Cerebral small vessel disease (CSVD) is a major cause of vascular cognitive impairment and functional loss in elderly patients. Progressive remodeling of cerebral microvessels due to arterial hypertension or other vascular risk factors, such as aging, can cause dementia or stroke. Typical imaging characteristics of CSVD include cerebral microbleeds (CMB), brain atrophy, small subcortical infarctions, white matter hyperintensities (WMH), and enlarged perivascular spaces (EPVS). Nevertheless, no animal models that reflect all the different aspects of CSVD have been identified. Here, we generated a new CSVD animal model using D-galactose (D-gal) combined with cerebral hypoperfusion in spontaneously hypertensive rats (SHR), which showed all the hallmark pathological features of CSVD and was based on vascular risk factors. SHR were hypodermically injected with D-gal (400 mg/kg/d) and underwent modified microcoil bilateral common carotid artery stenosis surgery. Subsequently, neurological assessments and behavioral tests were performed, followed by vascular ultrasonography, electron microscopy, flow cytometry, and histological analyses. Our rat model showed multiple cerebrovascular pathologies, such as CMB, brain atrophy, subcortical small infarction, WMH, and EPVS, as well as the underlying causes of CSVD pathology, including oxidative stress injury, decreased cerebral blood flow, structural and functional damage to endothelial cells, increased blood-brain barrier permeability, and inflammation. The use of this animal model will help identify new therapeutic targets and subsequently aid the development and testing of novel therapeutic interventions. Main process of the study: Firstly, we screened for optimal conditions for mimicking aging by injecting D-gal into rats for 4 and 8 weeks. Subsequently, we performed modified microcoil BCAS intervention for 4 and 8 weeks in rats to screen for optimal hypoperfusion conditions. Finally, based on these results, we combined D-gal for 8 weeks and modified microcoil BCAS for 4 weeks to explore the changes in SHR.

Vascular cognitive impairment and dementia (VCID) is a series of cognitive dysfunction associated with cerebrovascular diseases and currently lacks effective treatments. The white matter, which is essential for neuronal information processing and integration, is nourished by a network of capillaries and is vulnerable to chronic hypoperfusion. Here, we show that metformin, a widely used drug for the treatment of type 2 diabetes, alleviates the white matter damage and improves cognitive impairment in a mouse model of VCID established by bilateral carotid artery stenosis (BCAS)-induced chronic hypoperfusion. Mechanistically, metformin restores the dysfunctions of oligodendrocyte precursor cells (OPCs) under hypoxia. Metformin up-regulates prolyl hydroxylases 2 via activating the AMP-activated protein kinase pathway, leading to hypoxia-inducible factor-1α (HIF-1α) degradation in OPCs. These findings suggest that metformin may have a promising therapeutic role in alleviating cognitive abnormalities by ameliorating white matter damage of VCID.

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.

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.

The 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.
Twelve 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.
The 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.
The BCCAO is an ideal rat model for studying the pathophysiological mechanisms of vascular dementia.

Blood-brain barrier (BBB) disruption is a pivotal pathophysiological process in ischemic stroke. Although temporal changes in BBB permeability during the acute phase have been widely studied, little is known about the chronic phase of cerebrovascular changes that may have a large impact on the long-term outcome. Therefore, this study was aimed to measure cerebral vascular abnormalities using CT perfusion in nine rhesus monkeys subjected to transient middle cerebral artery occlusion (tMCAO) for ≥1 year (MCAO-1Y+). The level of cerebral perfusion demonstrated by mean transit time was significantly higher in the ipsilateral caudate nucleus, white matter, thalamus, hippocampus, and contralateral thalamus in MCAO-1Y+ compared with the other nine age-matched control monkeys. The increase in BBB permeability measured through the permeability surface was found in the same ten regions of interest ipsilaterally and contralaterally. We also found decreased levels of Aβ 42/40 ratio in the cerebrospinal fluid (CSF), suggesting a potential link between post-MCAO cognitive decline and Aβ metabolism. Overall, we demonstrated significant cerebral hypoperfusion, BBB disruption, and CSF Aβ decrease during the rehabilitation stage of ischemic stroke in a non-human primate model. Future studies are needed to elucidate the cause-effect relationship between cerebrovascular disruptions and long-term neurological deficits.

[This corrects the article DOI: 10.3389/fphar.2021.794933.].

Impaired cerebral hemodynamic autoregulation, vasoconstriction, and cardiovascular and metabolic dysfunctions cause cerebral hypoperfusion (CH) that triggers pro-oxidative and inflammatory events. The sequences linked to ion-channelopathies and calcium and glutamatergic excitotoxicity mechanisms resulting in widespread brain damage and neurobehavioral deficits, including memory, neurological, and sensorimotor functions. The vasodilatory, anti-inflammatory, and antioxidant activities of cucurbitacin E (CuE) can alleviate CH-induced neurobehavioral impairments. In the present study, the neuroprotective effects of CuE were explored in a rat model of CH. Wistar rats were subjected to permanent bilateral common carotid artery occlusion to induce CH on day 1 and administered CuE (0.25, 0.5 mg/kg) and/or Bay-K8644 (calcium agonist, 0.5 mg/kg) for 28 days. CH caused impairment of neurological, sensorimotor, and memory functions that were ameliorated by CuE. CuE attenuated CH-triggered lipid peroxidation, 8-hydroxy-2\'-deoxyguanosine, protein carbonyls, tumor necrosis factor-α, nuclear factor-kappaB, myeloperoxidase activity, inducible nitric oxide synthase, and matrix metalloproteinase-9 levels in brain resulting in a decrease in cell death biomarkers (lactate dehydrogenase and caspase-3). CuE decreased acetylcholinesterase activity, glutamate, and increased γ-aminobutyric acid levels in the brain. An increase in brain antioxidants was observed in CuE-treated rats subjected to CH. CuE has the potential to alleviate pathogenesis of CH and protect neurological, sensorimotor, and memory functions against CH.

Background: Perioperative cerebral hypoperfusion (CH) is common, although the underlying mechanism of cognitive impairment that results due to perioperative cerebral hypoperfusion remains to be determined. Isoflurane anesthesia induces neuronal injury via endoplasmic reticulum (ER) stress, whereas a sub-anesthetic dose of propofol improves postoperative cognitive function. However, the effects of the combination of isoflurane plus propofol, which is a common aesthetic combination administered to patients, on ER stress and cognition remain unknown. Methods: We sought to determine the effects of isoflurane plus propofol on ER stress and cognitive function in rats insulted by cerebral hypoperfusion. Ligation of the bilateral common carotid arteries (CCA) was adopted to develop the cerebral hypoperfusion rat model. A second surgery, open reduction and internal fixation (ORIF), requiring general anesthesia, was performed 30 days later so that the effects of anesthetics on the cognitive function of CH rats could be assessed. Rats received isoflurane alone (1.9%), propofol alone (40 mg·kg-1·h-1) or a combination of isoflurane and propofol (1% and 20 mg·kg-1·h-1 or 1.4% and 10 mg·kg-1·h-1). Behavioral studies (contextual fear conditioning [FC] test), histological analyses (Nissl staining) and biochemical analyses (western blotting of the harvested rat brain tissues) were employed. Results: Hippocampus-dependent memory of rats in group IP1 (1% isoflurane plus 20 mg·kg-1·h-1 propofol) was not impaired, and expression level of γ-aminobutyric acid A type receptor α1 subunit, a key cognition-related protein, remained normal. ER stress alleviator, binding immunoglobulin protein, increased extremely while ER stress transcription factor, C/EBP homologous protein, showed no statistical difference compared with the control group. Numbers of surviving neurons confirmed the substantial neuronal damage caused by propofol or isoflurane alone. Conclusions: These data suggest that ER stress contributes to the underlying mechanism of cognitive impairment and that the combination of isoflurane and propofol did not aggravate cognitive impairment and ER stress in aging rats with CH that were further subjected to ORIF surgery.

Delirium is a clinical syndrome characterized by a temporary organic mental disorder, as well as abnormal attention and cognition. It is a very common, serious, and costly disease with high misdiagnosis and death/disability rates, especially for older patients after surgery. Several factors, such as systemic neuroinflammation, neurotransmitters, cerebral hypoperfusion and microthrombosis, contribute to the progress of delirium; however, the exact pathophysiologic mechanisms are not well known. Therefore, there are no specific therapeutic approaches that can treat delirium effectively. Statins, as inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, have been identified as potential medications for the treatment of delirium because they can significantly reduce the incidence of delirium. The major objective of the current review is to summarize recent advances in the understanding of the effects and mechanisms of statins on delirium. In basic research, statins can alleviate delirium via attenuation of neuroinflammation, neurotransmitters, cerebral hypoperfusion, and microthrombosis, which may highlight their potential clinical application for the treatment of delirium. Despite this, the clinical effects of statins still provoke debate.