Panax ginseng extract attenuates neuronal injury and cognitive deficits in rats with vascular dementia induced by chronic cerebral hypoperfusion

Panax ginseng is a slow-growing perennial plant.Panax ginseng extract has numerous biological activities,including antitumor,anti-inflammatory and antistress activities.Panax ginseng extract also has a cognition-enhancing effect in rats with alcohol-induced memory impairment.In this study,we partially occluded the bilateral carotid arteries in the rat to induce chronic cerebral hypoperfusion,a wellknown model of vascular dementia.The rats were then intragastrically administered 50 or 100 mg/kg Panax ginseng extract.Morris water maze and balance beam tests were used to evaluate memory deficits and motor function,respectively.Protein quantity was used to evaluate cholinergic neurons.Immunofluorescence staining was used to assess the number of glial fibrillary acidic protein-positive cells.Western blot assay was used to evaluate protein levels of vascular endothelial growth factor,basic fibroblast growth factor,Bcl-2 and Bax.Treatment with Panax ginseng extract for 8 weeks significantly improved behavioral function and increased neuronal density and VEGF and b FGF protein expression in the hippocampal CA3 area.Furthermore,Panax ginseng extract reduced the number of glial fibrillary acidic protein-immunoreactive cells,and it decreased apoptosis by upregulating Bcl-2 and downregulating Bax protein expression.The effect of Panax ginseng extract was dose-dependent and similar to that of nimodipine,a commonly used drug for the treatment of vascular dementia.These findings suggest that Panax ginseng extract is neuroprotective against vascular dementia induced by chronic cerebral hypoperfusion,and therefore might have therapeutic potential for preventing and treating the disease.

Hippocampal expression of synaptic structural proteins and phosphorylated cAMP response element-binding protein in a rat model of vascular dementia induced by chronic cerebral hypoperfusion

The present study established a rat model of vascular dementia induced by chronic cerebral hypoperfusion through permanent ligation of bilateral common carotid arteries.At 60 days after modeling,escape latency and swimming path length during hidden-platform acquisition training in Morris water maze significantly increased in the model group.In addition,the number of accurate crossings over the original platform significantly decreased,hippocampal CA1 synaptophysin and growth-associated protein 43 expression significantly decreased,cAMP response element-binding protein expression remained unchanged,and phosphorylated cAMP response element-binding protein expression significantly decreased.Results suggested that abnormal expression of hippocampal synaptic structural protein and cAMP response element-binding protein phosphorylation played a role in cognitive impairment following chronic cerebral hypoperfusion.

3′-Daidzein sulfonate sodium protects against memory impairment and hippocampal damage caused by chronic cerebral hypoperfusion

3′-Daidzein sulfonate sodium（DSS） is a new synthetic water-soluble compound derived from daidzein,a soya isoflavone that plays regulatory roles in neurobiology.In this study,we hypothesized that the regulatory role of DSS in neurobiology exhibits therapeutic effects on hippocampal damage and memory impairment.To validate this hypothesis,we established rat models of chronic cerebral hypoperfusion（CCH） by the permanent occlusion of the common carotid arteries using the two-vessel occlusion method.Three weeks after modeling,rat models were intragastrically administered 0.1,0.2,and 0.4 mg/kg DSS,once a day,for 5 successive weeks.The Morris water maze test was performed to investigate CCH-induced learning and memory deficits.TUNEL assay was used to analyze apoptosis in the hippocampal CA1,CA3 regions and dentate gyrus.Hematoxylin-eosin staining was performed to observe the morphology of neurons in the hippocampal CA1,CA3 regions and dentate gyrus.Western blot analysis was performed to investigate the phosphorylation of PKA,ERK1/2 and CREB in the hippocampal PKA/ERK1/2/CREB signaling pathway.Results showed that DSS treatment greatly improved the learning and memory deficits of rats with CCH,reduced apoptosis of neurons in the hippocampal CA1,CA3 regions and dentate gyrus,and increased the phosphorylation of PKA,ERK1/2,and CREB in the hippocampus.These findings suggest that DSS protects against CCH-induced memory impairment and hippocampal damage possibly through activating the PKA/ERK1/2/CREB signaling pathway.

Mechanisms regulating cerebral hypoperfusion in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Cerebral small vessel disease (CSVD) is a leading cause of stroke and dementia. As the most common type of inherited CSVD, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by the NOTCH3 gene mutation which leads to Notch3 ectodomain deposition and extracellular matrix aggregation around the small vessels. It further causes smooth muscle cell degeneration and small vessel arteriopathy in the central nervous system. Compromised cerebral blood flow occurs in the early stage of CADASIL and is associated with white matter hyperintensity, the typical neuroimaging pathology of CADASIL. This suggests that cerebral hypoperfusion may play an important role in the pathogenesis of CADASIL. However, the mechanistic linkage between NOTCH3 mutation and cerebral hypoperfusion remains unknown. Therefore, in this mini-review, it examines the cellular and molecular mechanisms contributing to cerebral hypoperfusion in CADASIL.

Effects of chronic cerebral hypoperfusion of beta- and gamma-secretase on learning and memory in rats

BACKGROUND： Chronic cerebral hypoxia and ischemia have been shown to be related to occurrence of sporadic Alzheimer＇s disease, and β- and y-secretase play an important role in the generation of β-amyloid protein. Early clinical symptoms in Alzheimer＇s disease patients include learning and memory deficits. OBJECTIVE： To measure learning and memory, as well as β- and β-secretase activities in the hippocampus of a cerebral ischemia/hypoxia rat model with chronic cerebral hypoperfusion. DESIGN, TIME AND SETTING： A randomized, controlled, animal experiment was performed at the Department of Pathology, Capital Medical University from March to December, 2008. MATERIALS： β- and y-secretase activity kits were purchased from R ＆ D Systems, USA. METHODS： Male Sprague Dawiey rats, aged 23 weeks, were randomly assigned to model （n = 56） and sham-surgery （n = 46） groups. Cerebral hypoperfusion rat models were established by bilateral common carotid occlusion. MAIN OUTCOME MEASURES： Morris water maze was used to test changes in escape latency and path length, and β- and y-secretase activities were measured on days 10, 30, 90, and 180 following surgery. RESULTS： Progressive cognitive impairment resulted from 30 days of chronic cerebral hypoperfusion, which lasted for 180 days after cerebral hypoperfusion. β-secretase activity was increased at 10 days after hypoperfusion, which continued until 180 days, with a 14.25% increase compared to the sham-surgery group; y-secretase activity was increased by 10.5%. CONCLUSION： Chronic cerebral hypoperfusion results in impaired spatial memory and upregulated β- and y-secretase activities, which could play an important role in β-amyloid production.

Enhancement of oligodendrocyte autophagy alleviates white matter injury and cognitive impairment induced by chronic cerebral hypoperfusion in rats

Cognitive impairment caused by chronic cerebral hypoperfusion(CCH)is associated with white matter injury(WMI),possibly through the alteration of autophagy.Here,the autophagy—lysosomal pathway(ALP)dysfunction in white matter(WM)and its relationship with cognitive impairment were investigated in rats subjected to two vessel occlusion(2VO).The results showed that cognitive impairment occurred by the 28th day after 2VO.Injury and autophagy activation of mature oligodendrocytes and neuronal axons sequentially occurred in WM by the 3rd day.By the 14th day,abnormal accumulation of autophagy substrate,lysosomal dysfunction,and the activation of mechanistic target of rapamycin(MTOR)pathway were observed in WM,paralleled with mature oligodendrocyte death.This indicates autophagy activation was followed by ALP dysfunction caused by autophagy inhibition or lysosomal dysfunction.To target the ALP dysfunction,enhanced autophagy by systemic rapamycin treatment or overexpression of Beclin1(BECN1)in oligodendrocytes reduced mature oligodendrocyte death,and subsequently alleviated the WMI and cognitive impairment after CCH.These results reveal that early autophagy activation was followed by ALP dysfunction in WM after 2VO,which was associated with the aggravation of WMI and cognitive impairment.This study highlights that alleviating ALP dysfunction by enhancing oligodendrocyte autophagy has benefits for cognitive recovery after CCH.

Blood-brain barrier pathology in cerebral small vessel disease

Cerebral small vessel disease is a neurological disease that affects the brain microvasculature and which is commonly observed among the elderly.Although at first it was considered innocuous,small vessel disease is nowadays regarded as one of the major vascular causes of dementia.Radiological signs of small vessel disease include small subcortical infarcts,white matter magnetic resonance imaging hyperintensities,lacunes,enlarged perivascular spaces,cerebral microbleeds,and brain atrophy;however,great heterogeneity in clinical symptoms is observed in small vessel disease patients.The pathophysiology of these lesions has been linked to multiple processes,such as hypoperfusion,defective cerebrovascular reactivity,and blood-brain barrier dysfunction.Notably,studies on small vessel disease suggest that blood-brain barrier dysfunction is among the earliest mechanisms in small vessel disease and might contribute to the development of the hallmarks of small vessel disease.Therefore,the purpose of this review is to provide a new foundation in the study of small vessel disease pathology.First,we discuss the main structural domains and functions of the blood-brain barrier.Secondly,we review the most recent evidence on blood-brain barrier dysfunction linked to small vessel disease.Finally,we conclude with a discussion on future perspectives and propose potential treatment targets and interventions.

Therapeutic Benefit of Yangxue Qingnao Granule(养血清脑颗粒)on Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats

Objective：To observe the therapeutic effect of Yangxue Qingnao Granule（养血清脑颗粒, YXQNG） on cognitive impairment induced by chronic cerebral hypoperfusion and to investigate its impact on oxidative stress,apoptosis,and the cholinergic system.Methods：Adult male Wistar rats were subjected to chronic cerebral hypoperfusion by permanent occlusion of bilateral common carotid arteries（2-VO）.Thirty rats were randomly assigned to one of the five treatment groups in a 1：1：1：1：1 ratio：sham operation plus normal saline treatment,2-VO plus normal saline treatment,2-VO plus YXQNG at a dose of 2 g·kg（-1）·d^（-1） or 4 g·kg（-1）·d^（-1）, or 2-VO plus rivastigmine 2 mgkg^（-1）·d^（-1）.The Morris water maze test was used to assess the spatial memory retrieval.Apoptosis,total antioxide capacity（T-AOC）,acetylcholine esterase（AchE） and choline acetyl transferase（ChAT） activities in the hippocampus and the cortex were investigated.Results：In the chronic cerebral hypoperfusion model,the 2-VO plus saline treatment resulted in impaired special learning as shown by the significantly prolonged escape latency and shorter swim time in the first quadrant as compared to the sham operation.The impairment was associated with apoptosis and significant decreases in T-AOC,AchE and ChAT activities in the hippocampus and the cortex.Treatment with YXQNG at either 2 g·kg（-1）·d^（-1） or 4 g·kg（-1）·d^（-1） dose,or rivastigmine resulted in significantly shorter escape latencies and longer swim time in the first quadrant.YXQNG at both doses,but not rivastigmine,had significant reduction in apoptosis,and significant increases in T-AOC and ChAT activity in both the hippocampus and the cortex.Unlike rivastigmine,neither dose of YXQNG showed significant reduction in AchE activity.Conclusions：YXQNG ameliorated cognitive impairment induced by chronic cerebral hypoperfusion.The protective effect may be mediated through its regulation of apoptosis and activities of T-AOC and ChAT in the hippocampus and cortex of the rats in the chronic cerebral hypoperfusion model,a mechanism that is different from rivastigmine.

Digoxin Ameliorates Glymphatic Transport and Cognitive Impairment in a Mouse Model of Chronic Cerebral Hypoperfusion

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 glym・phatic 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.

Effects of different regional cerebral blood flow on white matter hyperintensity in CADASIL patients

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL)is an early-onset inherited small vessel disease.Decreased cerebral blood flow(CBF)may contribute to white matter hyperintensity(WMH)severity in CADASIL,but more evidence is needed to support this hypothesis.This study comprised six patients with CADASIL who harbored mutations in the coding sequence of NOTCH3 and twelve age-matched neurologically healthy controls.We collected clinical and imaging data from patients with CADASIL and divided the brain into four regions:WMH,normal-appearing white matter(NAWM),gray matter(GM),and global brain.We analyzed the relationship between CBF of each region and the WMH volume.Compared with the control group,CBF was significantly decreased in all four regions in the CADASIL group.Lower CBF in these regions was correlated with higher WMH volume in CADASIL.CBF in the NAWM,GM and global regions was positively correlated with that in WMH region.However,after correction tests,only CBF in the WMH region but not in NAWM,GM and global regions was associated with WMH volume.Our findings suggest that CBF in the WMH region is an influencing factor of the WMH severity in CADASIL.

Chronic hypoperfusion due to intracranial large artery stenosis is not associated with cerebralβ-amyloid deposition and brain atrophy

Background:Insufficient cerebral perfusion is suggested to play a role in the development of Alzheimer disease(AD).However,there is a lack of direct evidence indicating whether hypoperfusion causes or aggravates AD pathology.We investigated the effect of chronic cerebral hypoperfusion on AD-related pathology in humans.Methods:We enrolled a group of cognitively normal patients(median age:64 years)with unilateral chronic cerebral hypoperfusion.Regions of interest with the most pronounced hypoperfusion changes were chosen in the hypoperfused region and were then mirrored in the contralateral hemisphere to create a control region with normal perfusion.11C-Pittsburgh compound-positron emission tomography standard uptake ratios and brain atrophy indices were calculated from the computed tomography images of each patient.Results:The median age of the 10 participants,consisting of 4 males and 6 females,was 64 years(47-76 years).We found that there were no differences in standard uptake ratios of the cortex(volume of interest[VOI]:P=0.721,region of interest[ROI]:P=0.241)and grey/white ratio(VOI:P=0.333,ROI:P=0.445)and brain atrophy indices(Bicaudate,Bifrontal,Evans,Cella,Cella media,and Ventricular index,P>0.05)between the hypoperfused regions and contralateral normally perfused regions in patients with unilateral chronic cerebral hypoperfusion.Conclusion:Our findings suggest that chronic hypoperfusion due to large vessel stenosis may not directly induce cerebralβ-amyloid deposition and neurodegeneration in humans.

PRELIMINARY STUDY OF OMENTUM TRANSPOSITION TO BRAIN FOR TREATMENT OF ALZHEIMER’S DISEASE

Objective To learn the effect of omemtum transposition to the brain of patients with Alzheimer’s disease. Methods Ten consecutive patients, aged 58-81 years old, underwent graft of their elongated pedicled omentum onto their left frontal-temperal-parietal cerebral cortex. Those patients, who had more than five years of dementia with low mini mental-state examination (MMSE) scores of 2-15, were diagnosed by a neurologist. All subjects underwent single photon evoked computer tomography (SPECT) pre- and post-operatively. SPECT results were analyzed semi-quantitatively by calculation of the left/right radioactivity counts symmetry index (Si). The patients were followed up to one year. The outcome was evaluated by the neurologist with a modified scale of activities of daily living (mADL) as well as the MMSE. Results Three months following the surgery, the Si of SPECT increased from (98.7±1.9)% to (103.9±2.3)% (P=0.0307). The neurological and neuropsychological testing scores increased insignificantly during the follow-up period. By the one year, the MMSE score rose from 8.7±1.4 to 10.7±1.8(P>0.05), while the mADL from 13.3±1.8 to 16.9±2.0 (P>0.05). One of the patients suffered a heart attack, two had epileptic episodes postoperatively. Conclusion We believe that omental transposition to the brain augments cerebral blood flow, which might be helpful to decelerate the processing of Alzheimer’s disease. However, it is still a potentially risky procedure for the elderly.

Activation of glutamatergic neurons in the somatosensory cortex promotes remyelination in ischemic vascular dementia

Chronic cerebral hypoperfusion can cause progressive demyelination as well as ischemic vascular dementia,however no effective treatments are available.Here,based on magnetic resonance imaging studies of patients with white matter damage,we found that this damage is associated with disorganized cortical structure.In a mouse model,optogenetic activation of glutamatergic neurons in the somatosensory cortex significantly promoted oligodendrocyte progenitor cell(OPC)proliferation,remyelination in the corpus callosum,and recovery of cognitive ability after cerebral hypoperfusion.The therapeutic effect of such stimulation was restricted to the upper layers of the cortex,but also spanned a wide time window after ischemia.Mechanistically,enhancement of glutamatergic neuron-OPC functional synaptic connections is required to achieve the protection effect of activating cortical glutamatergic neurons.Additionally,skin stroking,an easier method to translate into clinical practice,activated the somatosensory cortex,thereby promoting OPC proliferation,remyelination and cognitive recovery following cerebral hypoperfusion.In summary,we demonstrated that activating glutamatergic neurons in the somatosensory cortex promotes the proliferation of OPCs and remyelination to recover cognitive function after chronic cerebral hypoperfusion.It should be noted that this activation may provide new approaches for treating ischemic vascular dementia via the precise regulation of glutamatergic neuron-OPC circuits.