Biology subjects

Buchan, A. M.

Publications and source records attributed to Buchan, A. M..

6 recordsLinked to original sources

bioRxiv2025

Shear stress targeted delivery of nitroglycerin to brain collaterals improves ischaemic stroke outcome

In patients with ischaemic stroke, retrograde perfusion of the penumbra by the leptomeningeal collateral vessels (LMCs) is a strong predictor of clinical outcome, thus raising the possibility that enhancing LMC flow could offer a novel therapeutic approach. Here, using computational modelling we show that LMCs experience elevated fluid shear stress that is significantly higher than that in other blood vessels during ischaemic stroke in animals and humans. We take advantage of this to selectively enhance flow in LMCs using shear-activated nanoparticle aggregates carrying the vasodilator nitroglycerin (NG-NPAs) that specifically release drug in regions of vessels with high shear stress ([≥]100 dyne/cm2). The NG-NPAs significantly increased LMC-mediated penumbral perfusion, decreased infarct volume, and reduced neurological deficit without altering systemic blood pressure in a rat ischaemic stroke model. The NG-NPAs also did not cause known common side effects of systemic nitrate administration, such as systemic hypotension, cerebral vascular steal, cortical vein dilation, or intracranial pressure elevation. Systemic administration of free NG at the maximal tolerated dose, which was ten times higher than the dose of NG used in the NG-NPAs, did not enhance LMC perfusion and dropped blood pressure. Thus, packaging NG within shear-activated NPAs can potentially enable this widely available vasodilator to become a highly effective therapeutic for ischaemic stroke.

physiology↗

bioRxiv2025

2-Deoxy-D-glucose chemical exchange-sensitive spin-lock MRI of cerebral glucose metabolism after stroke in the rat

Rapid breakdown of cerebral glucose metabolism is a hallmark in stroke pathology. Metabolic activity delineates the penumbra from the infarct core, representing tissue that is potentially salvageable by therapeutic interventions. Tools to image dynamics of glucose and its spatial distribution could provide biomarkers of disease severity and of the success of therapeutic interventions. Here, we developed a new protocol to measure glucose metabolism in a rat model of stroke using chemical exchange-sensitive spin-lock (CESL) MRI of the glucose analog 2-deoxy-D-glucose (2DG). We further implemented a protocol that combines 2DG-CESL-MRI with perfusion and diffusion MRI to relate this new signal to established definitions of hypoperfused tissue, cytotoxic edema and the penumbra. We found that 2DG-CESL-MRI provides a biomarker of disturbed glucose metabolism after stroke with high effect size. This is the first study to investigate CESL MRI of 2DG in the context of metabolism imaging in rodent stroke.

neuroscience↗

bioRxiv2024

Rapamycin Treatment Reduces Brain Pericyte Constriction in Ischemic Stroke

The contraction and subsequent death of brain pericytes may play a role in microvascular no-reflow following the re-opening of an occluded artery during ischemic stroke. Mammalian target of rapamycin (mTOR) inhibition has been shown to reduce motility/contractility of various cancer cell lines and reduce neuronal cell death in stroke. However, the effects of mTOR inhibition on brain pericyte contraction and death during ischemia have not yet been investigated. Cultured pericytes exposed to simulated ischemia for 12 hours in vitro contracted after less than 1 h, which was about 7h prior to cell death. Rapamycin significantly reduced the rate of pericyte contraction during ischemia, however, it did not have a significant effect on pericyte viability at any time point. Rapamycin appeared to reduce pericyte contraction through a RhoA-dependent pathway, independent of changes in intracellular calcium. Using a mouse model of middle cerebral artery occlusion, rapamycin significantly increased the diameter of capillaries underneath pericytes and increased the number of open capillaries 30 minutes following recanalization. Our findings suggest rapamycin may be a useful adjuvant therapeutic to reduce pericyte contraction and improve cerebral reperfusion post-stroke.

neuroscience↗

bioRxiv2023

Post-stroke rapamycin treatment improves post-recanalization cerebral blood flow and outcome in rats

Ischaemic stroke treatment is limited to recanalizing the occluded vessel, while there is no approved adjunctive cerebroprotective therapy to protect either the neurons and parenchyma or the neurovascular unit. Pharmacological inhibition of mammalian target of rapamycin-1 (mTORC1) with rapamycin has shown promise in reducing infarct volume and improving functional outcomes. However, previous studies that investigated the effects of rapamycin on the vasculature and cerebral blood flow (CBF), administered rapamycin prior to or during stroke induction, thus limiting the potential for clinical translation. Therefore we investigated whether rapamycin maintains its cerebrovascular protective effect when administered immediately after recanalization following 90 minutes stroke in Wistar rats. We show, that rapamycin significantly improved post-recanalization cerebral blood flow (CBF), suggesting a beneficial neurovascular effect of rapamycin. Rats treated with rapamycin had smaller infarct volumes and improved functional outcomes compared to the control animals at three days post-stroke. The mechanisms of the overall positive effects seen in this study are likely due to rapamycins hyperacute effects on the neurovasculature, as shown with increased CBF during this phase. This paper shows that rapamycin treatment is a promising adjunct cerebroprotective therapy option for ischemic stroke.

neuroscience↗

bioRxiv2022

The effects of fasting on ischemic infarcts in the rat

BackgroundInflammation has been found to be largely detrimental early in the acute phase of stroke but beneficial at more chronic stages. Fasting has been shown to reduce inflammation acutely. We aimed to determine whether post-ischemic fasting improves stroke outcomes through attenuated inflammation. MethodsAfter an endothelin-1 lesion was created in the striatum, animals were subjected to either normal feeding or water-only fasting for 24 hours. ResultsIt was found that at 24 hours, fasting reduced infarct volume and BBB breakdown and lowered both circulating and brain neutrophils. ConclusionsThese findings suggest that fasting is a potentially beneficial non-pharmacological additive therapeutic option for cerebral ischemia, which might act by reducing inflammation in the acute disease stage.

neuroscience↗

bioRxiv2020

A retrospective analysis of gender parity in scientific authorship in a biomedical research centre

ObjectiveScientific authorship is a vital marker of success in academic careers and gender equity is a key performance metric in research. However, there is little understanding of gender equity in publications in biomedical research centres funded by the National Institute for Health Research (NIHR). This study assesses the gender parity in scientific authorship of biomedical research. DesignA retrospective descriptive study. SettingNIHR Oxford Biomedical Research Centre. Data2409 publications accepted or published from 1 April 2012 to 31 March 2017. Main outcome measuresGender of authors, defined as a binary variable comprising either male or female categories, in six authorship categories: first author, joint first authors, first corresponding author, joint corresponding authors, last author and joint last authors. ResultsPublications comprised clinical research (39%, n=939), basic research (27%, n=643), and other types of research (34%, n=827). The proportion of female authors as first author (41%), first corresponding authors (34%) and last author (23%) was statistically significantly lower than male authors in these authorship categories. Of total joint first authors (n=458), joint corresponding authors (n=169), and joint last authors (n=229), female only authors comprised statistically significant smaller proportions i.e. 15% (n=69), 29% (n=49) and 10% (n=23) respectively, compared to male only authors in these joint authorship categories. There was a statistically significant association between gender of the last author(s) with gender of the first author(s) ({chi} 2 33.742, P < 0.001), corresponding author(s) ({chi}2 540.774, P < 0.001) and joint last author(s) ({chi} 2 91.291, P < 0.001). ConclusionsAlthough there are increasing trends of female authors as first authors (41%) and last authors (23%), female authors are underrepresented compared to male authors in all six categories of scientific authorship in biomedical research. Further research is needed to encourage gender parity in different categories of scientific authorship. Strengths and limitations of this studyO_LIThis is the first study to investigate gender parity in six categories of scientific authorship: first authors, first corresponding authors, last authors and three joint authorship categories i.e. joint first authors, joint corresponding authors and joint last authors in biomedical research. C_LIO_LIThis study provides an important benchmark on gender equity in scientific authorship for other NIHR funded centres and organisations in England. C_LIO_LIThe generalisability of the findings of this study may be limited due to differences in medical specialities, research areas, institutional cultures, and levels of support to individual researchers. C_LIO_LIUsing secondary sources for determining the gender of authors may have limitations, which could be avoided by seeking relevant information from original authors and institution affiliation at the time of submission. C_LI

scientific communication and education↗