Quantification of leptomeningeal collateral blood flow in hypertensive rats during ischemic stroke.

Objectives: There is increasing evidence that poor leptomeningeal collateral blood flow in hypertensive animals is due to increased vascular myogenic tone, indicating that therapies to enhance collateral blood flow during ischemic stroke may be particularly effective. To develop such therapies, we need a greater understanding of the factors that regulate collateral blood flow in the setting of hypertension. Therefore, we aimed to quantify blood flow velocity, diameter and absolute blood flow in individual collateral vessels in an ischemic stroke model in spontaneously hypertensive rats (SHRs) and determine which factors had the greatest influence on blood flow.

The effect of nitroglycerin treatment on cerebral ischaemia: A systematic review and meta-analysis of animal studies.

Background: Nitroglycerin has been of considerable interest as a treatment for ischaemic stroke. Recent clinical trials with nitroglycerin transdermal patches during the acute phase of stroke failed to improve functional outcomes. Systematic review and meta-analysis of the effectiveness of nitroglycerin in preclinical models of ischaemic stroke has not previously been reported, despite several clinical trials.

Leakage beyond the primary lesion: 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-β accumulation in the hippocampus, a region remote from the primary infarct. Interestingly, there is emerging evidence suggesting that deposition of amyloid-β 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.

Tuberous sclerosis complex-1 (TSC1) contributes to selective neuronal vulnerability in Alzheimer's disease.

Aims: Selective neuronal vulnerability of hippocampal Cornu Ammonis (CA)-1 neurons is a pathological hallmark of Alzheimer's disease (AD) with an unknown underlying mechanism. We interrogated the expression of tuberous sclerosis complex-1 (TSC1; hamartin) and mTOR-related proteins in hippocampal CA1 and CA3 subfields.

Methods: A human post-mortem cohort of mild (n = 7) and severe (n = 10) AD and non-neurological controls (n = 9) was used for quantitative and semi-quantitative analyses.

Neurovascular coupling mechanisms in health and neurovascular uncoupling in Alzheimer's disease.

To match the metabolic demands of the brain, mechanisms have evolved to couple neuronal activity to vasodilation, thus increasing local cerebral blood flow and delivery of oxygen and glucose to active neurons. Rather than relying on metabolic feedback signals such as the consumption of oxygen or glucose, the main signalling pathways rely on the release of vasoactive molecules by neurons and astrocytes, which act on contractile cells. Vascular smooth muscle cells and pericytes are the contractile cells associated with arterioles and capillaries, respectively, which relax and induce vasodilation.

Growth Hormone Increases BDNF and mTOR Expression in Specific Brain Regions after Photothrombotic Stroke in Mice.

Aims: We have shown that growth hormone (GH) treatment poststroke increases neuroplasticity in peri-infarct areas and the hippocampus, improving motor and cognitive outcomes. We aimed to explore the mechanisms of GH treatment by investigating how GH modulates pathways known to induce neuroplasticity, focusing on association between brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR) in the peri-infarct area, hippocampus, and thalamus.

Methods: Recombinant human growth hormone (r-hGH) or saline was delivered (0.

Decreased Intracranial Pressure Elevation and Cerebrospinal Fluid Outflow Resistance: A Potential Mechanism of Hypothermia Cerebroprotection Following Experimental Stroke.

Background: Elevated intracranial pressure (ICP) occurs 18-24 h after ischaemic stroke and is implicated as a potential cause of early neurological deterioration. Increased resistance to cerebrospinal fluid (CSF) outflow after ischaemic stroke is a proposed mechanism for ICP elevation. Ultra-short duration hypothermia prevents ICP elevation 24 h post-stroke in rats.

Short-duration hypothermia completed prior to reperfusion prevents intracranial pressure elevation following ischaemic stroke in rats.

Reperfusion therapies re-establish blood flow after arterial occlusion and improve outcome for ischaemic stroke patients. Intracranial pressure (ICP) elevation occurs 18-24 h after experimental stroke. This elevation is prevented by short-duration hypothermia spanning the time of reperfusion.

Ultra-Short Duration Hypothermia Prevents Intracranial Pressure Elevation Following Ischaemic Stroke in Rats.

There is a transient increase in intracranial pressure (ICP) 18-24 h after ischaemic stroke in rats, which is prevented by short-duration hypothermia using rapid cooling methods. Clinical trials of long-duration hypothermia have been limited by feasibility and associated complications, which may be avoided by short-duration cooling. Animal studies have cooled faster than is achievable in patients.

Short-Duration Hypothermia Induction in Rats using Models for Studies examining Clinical Relevance and Mechanisms.

Therapeutic hypothermia (TH) is a powerful neuroprotective strategy that has provided robust evidence for neuroprotection in pre-clinical studies of neurological disorders. Despite strong pre-clinical evidence, TH has not shown efficacy in clinical trials of most neurological disorders. The only successful trials employing therapeutic hypothermia were related to cardiac arrest in adults and hypoxic ischemic injury in neonates.

The rise of pericytes in neurovascular research.

The popularity of pericyte research is increasing, and this was not more evident than at the recent 2019 Brain meeting in Yokohama which featured a large number of presentations focused on brain pericyte research, including the Presidential Symposium. In this article, we will provide a history of brain pericyte research, present the results of our analysis showing a substantial increase in brain pericyte research presented at Brain meetings since 2005, suggest reasons for their increased popularity, and comment on what the future holds for brain pericyte research.

Rapamycin Induces an eNOS (Endothelial Nitric Oxide Synthase) Dependent Increase in Brain Collateral Perfusion in Wistar and Spontaneously Hypertensive Rats.

Background And Purpose: Rapamycin is a clinically approved mammalian target of rapamycin inhibitor that has been shown to be neuroprotective in animal models of stroke. However, the mechanism of rapamycin-induced neuroprotection is still being explored. Our aims were to determine if rapamycin improved leptomeningeal collateral perfusion, to determine if this is through eNOS (endothelial nitric oxide synthase)-mediated vessel dilation and to determine if rapamycin increases immediate postreperfusion blood flow.

Investigation of the novel mTOR inhibitor AZD2014 in neuronal ischemia.

Introduction: Hamartin, a component of the tuberous sclerosis complex (TSC) that actively inhibits the mammalian target of rapamycin (mTOR), may mediate the endogenous resistance of Cornu Ammonis 3 (CA3) hippocampal neurons following global cerebral ischemia. Pharmacological compounds that selectively inhibit mTOR may afford neuroprotection following ischemic stroke. We hypothesize that AZD2014, a novel mTORC1/2 inhibitor, may protect neurons following oxygen and glucose deprivation (OGD).

The effect of rapamycin treatment on cerebral ischemia: A systematic review and meta-analysis of animal model studies.

Background: Amplifying endogenous neuroprotective mechanisms is a promising avenue for stroke therapy. One target is mammalian target of rapamycin (mTOR), a serine/threonine kinase regulating cell proliferation, cell survival, protein synthesis, and autophagy. Animal studies investigating the effect of rapamycin on mTOR inhibition following cerebral ischemia have shown conflicting results.

Rapamycin in ischemic stroke: Old drug, new tricks?

The significant morbidity that accompanies stroke makes it one of the world's most devastating neurological disorders. Currently, proven effective therapies have been limited to thrombolysis and thrombectomy. The window for the administration of these therapies is narrow, hampered by the necessity of rapidly imaging patients.

The role of the endoplasmic reticulum stress response following cerebral ischemia.

Background Cornu ammonis 3 (CA3) hippocampal neurons are resistant to global ischemia, whereas cornu ammonis (CA1) 1 neurons are vulnerable. Hamartin expression in CA3 neurons mediates this endogenous resistance via productive autophagy. Neurons lacking hamartin demonstrate exacerbated endoplasmic reticulum stress and increased cell death.

Intracranial Pressure Elevation 24 h after Ischemic Stroke in Aged Rats Is Prevented by Early, Short Hypothermia Treatment.

Stroke is predominantly a senescent disease, yet most preclinical studies investigate treatment in young animals. We recently demonstrated that short-duration hypothermia-treatment completely prevented the dramatic intracranial pressure (ICP) rise seen post-stroke in young rats. Here, our aim was to investigate whether a similar ICP rise occurs in aged rats and to determine whether short-duration hypothermia is an effective treatment in aged animals.

Ischemic penumbra as a trigger for intracranial pressure rise - A potential cause for collateral failure and infarct progression?

We have recently shown that intracranial pressure (ICP) increases dramatically 24 h after minor intraluminal thread occlusion with reperfusion, independent of edema. Some of the largest ICP rises were observed in rats with the smallest final infarcts. A possible alternate mechanism for this ICP rise is an increase of cerebrospinal fluid (CSF) volume secondary to choroid plexus damage (a known complication of the intraluminal stroke model used).

Intracranial pressure elevation after ischemic stroke in rats: cerebral edema is not the only cause, and short-duration mild hypothermia is a highly effective preventive therapy.

Correction to: Journal of Cerebral Blood Flow & Metabolism (2015) 35, 592–600; doi:10.1038/jcbfm.2014.

Intracranial pressure elevation reduces flow through collateral vessels and the penetrating arterioles they supply. A possible explanation for 'collateral failure' and infarct expansion after ischemic stroke.

Recent human imaging studies indicate that reduced blood flow through pial collateral vessels ('collateral failure') is associated with late infarct expansion despite stable arterial occlusion. The cause for 'collateral failure' is unknown. We recently showed that intracranial pressure (ICP) rises dramatically but transiently 24 hours after even minor experimental stroke.

Intracranial pressure elevation after ischemic stroke in rats: cerebral edema is not the only cause, and short-duration mild hypothermia is a highly effective preventive therapy.

In both the human and animal literature, it has largely been assumed that edema is the primary cause of intracranial pressure (ICP) elevation after stroke and that more edema equates to higher ICP. We recently demonstrated a dramatic ICP elevation 24 hours after small ischemic strokes in rats, with minimal edema. This ICP elevation was completely prevented by short-duration moderate hypothermia soon after stroke.

Cerebrospinal fluid is drained primarily via the spinal canal and olfactory route in young and aged spontaneously hypertensive rats.

Background: Many aspects of CSF dynamics are poorly understood due to the difficulties involved in quantification and visualization. In particular, there is debate surrounding the route of CSF drainage. Our aim was to quantify CSF flow, volume, and drainage route dynamics in vivo in young and aged spontaneously hypertensive rats (SHR) using a novel contrast-enhanced computed tomography (CT) method.