-aging drugs including metformin, rapamycin, and nicotinamide mono nucleotide (NMN), and the underlying mechanism remain uncertain. Here, we examined the role of metformin, rapamycin, and NMN in cognitive function, white matter integrity, microglial response, and phagocytosis in a rat model of VCI by bilateral common carotid artery occlusion (BCCAO). BCCAO-induced chronic cerebral hypoperfusion could cause spatial working memory deficits and white matter lesions (WMLs), along with increasing microglial activation and phagocytosis compared to sham-operated rats. We found the cognitive impairment was significantly improved in BCCAO rats pretreated with these three drugs for 14 days before BCCAO compared with the vehicle group by the analysis of the Morris water maze and new object recognition tests. Pretreatment of metformin, rapamycin, or NMN also increased myelin basic protein (MBP, a marker for myelin) expression and reduced SMI32 (a marker for demyelinated axons) intensity and SMI32/MBP ratio compared with the vehicle group, suggesting that these drugs could ameliorate BCCAO-induced WMLs. The findings were confirmed by Luxol fast blue (LFB) stain, which is designed for staining myelin/myelinated axons. We further found that pretreatment of metformin, rapamycin, or NMN reduced microglial activation and the number of M1 microglia, but increased the number of M2 microglia compared to the vehicle group. Importantly, the number of MBP+/Iba1+/CD68+ microglia was significantly reduced in the BCCAO rats pretreated with these three drugs compared with the vehicle group, suggesting that these drugs suppress microglial phagocytosis. No significant difference was found between the groups pretreated with metformin, rapamycin, or NMN. Our data suggest that metformin, rapamycin, or NMN could protect or attenuate cognitive impairment and WMLs by modifying microglial polarization and inhibiting phagocytosis. The findings may open a new avenue for VCI treatment.

Shengyu Decoction treating vascular cognitive impairment by promoting AKT/HIF-1α/VEGF related cerebrovascular generation and ameliorating MAPK/NF-κB mediated neuroinflammation

Ethnopharmacological relevanceShengyu Decoction (SYD), a classical Chinese medicine formula, is good at nourishing blood, promoting blood circulation, and soothe the nerves. SYD can improve cognitive ability. This decoction is suitable for treating vascular cognitive impairment (VCI). however, its active ingredients and possible mechanism have not been investigated. Aim of the studyThis study was conducted to observe the effects of SYD on improving the cognitive abilities of rats with VCI, to explore its active ingredients and mechanism. Materials and methodsThe rats with VCI model were established by bilateral common carotid artery occlusion (BCCAO), and the effects of SYD (5, 2.5 g/kg) on the cognitive abilities of VCI rats were evaluated using the Morris water maze (MWM) and neurological assessment. The pathological changes of hippocampal CA1 were observed by H &E and Nissl staining. The effect of SYD on cerebral blood flow (CBF) was evaluated by Laser Speckle Contrast Imager. The expression of CD31 in the cerebral cortex was measured by immunofluorescence (IF) to evaluate the number of cerebral micro vessels. The levels of IL-6, IL-1β, and TNF-α in the hippocampus were determined using an ELISA kit, and the active components in the plasma and brain tissues of rats after SYD administration were analyzed using UPLC-Q-TOF-MS/MS. The interaction network of the compound-target pathway was established using the SWISS Target, GO, and DAVID databases. The expression of AKT/HIF-1α/VEGF and p38 MAPK signaling pathway in the brain tissues was determined using western blotting (WB). ResultsSYD (2.5, 5 g/kg) significantly improved the cognitive abilities of VCI rats in the MWM and neurological assessment. H&E and Nissl staining showed that SYD significantly ameliorated the pathological hippocampal CA1 area and increased the number of Nissl bodies. The Laser Speckle Contrast Imager showed that the cortical CBF of VCI rats in the SYD group was significantly increased, and the IF results showed that CD31 expression was significantly increased in the SYD group. The ELISA results showed that the contents of IL-6, IL-1β, and TNF-α in SYD were significantly reduced. A total of 29 compounds were found in the plasma and brain tissues of the rats treated with SYD. Network pharmacology revealed 99 targets for the treatment of VCI. Pathway enrichment analysis showed that the HIF-1 and MAPK signaling pathways might be important for SYD to ameliorate VCI. WB showed that the expressions of AKT, HIF-1α, and VEGF in the brain tissues of rats were significantly increased; in addition, NF-κB and p38 MAPK were significantly reduced in the SYD group. ConclusionSYD can improve the cognitive abilities of VCI rats. The mechanism of action of its active ingredients improves cognitive impairment by affecting the AKT/HIF-1α/VEGF and p38 MAPK/NF-κB signaling pathways, promoting cerebrovascular generation, and ameliorating neuroinflammation.

Berberine protects against chronic cerebral hypoperfusion-induced cognitive impairment and hippocampal damage via regulation of the ERK/Nrf2 pathway

Vascular cognitive impairment caused by chronic cerebral hypoperfusion (CCH) seriously affects the quality of life of elderly patients and places a great burden on society and family. With the development of traditional Chinese medicine (TCM), TCM approaches to the prevention and treatment of senile ischemic cerebrovascular disease has received increasing attention. In this study, rats with bilateral common carotid artery occlusion (BCCAO) were treated with berberine (BBR). Their learning and memory function, neuronal injury and repair, the extracellular regulatory protein kinase (ERK)/nuclear factor-E2-related factor 2 (Nrf2) signaling pathway, and impairment and improvement of the blood–brain barrier (BBB) were evaluated. This study found that BBR can alleviate the pathological injury to the brain, reduce neuronal loss and promote neuronal cell survival after CCH by interfering with the ERK/Nrf2 signaling pathway. BBR can reduce BBB injury in CCH rats by inhibiting the expression of VEGF-A and MMP-9 in plasma, which reveals a protective effect of BBR on vascular cognitive impairment. This study provides a new research direction for BBR in the treatment of ischemic cerebrovascular disease.

Hemodynamic changes and neuronal damage detected by 9.4 T MRI in rats with chronic cerebral ischemia and cognitive impairment

IntroductionThe bilateral common carotid artery occlusion (BCCAO) rat model is an ideal animal model for simulating the pathology of chronic brain hypoperfusion in humans. However, dynamic changes in neuronal activity, cellular edema, and neuronal structural integrity in vivo after BCCAO have rarely been reported. The purpose of this study is to use a 9.4 T MRI to explore the pathophysiological mechanisms of vascular dementia.Materials and MethodsTwelve Sprague–Dawley (SD) rats were randomly divided into two groups: the sham group and the model group (n = 6 for each group). Rats were subjected to MRI using T2*WI, diffusion tensor imaging (DTI), and DWI sequences by MRI at the following six time points: presurgery and 6 h, 3 days, 7 days, 21 days, and 28 days postsurgery. Then, the T2*, fractional anisotropy (FA), and average apparent diffusion coefficient (ADC) values were measured in the bilateral cortices and hippocampi. After MRI scanning, all rats in both groups were subjected to the Y‐maze test, novel object recognition test, and open‐field test to assess their learning, memory, cognition, and locomotor activity.ResultsThe T2*, FA, and ADC values in the cerebral cortex and hippocampus decreased sharply at 6 h after BCCAO in the model group compared with those of the sham group. By Day 28, the T2* and ADC values gradually increased to close to those in the sham group, but the FA values changed little, and the rats in the model group had worse learning, memory, and cognition and less locomotor activity than the rats in the sham group.ConclusionsThe BCCAO is an ideal rat model for studying the pathophysiological mechanisms of vascular dementia.

Alamandine Induces Neuroprotection in Ischemic Stroke Models.

Stroke, a leading cause of mortality and disability, characterized by neuronal death, can be induced by a reduction or interruption of blood flow. In this study, the role of Alamandine, a new peptide of the renin-angiotensin system, was evaluated in in-vitro and in-vivo brain ischemia models. In the in-vitro model, hippocampal slices from male C57/Bl6 mice were placed in a glucose-free aCSF solution and bubbled with 95% N2 and 5% CO2 to mimic brain ischemia. An Alamandine concentration-response curve was generated to evaluate cell damage, glutamatergic excitotoxicity, and cell death. In the in-vivo model, cerebral ischemia/ reperfusion was induced by bilateral occlusion of common carotid arteries (BCCAo-untreated) in SD rats. An intracerebroventricular injection of Alamandine was given 20-30 min before BCCAo. Animals were subjected to neurological tests 24 h and 72 h after BCCAo. Cytokine levels, oxidative stress markers, and immunofluorescence were assessed in the brain 72 h after BCCAo. Alamandine was able to protect brain slices from cellular damage, excitotoxicity and cell death. When the Alamandine receptor was blocked, protective effects were lost. ICV injection of Alamandine attenuated neurological deficits of animals subjected to BCCAo and reduced the number of apoptotic neurons/cells. Furthermore, Alamandine induced anti-inflammatory effects in BCCAo animals as shown by reductions in TNFα, IL- 1β, IL-6, and antioxidant effects through attenuation of the decreased SOD, catalase, and GSH activities in the brain. This study showed, for the first time, a neuroprotective role for Alamandine in different ischemic stroke models.

Takayasu arteritis with congestive heart failure in 26-year-old male: a case report

BackgroundTakayasu arteritis (TA) is included in large vessel vasculitis with unknown aetiopathogenesis. TA is one of the rare diseases with a predilection for young women. The diagnosis of TA is difficult due to variation in clinical presentations and non-specific initial symptoms. This case demonstrates rare TA in a young male with congestive heart failure as the predominant manifestation.Case presentationWe report a 26-year-old male presented with severe dyspnea, palpitation, orthopnea, paroxysmal nocturnal dyspnea, and claudication in the left arm. Four limbs blood pressure discrepancy was present. Chest X-ray showed cardiomegaly with calcification aortic arch and pulmonary edema. Echocardiography revealed that left ventricular ejection fraction decreased with severe aortic and mitral valve regurgitation. Computed tomography angiography showed stenosis of the left common carotid artery and total occlusion of the left subclavian artery with collateral artery. There was vascular thickness and calcification from the peri-aortic valve, ascending aorta, aortic arch, and thoracic descending aorta until abdominal aorta with high-grade stenosis on the inferior side of the renal artery branching accompanied by a post-stenotic dilatation.ConclusionsThis patient’s heart failure was precipitated by secondary hypertension and aortic regurgitation caused by vasculitis of TA. In general, there is no difference in the management of congestive heart failure in patients with TA. Optimized pharmacology therapy with combination steroid and methotrexate successfully inducing remission of TA after 3-months follow-up.

Prophylactic Zinc Administration Combined with Swimming Exercise Prevents Cognitive-Emotional Disturbances and Tissue Injury following a Transient Hypoxic-Ischemic Insult in the Rat.

Exercise performance and zinc administration individually yield a protective effect on various neurodegenerative models, including ischemic brain injury. Therefore, this work was aimed at evaluating the combined effect of subacute prophylactic zinc administration and swimming exercise in a transient cerebral ischemia model. The prophylactic zinc administration (2.5 mg/kg of body weight) was provided every 24 h for four days before a 30 min common carotid artery occlusion (CCAO), and 24 h after reperfusion, the rats were subjected to swimming exercise in the Morris Water Maze (MWM). Learning was evaluated daily for five days, and memory on day 12 postreperfusion; anxiety or depression-like behavior was measured by the elevated plus maze and the motor activity by open-field test. Nitrites, lipid peroxidation, and the activity of superoxide dismutase (SOD) and catalase (CAT) were assessed in the temporoparietal cortex and hippocampus. The three nitric oxide (NO) synthase isoforms, chemokines, and their receptor levels were measured by ELISA. Nissl staining evaluated hippocampus cytoarchitecture and Iba-1 immunohistochemistry activated the microglia. Swimming exercise alone could not prevent ischemic damage but, combined with prophylactic zinc administration, reversed the cognitive deficit, decreased NOS and chemokine levels, prevented tissue damage, and increased Iba-1 (+) cell number. These results suggest that the subacute prophylactic zinc administration combined with swimming exercise, but not the individual treatment, prevents the ischemic damage on day 12 postreperfusion in the transient ischemia model.

Neuroprotective Effects of Theobromine in permanent bilateral common carotid artery occlusion rat model of cerebral hypoperfusion.

Cerebral hypoperfusion (CH) is a common underlying mechanism of dementia disorders linked to aberrations in the neurovascular unit. Hemodynamic disturbances adversely affect cellular energy homeostasis that triggers a sequence of events leading to irrevocable damage to the brain and neurobehavioral discrepancies. Theobromine is a common ingredient of many natural foods consumed by a large population worldwide. Theobromine has shown health benefits in several studies, attributed to regulation of calcium homeostasis, phosphodiesterase, neurotransmission, and neurotrophins. The current study evaluated the neuroprotective potential of theobromine against CH in the permanent bilateral common carotid artery occlusion (BCCAO) prototype. Wistar rats were distributed in Sham-operated (S), S + T100, CH, CH + T50, and CH + T100 groups. Animals received permanent BCCAO or Sham treatment on day 1. Theobromine (50, 100mg/kg) was given orally in animals subjected to BCCAO for 14 days daily. CH caused neurological deficits (12-point scale), motor dysfunction, and memory impairment in rats. Treatment with theobromine significantly attenuated neurological deficits and improved sensorimotor functions and memory in rats with CH. In biochemistry investigation of the entire brain, findings disclosed reduction in brain oxidative stress, inflammatory intermediaries (tumor necrosis factor-α, interleukin-1β and - 6, nuclear factor-κB), markers of cell demise (lactate dehydrogenase, caspase-3), acetylcholinesterase activity, and improvement in γ-aminobutyric acid quantity in rats that were given theobromine for 14 days daily after CH. Histopathological analysis substantiated attenuation of neurodegenerative changes by theobromine. The findings of this study indicated that theobromine could improve neurological scores, sensorimotor abilities, and memory in CH prototype.

Endovascular Intervention in a Narrowing Vessel of the Left Vertebral Artery with Bilateral Common Carotid Artery Occlusion and Aneurysm Rupture and Hemorrhage in the V4 Segment of the Right Vertebral Artery.

In this study, a case of bilateral common carotid artery occlusion and aneurysm in the V4 segment of the right vertebral artery with constriction of the left vertebral artery is presented. By improving digital subtraction angiography, an elderly female patient with subarachnoid haemorrhage (SAH) was diagnosed with a V4 segment of right vertebral artery aneurysm, a microaneurysm at the beginning of basilar aneurysms, bilateral common carotid artery occlusion, and narrowing vessel of left vertebral artery (DSA). Through the compensation of the basilar artery, the bilateral vertebral arteries provide intracranial and extracranial blood. Because the vertebral artery is narrowed, the right vertebral artery has priority in intracranial and extracranial blood delivery. Many members of the patient's immediate family have vasculitis, which has yet to be proven by appropriate laboratory testing but is thought to be the major cause of big artery occlusion. After cerebral angiography, the major source of this subarachnoid haemorrhage was determined to be a V4 segment of right vertebral artery aneurysm. Endovascular stent-assisted coil embolization was used to treat a V4 section of the right vertebral artery aneurysm. Because the basilar aneurysm was distal to the artery, interventional embolization was difficult to do, and it was not the major cause of the subarachnoid haemorrhage, the patient was advised to have follow-up surveillance, and she recovered well following the procedure. The combination of endovascular intervention of bilateral common carotid artery blockage and V4 segment of right vertebral artery aneurysm yielded excellent clinical outcomes in this instance. Endovascular treatment of a bilateral common carotid artery blockage paired with a V4 segment of a right vertebral artery aneurysm yielded excellent clinical outcomes in this patient, although long-term follow-up is necessary.

High-fat diet exacerbates cognitive decline in mouse models of Alzheimer's disease and mixed dementia in a sex-dependent manner

BackgroundApproximately 70% of Alzheimer’s disease (AD) patients have co-morbid vascular contributions to cognitive impairment and dementia (VCID); this highly prevalent overlap of dementia subtypes is known as mixed dementia (MxD). AD is more prevalent in women, while VCID is slightly more prevalent in men. Sex differences in risk factors may contribute to sex differences in dementia subtypes. Unlike metabolically healthy women, diabetic women are more likely to develop VCID than diabetic men. Prediabetes is 3× more prevalent than diabetes and is linked to earlier onset of dementia in women, but not men. How prediabetes influences underlying pathology and cognitive outcomes across different dementia subtypes is unknown. To fill this gap in knowledge, we investigated the impact of diet-induced prediabetes and biological sex on cognitive function and neuropathology in mouse models of AD and MxD.MethodsMale and female 3xTg-AD mice received a sham (AD model) or unilateral common carotid artery occlusion surgery to induce chronic cerebral hypoperfusion (MxD model). Mice were fed a control or high fat (HF; 60% fat) diet from 3 to 7 months of age. In both sexes, HF diet elicited a prediabetic phenotype (impaired glucose tolerance) and weight gain.ResultsIn females, but not males, metabolic consequences of a HF diet were more severe in AD or MxD mice compared to WT. In both sexes, HF-fed AD or MxD mice displayed deficits in spatial memory in the Morris water maze (MWM). In females, but not males, HF-fed AD and MxD mice also displayed impaired spatial learning in the MWM. In females, but not males, AD or MxD caused deficits in activities of daily living, regardless of diet. Astrogliosis was more severe in AD and MxD females compared to males. Further, AD/MxD females had more amyloid beta plaques and hippocampal levels of insoluble amyloid beta 40 and 42 than AD/MxD males. In females, but not males, more severe glucose intolerance (prediabetes) was correlated with increased hippocampal microgliosis.ConclusionsHigh-fat diet had a wider array of metabolic, cognitive, and neuropathological consequences in AD and MxD females compared to males. These findings shed light on potential underlying mechanisms by which prediabetes may lead to earlier dementia onset in women.

Triad3A-Dependent TLR4 Ubiquitination and Degradation Contributes to the Anti-Inflammatory Effects of Pterostilbene on Vascular Dementia.

Pterostilbene, a methylated stilbene derived from many plant foods, has significant anti-inflammatory activity. Meanwhile, vascular dementia (VaD) is the second most common subtype of dementia, in which inflammation is one of the major pathogenic contributors. However, the protective effect of pterostilbene on VaD is not well understood. In this work, we investigated the effect of pterostilbene on VaD and explored its underlying mechanisms using in vivo and in vitro models. Y-maze and Morris water maze tests showed pterostilbene-attenuated cognitive impairment in mice with bilateral common carotid artery occlusion (BCCAO). The hippocampal neuronal death and microglial activation in BCCAO mice were also reduced by pterostilbene treatment. Further, pterostilbene inhibited the expression of TLR4 and downstream inflammatory cytokines in these mice, with similar results observed in an oxygen-glucose deprivation and reperfusion (OGD/R) BV-2 cell model. In addition, its anti-inflammatory effect on OGD/R BV-2 cells was partially blocked by TLR4 overexpression. Moreover, Triad3A-TLR4 interactions were increased by pterostilbene following enhanced ubiquitination and degradation of TLR4, and the inhibitory effect of pterostilbene on inflammation was blocked by Triad3A knockdown in OGD/R-stimulated BV-2 cells. Together, these results reveal that pterostilbene could reduce vascular cognitive impairment and that Triad3A-mediated TLR4 degradation might be the key target.

Ocular Ischemic Syndrome and Its Related Experimental Models.

Ocular ischemic syndrome (OIS) is one of the severe ocular disorders occurring from stenosis or occlusion of the carotid arteries. As the ophthalmic artery is derived from the branch of the carotid artery, stenosis or occlusion of the carotid arteries could induce chronic ocular hypoperfusion, finally leading to the development of OIS. To date, the pathophysiology of OIS is still not clearly unraveled. To better explore the pathophysiology of OIS, several experimental models have been developed in rats and mice. Surgical occlusion or stenosis of common carotid arteries or internal carotid arteries was conducted bilaterally or unilaterally for model development. In this regard, final ischemic outcomes in the eye varied depending on the surgical procedure, even though similar findings on ocular hypoperfusion could be observed. In the current review, we provide an overview of the pathophysiology of OIS from various experimental models, as well as several clinical cases. Moreover, we cover the status of current therapies for OIS along with promising preclinical treatments with recent advances. Our review will enable more comprehensive therapeutic approaches to prevent the development and/or progression of OIS.

Evaluation of the neuroprotective activity of gamma‐benzylidenes digoxin derivatives against brain ischemia

Brain ischemia is one of the diseases with the highest mortality rate today. Among the victims who do not die, most will have some functional disability as a sequel. Currently, tissue plasminogen activator (rt‐PA) is the only pharmacological treatment for ischemia and there are no treatments with neuroprotective effects for this disease. Recently, cardiotonic steroids (CTS) have been shown to promote neuroprotection against ischemia. However, CTS are drugs that have a narrow therapeutic index and their utilization in clinic are restrict. BD‐15 is a new a non‐toxic benzylidine digoxin derivative that was demonstrated to direct increase of the α3‐Na,K‐ATPase activity, and to prevent chemical ischemia in N2a cells model, but it was never tested in a ischemia model in animal. We report here the results of the use of BD‐15 against cognitive damage and neurotoxic actions caused during brain ischemia. Wistar rats were divided in 4 groups (6 animals per group): Control, Control + BD 100 µg/kg treatment, Ischemia and Ischemia + BD‐15 100 µg/kg treatment. Transient brain ischemia was induced with bilateral occlusion of both common carotid arteries for 30 minutes, and after that the animal were followed by three days of reperfusion, with or without BD‐15 treatment (one dose per day IP, 100 µg/kg) and the hippocampus was collected to perform biochemical analysis such as: membrane lipid profile and peroxidation and membrane enzyme activities (PMCA, SERCA, and acetylcholinesterase); histological analysis for infarct volume quantification using TTC dye, and behavioral parameters assessed by the open field behavior test (the parameters evaluated were the number of times the animal changed quadrant, raised its body and presented self‐cleaning behavior and the number of visits to the central quadrants) were also evaluated. In histological analysis, the ischemia provoked a brain tissue damage after 3 days reperfusion, and BD‐15 treatment was able to impair this damage. Ischemia provoked an decrease in the total Na,K‐ATPase activity and an increase of the expression levels of the pump and BD‐15 prevent that changes caused by ischemia. The same profile was found for total PMCA activity and PMCA4 expression levels. BD‐15 was also able to prevent the decrease of activity of SERCA, Mg‐ATPase and acetylcholinesterase caused by ischemia. The membrane lipid peroxidation (thiobarbituric acid reactive substance), was increased in the ischemic group, and again BD‐15 was able to prevent this effect. Regarding the lipid profile, we observed an increase in the content of phospholipids and cholesterol in the ischemic group, and an decrease in the groups treated with BD‐15. The behavioral parameters demonstrated that BD‐15 prevents the motor damage caused by ischemia. In conclusion, BD‐15 is a non‐toxic CTS that demonstrate the prevention of brain damages provoked by ischemia, and appear to promote neuroprotection in animals exposed to global ischemia.

Menopause Diminishes Female Protection against Vascular Contributions to Cognitive Impairment and Dementia

Around mid‐life, ovarian production of estrogen stops in a sex‐specific endocrine transition called menopause. While most women who have dementia are post‐menopausal, menopause is seldom included in rodent models of dementia despite its significance in dementia risk factors in women. Before, but not after menopause, women are less likely than men to suffer from stroke, obesity, and diabetes: known risk factors for vascular contributions to cognitive impairment and dementia (VCID). Here, we aim to determine if and how menopause worsens VCID. We hypothesize that menopause will increase metabolic dysfunction, cognitive impairment, and brain pathology in a mouse model of VCID. To model menopause, we utilized 4‐vinylcyclohexene diepoxide to induce accelerated ovarian failure. To model VCID, we performed a unilateral common carotid artery occlusion surgery. We assessed cognitive deficits using behavioral tests: open field, novel object recognition, Barnes maze, and nest building. To track metabolic changes, we recorded weight gain, adiposity, and glucose tolerance. We found that menopause led to weight gain, increased visceral adiposity, impaired glucose tolerance and impaired episodic‐like memory (novel object test). While these mice did not have cognitive impairments due to VCID alone, there was a significant correlation between the degree of blood flow deficit and activities of daily living (nest building test). While we have found that menopause had negative metabolic and cognitive consequences, there were no effects of VCID alone on cognitive function in young female mice, potentially due to the protective effect of ovarian estrogen production. Deficits in episodic‐like memory and activities of daily living appeared when menopause and VCID co‐occurred. Additionally, we are examining changes to estrogen receptor expression in the brain and integrity of the brain’s white matter, as white matter is particularly vulnerable to damage due to hypoperfusion. Further investigation into pathological features (brain inflammation, white matter, and vascular damage) may uncover the mechanisms through which menopause impacts cognitive function.