Enlighten-Research publications by members of the University of Glasgow http://eprints.gla.ac.uk Minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label phase 3 trial with blinded endpoint

Key words: autophagy, Beclin 1, 3-methyladenine, amyloid β, c-secretase inhibitor, cerebral infarction, thalamus, secondary degeneration-S-phenylglycine t-butyl ester; LC3, microtubule-associated protein 1 light chain 3A; MCA, middle cerebral artery; MCAO, middle cerebral artery occlusion; RHRSP, stroke-prone renovascular hypertensive rats; shRNA, short-hairpin RNA Cerebral infarction can cause secondary degeneration of thalamus and delay functional recovery. However, the mechanisms underlying secondary degeneration are unclear. The present study aimed to determine the occurrence and contribution of autophagy to thalamic degeneration after cerebral infarction. Focal cerebral infarction was induced by distal middle cerebral artery occlusion (MCAO). Autophagic activation, Beclin 1 expression and amyloid b (Ab) deposits were determined by immunofluorescence, immunoblot and electron microscopy. Secondary damage to thalamus was assessed with Nissl staining and immunofluorescence analysis. Apoptosis was determined using TUNEL staining. The contribution of autophagy to the secondary damage was evaluated by shRNA-mediated downregulation of Beclin 1 and the autophagic inhibitor, 3-methyladenine (3-MA). The potential role of Ab in autophagic activation was determined with N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT). The results showed that the conversion of LC3-II, the formation of autophagosomes, and the levels of activated cathepsin B and Beclin 1 were significantly increased in the ipsilateral thalamus at 7 and 14 d after MCAO (p , 0.05 or 0.01). Both Beclin 1 knockdown and 3-MA treatment significantly reduced LC3-II conversion and autophagosome formation, which were accompanied by obvious decreases in neuronal loss, gliosis and apoptosis in the ipsilateral thalamus (p , 0.05 or 0.01). Additionally, DAPT treatment markedly reduced Ab deposits, which coincided with decreases in LC3-II conversion and autophagosome formation (p , 0.01). These results suggest that inhibition of autophagy by Beclin 1 knockdown can attenuate the secondary thalamic damage after focal cerebral infarction. Furthermore, Ab deposits may be involved in the activation of autophagy.

BackgroundIschemic postconditioning (IPost) protects the reperfused heart from infarction which has drawn much attention recently. However, studies to date have rarely investigated the role of microRNAs (miRNAs) in IPost. The aims of this study were to investigate whether miR-21 is involved in the protective effect of IPost against myocardial ischemia-reperfusion (I/R) injury and disclose the potential molecular mechanisms involved.Methods and ResultsWe found that miR-21 was remarkably up-regulated in mouse hearts after IPost. To determine the protective role of IPost-induced miR-21 up-regulation, the mice were divided into the following four groups: I/R group; I/R+IPost group (I/R mice treated with IPost); Antagomir-21+IPost+I/R group (I/R mice treated with anagomir-21 and IPost); Scramble+IPost+I/R group (I/R mice treated with scramble and IPost). The results showed IPost could reduce I/R injury-induced infarct size of the left ventricle, improve cardiac function, and prevent myocardial apoptosis, while knockdown of miR-21 with antagomir-21 could reverse these protective effects of IPost against mouse I/R injury. Furthermore, we confirmed that miR-21 plays a protective role in myocardial apoptosis through PTEN/Akt signaling pathway, which was abrogated by the PI3K inhibitor LY294002. The protective effect of miR-21 on myocardial apoptosis was further revealed in mouse hearts after IPost treatment in vivo.ConclusionsOur data clearly demonstrate that miR-21 is involved in IPost-mediated cardiac protection against I/R injury and dysfunction through the PTEN/Akt signaling pathway in vivo. Identifying the beneficial roles of IPost-regulated miRNAs in cardiac protection, which may be a rational target selection for ischemic cardioprotection.

White matter lesions (WMLs), also known as leukoaraiosis (LA) or white matter hyperintensities (WMHs), are characterized mainly by hyperintensities on T2-weighted or fluid-attenuated inversion recovery (FLAIR) images. With the aging of the population and the development of imaging technology, the morbidity and diagnostic rates of WMLs are increasing annually. WMLs are not a benign process. They clinically manifest as cognitive decline and the subsequent development of dementia. Although WMLs are important, their pathogenesis is still unclear. This review elaborates on the advances in the understanding of the pathogenesis of WMLs, focusing on anatomy, cerebral blood flow autoregulation, venous collagenosis, blood brain barrier disruption, and genetic factors. In particular, the attribution of WMLs to chronic ischemia secondary to venous collagenosis and cerebral blood flow autoregulation disruption seems reasonable. With the development of gene technology, the effect of genetic factors on the pathogenesis of WMLs is gaining gradual attention.

Serum uric acid (sUA) level may be associated with cognitive impairment/dementia. It is possible this relationship varies with dementia subtype, particularly between vascular dementias (VaD) and Alzheimer's (AD) or Parkinson's disease (PDD)-related dementia. We aimed to present a synthesis of all published data on sUA and relationship with dementia/cognition through systematic review and meta-analysis. We included studies that assessed the association between sUA and any measure of cognitive function or a clinical diagnosis of dementia. We pre-defined subgroup analyses for patients with AD, VaD, PDD, mild cognitive impairment (MCI), and mixed or undifferentiated. We assessed risk of bias/generalizability, and where data allowed, we performed meta-analysis to describe pooled measures of association across studies. From 4811 titles, 46 papers (n = 16,688 participants) met our selection criteria. Compared to controls, sUA was lower in dementia (SDM -0.33 (95%CI)). There were differences in association by dementia type with apparent association for AD (SDM -0.33 (95%CI)) and PDD (SDM -0.67 (95%CI)) but not in cases of mixed dementia (SDM 0.19 (95%CI)) or VaD (SDM -0.05 (95%CI)). There was no correlation between scores on Mini-Mental State Examination and sUA level (summary r 0.08, p = 0.27), except in patients with PDD (r 0.16, p = 0.003). Our conclusions are limited by clinical heterogeneity and risk of bias in studies. Accepting this caveat, the relationship between sUA and dementia/cognitive impairment is not consistent across all dementia groups and in particular may differ in patients with VaD compared to other dementia subtypes.