Biology subjects

Beard, D. J.

Publications and source records attributed to Beard, D. J..

4 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↗

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↗

bioRxiv2023

Leakage beyond the primary infarction: A temporal analysis of cerebrovascular dysregulation at sites of hippocampal secondary neurodegeneration following cortical photothrombotic stroke

We have previously demonstrated that a cortical stroke causes persistent impairment of hippocampal-dependent cognitive tasks concomitant with secondary neurodegenerative processes such as amyloid-{beta} accumulation in the hippocampus, a region remote from the primary infarct. Interestingly, there is emerging evidence suggesting that deposition of amyloid-{beta} around cerebral vessels may lead to cerebrovascular structural changes, neurovascular dysfunction, and disruption of blood-brain barrier integrity. However, there is limited knowledge about the temporal changes of hippocampal cerebrovasculature after cortical stroke. In the current study, we aimed to characterise the spatiotemporal cerebrovascular changes after cortical stroke. This was done using the photothrombotic stroke model targeting the motor and somatosensory cortices of mice. Cerebrovascular morphology as well as the colocalization of amyloid-{beta} with vasculature and blood-brain-barrier integrity were assessed in the cortex and hippocampal regions at 7, 28 and 84 days post-stroke. Our findings showed transient cerebrovascular remodelling in the peri-infarct area up to 28 days post-stroke. Importantly, the cerebrovascular changes were extended beyond the peri-infarct region to the ipsilateral hippocampus and were sustained out to 84 days post-stroke. When investigating vessel diameter, we showed a decrease at 84 days in the peri-infarct and CA1 regions that was exacerbated in vessels with amyloid-{beta} deposition. Lastly, we showed sustained vascular leakage in the peri-infarct and ipsilateral hippocampus, indicative of a compromised blood-brain-barrier. Our findings indicate that hippocampal vasculature may represent an important therapeutic target to mitigate the progression of post-stroke cognitive impairment.

neuroscience↗