Adenosine A2A Receptor in Bone Marrow-Derived Cells Mediated Macrophages M2 Polarization via PPARγ-P65 Pathway in Chronic Hypoperfusion Situation

Background: The role of adenosine A2A receptor (A2AR) in the ischemic white matter damage induced by chronic cerebral hypoperfusion remains obscure. Here we investigated the role of A2AR in the process of macrophage polarizations in the white matter damage induced by chronic cerebral hypoperfusion and explored the involved signaling pathways.Methods: We combined mouse model and macrophage cell line for our study. White matter lesions were induced in A2AR knockout mice, wild-type mice, and chimeric mice generated by bone marrow cells transplantation through bilateral common carotid artery stenosis. Microglial/macrophage polarization in the corpus callosum was detected by immunofluorescence. For the cell line experiments, RAW264.7 macrophages were treated with the A2AR agonist CHS21680 or A2AR antagonist SCH58261 for 30 min and cultured under low-glucose and hypoxic conditions. Macrophage polarization was examined by immunofluorescence. The expression of peroxisome proliferator activated receptor gamma (PPARγ) and transcription factor P65 was examined by western blotting and real-time polymerase chain reaction (RT-PCR). Inflammatory cytokine factors were assessed by enzyme-linked immunosorbent assay (ELISA) and RT-PCR.Results: Both global A2AR knockout and inactivation of A2AR in bone marrow-derived cells enhanced M1 marker expression in chronic ischemic white matter lesions. Under low-glucose and hypoxic conditions, CGS21680 treatment promoted macrophage M2 polarization, increased the expression of PPARγ, P65, and interleukin-10 (IL-10) and suppressed the expression of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). The CGS21680-induced upregulation of P65 and IL-10 was abolished in macrophages upon PPARγ knockdown. The downregulation of TNF-α and IL-1β by CGS21680 was less affected by PPARγ knockdown.Conclusions: In the cerebral hypoperfusion induced white matter damage, A2AR signaling in bone marrow-derived cells induces macrophage M2 polarization and increases the expression of the anti-inflammatory factor IL-10 via the PPARγ-P65 pathway, both of which might explain its neuroprotective effect.

Post-stroke executive function impairments in relation to white matter damage due to stroke lesions versus leukoaraiosis

BACKGROUND There is a high prevalence of executive function impairments among stroke survivors. However, the underlying aetiology remains unclear. In particular, we address whether focal, stroke-specific white matter damage or diffuse comorbid white matter damage (leukoaraiosis) is more associated with executive function impairments. METHODS This project is a retrospective analysis of data collected within the Oxford Cognitive Screening programme. Patients were recruited in the acute stage of stroke if they had a confirmed diagnosis of stroke, were at least 18 years of age, were able to remain alert for 20 minutes, and were able to provide informed consent. Patients in the present analysis completed follow up neuropsychological assessment at six-months with the Oxford Cognitive Screen-Plus to assess executive function. Stroke lesions were manually delineated on acute clinical brain scans allowing us to quantify focal stroke-specific white matter damage using the HCP-842 tractography atlas. Leukoaraiosis was visually rated on clinical scans using the Age-Related White Matter Changes scale. RESULTS This study included data from 90 stroke patients (mean age = 73.76 years; 47.78% female). Multiple linear regression analyses showed that the presence of leukoaraiosis predicted poorer executive functioning six-months after stroke (B = -0.33, p = .031, 95% CI [-0.64 -0.03]). However, post-stroke executive functioning was not predicted by stroke-specific damage to white matter tracts. CONCLUSIONS Overall, these results provide novel insight into the neural substrates underlying post-stroke executive dysfunction and highlight the prognostic utility of using routine clinical CT scans to assess leukoaraiosis.

A Narrative Review of Circular RNAs in Brain Development and Diseases of Preterm Infants

Circular RNAs (circRNAs) generated by back-splicing are the vital class of non-coding RNAs (ncRNAs). Circular RNAs are highly abundant and stable in eukaryotes, and many of them are evolutionarily conserved. They are blessed with higher expression in mammalian brains and could take part in the regulation of physiological and pathophysiological processes. In addition, premature birth is important in neurodevelopmental diseases. Brain damage in preterm infants may represent the main cause of long-term neurodevelopmental disorders in surviving babies. Until recently, more and more researches have been evidenced that circRNAs are involved in the pathogenesis of encephalopathy of premature. We aim at explaining neuroinflammation promoting the brain damage. In this review, we summarize the current findings of circRNAs properties, expression, and functions, as well as their significances in the neurodevelopmental impairments, white matter damage (WMD) and hypoxic-ischemic encephalopathy (HIE). So we think that circRNAs have a direct impact on neurodevelopment and brain injury, and will be a powerful tool in the repair of the injured immature brain. Even though their exact roles and mechanisms of gene regulation remain elusive, circRNAs have potential applications as diagnostic biomarkers for brain damage and the target for neuroprotective intervention.

Histological Findings After Aortic Cross-Clamping in Preclinical Animal Models

Spinal cord ischemic injury and paralysis are devastating complications after open surgical repair of thoracoabdominal aortic aneurysms. Preclinical models have been developed to simulate the clinical paradigm to better understand the neuropathophysiology and develop therapeutic treatment. Neuropathological findings in the preclinical models have not been comprehensively examined before. This systematic review studies the past 40 years of the histological findings after open surgical repair in preclinical models. Our main finding is that damage is predominantly in the grey matter of the spinal cord, although white matter damage in the spinal cord is also reported. Future research needs to examine the neuropathological findings in preclinical models after endovascular repair, a newer type of surgical repair used to treat aortic aneurysms.

Impact of sex differences on thrombin-induced hydrocephalus and white matter injury: the role of neutrophils

Background Thrombin has been implicated in playing a role in hydrocephalus development following intraventricular hemorrhage (IVH). However, the mechanisms underlying the sex differences to the detrimental effects of thrombin post-IVH remain elusive. Method Three-month old male and female Sprague-Dawley rats underwent unilateral intracerebroventricular (ICV) injections of 3U or 5U thrombin, or saline, to examine differences in thrombin-induced hydrocephalus and white matter injury. Mortality, and lateral ventricle volume and white matter injury were measured on magnetic resonance imaging evaluation at 24 h post-injection. In addition, male rats were pretreated with 17-β estradiol (E2, 5 mg/kg) or vehicle at 24 and 2 h prior to ICV injection of 3U thrombin. All rats were euthanized at 24 h post-injection for histology and immunohistochemistry. Results ICV injection of 5U thrombin caused 100 and 0% mortality in female and male rats, respectively. 3U of thrombin resulted in significant ventricular dilation and white matter damage at 24 h in both male and female rats, but both were worse in females (p < 0.05). Furthermore, neutrophil infiltration into choroid plexus and periventricular white matter was enhanced in female rats and may play a critical role in the sex difference in brain injury. Pre-treating male rats with E2, increased thrombin (3U)-induced hydrocephalus, periventricular white matter injury and neutrophil infiltration into the choroid plexus and white matter. Conclusions ICV thrombin injection induced more severe ventricular dilation and white matter damage in female rats compared to males. Estrogen appears to contribute to this difference which may involve greater neutrophil infiltration in females. Understanding sex differences in thrombin-induced brain injury may shed light on future interventions for hemorrhagic stroke.

Cognitive Impairment in Multiple System Atrophy Is Related to White Matter Damage Detected by the T1-Weighted/T2-Weighted Ratio

<b><i>Introduction:</i></b> This study aimed to use a novel MRI contrast, the standardized T1-weighted/T2-weighted (sT1w/T2w) ratio, to assess damage of the white matter and gray matter in multiple system atrophy (MSA). Furthermore, this study investigated whether the sT1w/T2w ratio was associated with cognitive impairment in MSA. <b><i>Methods:</i></b> The white matter and gray matter sT1w/T2w ratio of 37 MSA patients and 19 healthy controls were measured. Correlation analyses were used to evaluate the relationship between sT1w/T2w ratio values and clinical variables, and a multivariate analysis was used to identify independent factors associated with cognitive impairment in MSA. <b><i>Results:</i></b> MSA patients showed a higher white matter sT1w/T2w ratio value than controls (<i>p</i> &#x3c; 0.001), and the white matter sT1w/T2w ratio value was significantly correlated with the International Cooperative Ataxia Rating Scale score (<i>r</i> = 0.377, <i>p</i> = 0.021) and the Addenbrooke’s cognitive examination III score (<i>r</i> = −0.438, <i>p</i> = 0.007). Cognitively impaired MSA patients had a significantly higher white matter sT1w/T2w ratio value than cognitively preserved MSA patients (<i>p</i> = 0.010), and the multiple logistic regression analysis revealed that the median white matter sT1w/T2w ratio value was independently associated with cognitive impairment in MSA. <b><i>Conclusion:</i></b> The sT1w/T2w ratio is sensitive to degenerative changes in the white matter that is associated with cognitive ability in MSA patients.