Effects of Deep Hypothermic Circulatory Arrest on the Blood Brain Barrier in a Cardiopulmonary Bypass Model – A Pilot Study

Bartels, Karsten; Ma, Qing; Venkatraman, Talaignair N.; Campos, Christopher R.; Smith, Lydia; Cannon, Ronald E.; Podgoreanu, Mihai V.; Lascola, Christopher D.; Miller, David S.; Mathew, Joseph P.

doi:10.1016/j.hlc.2014.04.131

Cited by 24 publications

(15 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In normal physiology, tight junctions between endothelial cells maintain the integrity of the blood-CSF barrier. However, the blood-brain barrier (BBB) is disrupted after HCA [7, 12, 29, 30], which creates an opportunity for nanoparticles to enter the brain parenchyma. Although the precise size of blood-CSF barrier leakage in the HCA-induced brain injury is unclear in this model, our results suggest that crossing of the BBB is facilitated by the hydroxyl-terminated PAMAM dendrimers’ sub-10 nm size and neutrally-charged surface properties.…”

Section: Resultsmentioning

confidence: 99%

Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model

Zhang

Magruder

Lin³

et al. 2017

Journal of Controlled Release

View full text Add to dashboard Cite

Hypothermic circulatory arrest (HCA) provides neuroprotection during cardiac surgery but entails an ischemic period that can lead to excitotoxicity, neuroinflammation, and subsequent neurologic injury. Hydroxyl polyamidoamine (PAMAM) dendrimers target activated microglia and damaged neurons in the injured brain, and deliver therapeutics in small and large animal models. We investigated the effect of dendrimer size on brain uptake and explored the pharmacokinetics in a clinically-relevant canine model of HCA-induced brain injury. Generation 6 (G6, ~6.7 nm) dendrimers showed extended blood circulation times and increased accumulation in the injured brain compared to generation 4 dendrimers (G4, ~4.3 nm), which were undetectable in the brain by 48 hrs after final administration. High levels of G6 dendrimers were found in cerebrospinal fluid (CSF) of injured animals with a CSF/serum ratio of ~20% at peak, a ratio higher than that of many neurologic pharmacotherapies already in clinical use. brain penetration (measured by drug CSF/serum level) of G6 dendrimers correlated with the severity of neuroinflammation observed. G6 dendrimers also showed decreased renal clearance rate, slightly increased liver and spleen uptake compared to G4 dendrimers. These results, in a large animal model, may offer insights into the potential clinical translation of dendrimers.

show abstract

Section: Resultsmentioning

confidence: 99%

Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model

Zhang

Magruder

Lin³

et al. 2017

Journal of Controlled Release

View full text Add to dashboard Cite

show abstract

“…Animal studies have suggested the POCD may be caused be either excessive neuroinflammation after surgery (79), a failure to resolve inflammation (80,81), blood-brain barrier/endothelial dysfunction (82–84), and/or pre-existing Alzheimer’s disease pathology (reviewed in (28)). Activation of the innate immune system is increasingly appreciated as an underlying factor in several neurodegenerative conditions, including Alzheimer’s disease.…”

Section: What Causes Pocd?mentioning

confidence: 99%

Postoperative Cognitive Dysfunction

Berger

Nadler

Browndyke

et al. 2015

Anesthesiology Clinics

220

119

View full text Add to dashboard Cite

Ever since Bedford’s seminal Lancet case series in 1955, we have known that perioperative care is sometimes followed by significant cognitive dysfunction (1). Although the safety of perioperative care has improved dramatically since 1955, the descriptions of cognitive dysfunction in that case series are eerily similar to the complaints of current patients suffering from post-operative cognitive dysfunction (POCD). POCD remains a common post-operative complication associated with significant morbidity and even mortality, especially among elderly patients. There has been a great deal of interest in and controversy about POCD, from how it is measured, to how long it lasts, to its precise implications for patients. This interest and controversy is reflected partly in the increasing number of papers published on this subject recently (shown in Figure 1). Recent work has also suggested surgery may be associated with cognitive improvement in some patients (2–4), termed Post-Operative Cognitive Improvement (POCI). As the number of surgeries performed worldwide approaches 250 million per year (5) (with an increasing number elderly patients), optimizing postoperative cognitive function and preventing/treating POCD are major public health issues. In this article we review the literature on POCD and POCI, and discuss current research challenges in this area.

show abstract

“…Similar neuropathology with macrophage infiltration and defective phagocytosis has been highlighted in the brain of AD patients (66) and this may be mediated by changes in BBB permeability during the neurodegenerative process (67). Changes in BBB permeability and function have been reported in several models of surgery-induced cognitive decline, including orthopedic (30), cardiac (68) and abdominal (54) surgery-induced cognitive decline, suggesting a role of endothelial and other glia cells contributing to cognitive decline.…”

Section: Neuroinflammation and Cns Functionmentioning

confidence: 56%

The Role of Inflammation in Postoperative Cognitive Dysfunction

Xu¹,

Yang²,

Terrando³

2014

J Anesth Perioper Med

View full text Add to dashboard Cite

Aim of review:Postoperative cognitive dysfunction (POCD) is a common complication following surgery, especially in the elderly population. Surgery exposes patients to extensive trauma, blood loss, and tissue injury, all of which contribute to an inflammatory response. In recent years, inflammation has been shown to be a key contributor to the pathogenesis of cognitive decline and neuroinflammatory processes, both in animal models and initial clinical observations. Method: We review the recent literatures on the proposed mechanisms whereby peripheral trauma leads to cognitive impairments and some of the new neuroprotective strategies that may be implemented to prevent neuroinflammation and POCD. Recent findings: Changes in pro-inflammatory cytokines, alarmins, macrophage activation and blood-brain barrier (BBB) dysfunction have been proven to be related to the pathogenesis of cognitive decline using a variety of models, reagents, and technologies. Strategies to harness these pathways through anti-inflammatory and pro-resolving strategies show remarkable effects in modulating neuronal function, synaptic plasticity, glia activity and memory processes. Summary: Further studies are needed to better identify the patients at higher risk for cognitive decline in the postoperative period and which interventions may be suitable for translation and new clinical trials.

show abstract

Effects of Deep Hypothermic Circulatory Arrest on the Blood Brain Barrier in a Cardiopulmonary Bypass Model – A Pilot Study

Cited by 24 publications

References 10 publications

Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model

Generation-6 hydroxyl PAMAM dendrimers improve CNS penetration from intravenous administration in a large animal brain injury model

Postoperative Cognitive Dysfunction

The Role of Inflammation in Postoperative Cognitive Dysfunction

Contact Info

Product

Resources

About