Chronic cerebral hypoperfusion leads to white matter injury (WMI), which plays a significant role in contributing to vascular cognitive impairment. While 13-docosenamide is a type of fatty acid amide, it remains unclear whether it has therapeutic effects on chronic cerebral hypoperfusion. In this study, we conducted bilateral common carotid artery stenosis (BCAS) surgery to simulate chronic cerebral hypoperfusion-induced WMI and cognitive impairment. Our findings showed that 13-docosenamide alleviates WMI and cognitive impairment in BCAS mice. Mechanistically, 13-docosenamide specifically binds to cannabinoid receptor 1 (CNR1) in oligodendrocyte precursor cells (OPCs). This interaction results in an upregulation of ubiquitin-specific peptidase 33 (USP33)-mediated CNR1 deubiquitination, subsequently increasing CNR1 protein expression, activating the phosphorylation of the AKT/mTOR pathway, and promoting the differentiation of OPCs. In conclusion, our study suggests that 13-docosenamide can ameliorate chronic cerebral hypoperfusion-induced WMI and cognitive impairment by enhancing OPC differentiation and could serve as a potential therapeutic drug.
Animals ; Oligodendrocyte Precursor Cells/metabolism* ; Mice ; Cell Differentiation/drug effects* ; Male ; Receptor, Cannabinoid, CB1/metabolism* ; Mice, Inbred C57BL ; Ubiquitin Thiolesterase/metabolism* ; Ubiquitination/drug effects* ; Carotid Stenosis/complications* ; Cognitive Dysfunction/drug therapy*

The glymphatic system plays a pivotal role in maintaining cerebral homeostasis. Chronic cerebral hypoperfusion, arising from small vessel disease or carotid stenosis, results in cerebrometabolic disturbances ultimately manifesting in white matter injury and cognitive dysfunction. However, whether the glymphatic system serves as a potential therapeutic target for white matter injury and cognitive decline during hypoperfusion remains unknown. Here, we established a mouse model of chronic cerebral hypoperfusion via bilateral common carotid artery stenosis. We found that the hypoperfusion model was associated with significant white matter injury and initial cognitive impairment in conjunction with impaired glymphatic system function. The glymphatic dysfunction was associated with altered cerebral perfusion and loss of aquaporin 4 polarization. Treatment of digoxin rescued changes in glymphatic transport, white matter structure, and cognitive function. Suppression of glymphatic functions by treatment with the AQP4 inhibitor TGN-020 abolished this protective effect of digoxin from hypoperfusion injury. Our research yields new insight into the relationship between hemodynamics, glymphatic transport, white matter injury, and cognitive changes after chronic cerebral hypoperfusion.
Animals ; Brain Ischemia ; Carotid Stenosis/drug therapy* ; Cognitive Dysfunction/etiology* ; Digoxin ; Disease Models, Animal ; Mice ; Mice, Inbred C57BL ; White Matter

OBJECTIVE: To analyze the feasibility of using vascular plaque quantification (VPQ) to evaluate carotid atherosclerotic plaques and to observe the effect of statins on carotid atherosclerotic plaques. METHODS: Patients with carotid plaques from January 2016 to September 2018 in Peking University First Hospital Neurology Department were recruited and underwent three-dimonsional ultrasound (3DUS). Their gray scale median (GSM) and other parameters of carotid plaques were measured with VPQ. The patients were divided into low GSM group (GSM < 40) and high GSM group (GSM≥40). The clinical characteristics and plaque characteristics of the patients in the two groups were compared to analyze the stability of plaques. According to whether taking statins or not, the patients were further divided into statin group and non-statin group, plaque GSM and other parameters of their carotid plaques were measured and the changes of carotid plaques at the end of 3 months and 2 years were observed. RESULTS: A total of 120 patients were enrolled, including 79 males and 41 females, with an average age of (65.39±9.11) years. The patients were divided into low GSM group (31 cases) (GSM < 40) and high GSM group (89 cases) (GSM≥40). The stenosis of the lumen in the low GSM group was more severe (the area stenosis rate was 41.32%±21.37% vs. 29.79%±17.16%, P < 0.05). The nor-malized wall index (NWI) of plaque in low GSM group was significantly higher than that in high GSM group (0.61 ±0.14 vs. 0.52±0.12, P < 0.01). A total of 77 patients, including 51 males and 26 females, aged (64.96±9.58) years, were enrolled to observe the statin effects on carotid plaque. They were divided into statin group (n=56) and non-statin group (n=21) according to whether taking statins or not. At the baseline and 3-month follow-up, there were no significant differences in carotid plaque volume, area, degree of luminal stenosis and GSM between the two groups (P>0.05). At the end of the 2-year follow-up, GSM increased in the statin group [median 10.00 (2.00, 28.00)] but decreased in the non-statin group [median －7.00 (－11.00, 5.50)], with a statistically significant difference between the two groups (P < 0.01). There was no significant increase in carotid plaque volume in the statin group, while there was a slight increase in the non-statin group, but there was no significant difference between the two groups [median increase in plaque volume was 0.00 (－30.00, 40.00) mm³ in the statin group and 30.00 (10.00, 70.00) mm³ in the non-statin group, P>0.05]. CONCLUSION The VPQ technology of 3DUS can be used to evaluate carotid atherosclerotic plaques. Patients with low GSM (GSM < 40) have more severe vascular stenosis and higher normalized wall index. VPQ technology can also be used to observe the effect of statins on carotid plaque, the GSM of plaques increase in patients who are taking moderate-intensity statin treatment for two years.
Aged ; Carotid Stenosis/diagnostic imaging* ; Constriction, Pathologic ; Female ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use* ; Male ; Middle Aged ; Plaque, Atherosclerotic/drug therapy* ; Technology ; Ultrasonography

OBJECTIVE: To investigate the correlation between the carotid artery plaque and the change of plasma aldosterone level related indexes during captopril challenge test. METHODS: The patients with hypertension were enrolled as research objects and the captopril challenge test were carried out when they were hospitalized to screen the cause of hypertension. There were intact carotid artery duplex ultrasonography diagnostic data in them (83 cases). They were divided into the plaque group(57 cases) with carotid artery plaque and no plaque group( 26 cases) without carotid artery plaque according to the carotid artery duplex ultrasonography diagnostic data. The correlation between the carotid artery plaque and the changes of aldosterone concentration, renin activity and aldosterone to renin activity ratio(ARR) in two groups were analyzed. RESULTS: The detection rate of carotid artery plaque was 68.67%. Compare with no plaque group, the patients in plaque group were elder and the level of apolipoprotein A1,(APOA1) was lower (all P＜0.05). The ARR difference value before and after captopril challenge test was lower ( P＜0.05).The aldosterone difference value and the renin activity difference value before and after captopril challenge test were higher in plaque group (all P＜0.05).The aldosterone difference value and the renin activity difference value were positive in plaque group and were negative in no plaque group. The difference value of the ARR was negative in plaque group and was positive in no plaque group. Logistic regression analysis showed that the age, the difference value of ARR and the aldosterone before and after captopril challenge test could be associated independently with carotid artery plaque occurrence after excluding gender difference and other factors. CONCLUSION The detection rate of carotid artery plaque was high among hospitalized patients with hypertension, the difference value of ARR and the aldosterone before and after captopril challenge test could be associated independently with carotid artery plaque occurrence.
Aldosterone ; blood ; Angiotensin-Converting Enzyme Inhibitors ; pharmacology ; Captopril ; pharmacology ; Carotid Stenosis ; drug therapy ; Humans ; Hypertension ; drug therapy ; Inpatients ; Renin

OBJECTIVETo investigate the therapeutic effects of Qingre Quyu Granule (QQG) on the patients with severe carotid stenosis, and to explore the mechanism of it.

METHODSNinety-six patients with severe carotid stenosis were enrolled in the study and were classified into a QQG group (n=48) and a control group (n=48) randomly using consecutively numbered envelopes. The patients in the QQG group were given QQG and Western medicine, those in the control group were given Western medicine merely, the course of treatment was 16 weeks. All patients went through endarterectomy after treatment. Plaques were subjected to the analysis of CD3, CD68, soluble intercellular adhesion molecule 1 (ICAM-1), matrix metalloprotease-9 (MMP-9), CD40L, tenascin-C, and collagen content lipid content by immunohistochemistry or polarized light analysis.

RESULTSBy the end of experiment, the expressions of CD3, CD68, ICAM-1, MMP9, CD40L and tenascin-C on the plaques were statistically significant lower in the QQG group compared with the control group(P<0.01). The lipid content of the plaque was also significantly lower in the QQG group compared with the control group (P<0.01). The interstitial collagen in the tissue sections of the plaques was also significantly higher in the QQG group in comparison with the control group (P<0.01).

CONCLUSIONQQG could stabilize carotid artery plaques through inhibiting pro-inflammation factors and restraining the tenascin-C and MMP9 pathway.

Aged ; Antigens, CD ; metabolism ; Antigens, Differentiation, Myelomonocytic ; metabolism ; CD3 Complex ; metabolism ; CD40 Ligand ; metabolism ; Carotid Arteries ; metabolism ; pathology ; Carotid Stenosis ; blood ; complications ; drug therapy ; Collagen ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Female ; Humans ; Immunohistochemistry ; Inflammation ; complications ; pathology ; Intercellular Adhesion Molecule-1 ; metabolism ; Lipids ; blood ; Male ; Matrix Metalloproteinase 9 ; metabolism ; Plaque, Atherosclerotic ; blood ; complications ; drug therapy ; Tenascin ; metabolism

Adult ; Aged ; Carotid Stenosis ; diagnostic imaging ; pathology ; Drugs, Chinese Herbal ; therapeutic use ; Female ; Humans ; Hypertension ; diagnostic imaging ; drug therapy ; pathology ; Male ; Middle Aged ; Phytotherapy ; Ultrasonography

We describe two cases of branch retinal artery occlusion (BRAO) after carotid artery (CA) stenting. Case 1: A 57-year-old man diagnosed with left neovascular glaucoma was admitted to our department for trabeculectomy (He had complained of decreased visual acuity (VA) in the left eye for a month). A preoperative neck angio CT scan showed bilateral CA stenosis. After CA stenting, he contracted visual defects on the right superior area of his right eye. Upon examination, VA with correction was found to be 1.0 (OD), but right fundoscopy revealed ischemic retina whitening along the inferior temporal arcade. Case 2: A 64-year-old man received left CA stenting for severe stenosis in the Department of Neurology. The next day, he was referred to us for acute onset of a left naso-inferior visual field defect. Upon initial examination, his VA with correction was 0.8/0.16 (OD/OS) and fundoscopy revealed ischemic retina whitening at the superior posterior pole in the left eye. It was not necessary to treat the BRAO in these cases because the foveal capillary network was not invaded at 2 month follow ups, VA was preserved in both cases. In conclusion, ophthalmic evaluation is important after CA stenting because of a possible embolic occlusion of the retinal artery.
Angiography ; Carotid Stenosis/radiography/*surgery ; Fibrinolytic Agents/therapeutic use ; Fluorescein Angiography ; Follow-Up Studies ; Fundus Oculi ; Humans ; Male ; Middle Aged ; Retinal Artery Occlusion/diagnosis/drug therapy/*etiology ; Stents/*adverse effects ; Visual Acuity ; Visual Fields

We report a case of ocular ischemic syndrome accompanied by neovascular glaucoma that was successfully treated with Bevacizumab. A 70-year-old male patient diagnosed with neovascular glaucoma of the left eye 3-4 years prior complained of continuous left eye pain and declining visual acuity despite receiving the latest treatment methods. At the time of admission the patient had no light perception in the left eye and his intraocular pressure was 30 mmHg. Anterior segment and fundus examinations revealed neovascularization of the iris and stenosis of the retinal vessel. Hypofluorescence of the choroid and retinal vessels was observed on fluorescence fundus angiography. Left internal carotid artery stenosis was observed on a brain MRI. Despite being treated with eye solution and oral medication, intraocular pressure was not controlled. After 7 days, we performed an intravitreal Bevacizumab 1.25 mg/0.05mL injection. One day after the intravitreal Bevacizumab injection, the neovascularization had nearly regressed and intraocular pressure was 30 mmHg. Intravitreal Bevacizumab injection produced regression of neovascularization and proved effective for treatment of neovascular glaucoma in this case of ocular ischemic syndrome.
Aged ; Angiogenesis Inhibitors/*administration & dosage ; Antibodies, Monoclonal/*administration & dosage ; Carotid Stenosis/*complications/diagnosis ; Diagnosis, Differential ; Eye/*blood supply ; Fluorescein Angiography ; Fundus Oculi ; Glaucoma, Neovascular/diagnosis/*drug therapy/etiology ; Humans ; Injections ; Ischemia/*complications/diagnosis ; Magnetic Resonance Angiography ; Male ; Vascular Endothelial Growth Factor A ; Vitreous Body

We report a case of ocular ischemic syndrome accompanied by neovascular glaucoma that was successfully treated with Bevacizumab. A 70-year-old male patient diagnosed with neovascular glaucoma of the left eye 3-4 years prior complained of continuous left eye pain and declining visual acuity despite receiving the latest treatment methods. At the time of admission the patient had no light perception in the left eye and his intraocular pressure was 30 mmHg. Anterior segment and fundus examinations revealed neovascularization of the iris and stenosis of the retinal vessel. Hypofluorescence of the choroid and retinal vessels was observed on fluorescence fundus angiography. Left internal carotid artery stenosis was observed on a brain MRI. Despite being treated with eye solution and oral medication, intraocular pressure was not controlled. After 7 days, we performed an intravitreal Bevacizumab 1.25 mg/0.05mL injection. One day after the intravitreal Bevacizumab injection, the neovascularization had nearly regressed and intraocular pressure was 30 mmHg. Intravitreal Bevacizumab injection produced regression of neovascularization and proved effective for treatment of neovascular glaucoma in this case of ocular ischemic syndrome.
Aged ; Angiogenesis Inhibitors/*administration & dosage ; Antibodies, Monoclonal/*administration & dosage ; Carotid Stenosis/*complications/diagnosis ; Diagnosis, Differential ; Eye/*blood supply ; Fluorescein Angiography ; Fundus Oculi ; Glaucoma, Neovascular/diagnosis/*drug therapy/etiology ; Humans ; Injections ; Ischemia/*complications/diagnosis ; Magnetic Resonance Angiography ; Male ; Vascular Endothelial Growth Factor A ; Vitreous Body

OBJECTIVETo investigate the effect of two clopidogrel pretreatment duration on platelet activation in patients undergoing stenting.

METHODSFrom July 2006 to December 2007 40 elective carotid or vertebral artery stenting patients were assigned into two groups: Group A (n = 24) initiated clopidogrel (75 mg/d) > or = 5 d before stenting; group B (n = 16) initiated 3 - 4 days. Platelet-monocyte aggregates and fibrinogen receptors analyzed by flow cytometric, and platelet aggregation tests using optical aggregometry, as well as serum soluble CD40 ligand quantified by enzyme-linked immunosorbent assay were assessed in peripheral blood samples obtained immediately before and at 0.5, 18 h and 6 d after stenting.

RESULTSPlatelet-monocyte aggregates, fibrinogen receptors and serum soluble CD40 ligand were higher in group B than in group A (14.59% vs 8.70%, P = 0.012; 4.87% vs 2.42%, P = 0.024; 5.79 microg/L vs 2.64 microg/L, P = 0.020) at 18 h after stenting. Serum soluble CD40 ligand was higher in group B than in group A (0.49 microg/L vs 0.31 microg/L, P = 0.033) at 0.5 h after stenting.

CONCLUSIONSPremedication before stenting with clopidogrel 75 mg/d merely 3 - 4 d may be insufficient to achieve adequate platelet inhibition, whereas clopidogrel initiated at least 5 d could obtain preferable clinical antiplatelet efficacy.

Adult ; Aged ; Aged, 80 and over ; Carotid Stenosis ; blood ; therapy ; Female ; Humans ; Male ; Middle Aged ; Platelet Activation ; drug effects ; Platelet Aggregation Inhibitors ; administration & dosage ; Stents ; Ticlopidine ; administration & dosage ; analogs & derivatives ; Time Factors