Date of Presentation

5-2-2024 12:00 AM

College

Rowan-Virtua School of Osteopathic Medicine

Poster Abstract

Background: The blood-brain barrier (BBB) is responsible for maintaining brain homeostasis and ultimately proper neuronal function. Disruption of the BBB, leading to increased BBB permeability, has been reported in several neurodegenerative diseases, including Alzheimer’s disease (AD) and traumatic brain injury (TBI). Lipoxins (LXs) are a class of arachidonate-derived eicosanoids, which are a class of specialized pro-resolving lipid mediators (SPMs). SPMs are known to inhibit immune response through inhibition of cellular infiltration, downregulation of pro-inflammatory mediators and upregulation of anti-inflammatory mediators. Hence, LXs are recognized as “breaking signals” in the inflammatory process. One form of LXs, Lipoxin A4 (LXA4), has been found to decreased production of proinflammatory mediators, inhibit neutrophils chemotaxis and infiltration to the site of injury, and promote the phagocytic clearance of debris by macrophages. Therefore, LXA4 serves a critical role in resolution of inflammatory process by regulating the activation of monocytes and modulating the generation of reactive oxygen species (ROS).

Hypothesis: LXA4 treatment reinstates the BBB integrity in a rodent model of acute BBB breakdown and inflammation.

Methods: Nine-month-old female Sprague Dawley rats were given an intravenous (IV) injection of 15 mg/kg lipopolysaccharide (LPS) through the tail for inducing acute inflammation and BBB breach. After three hours, the rats were injected with 9 µg/kg LXA4 or Saline (Vehicle control). Four treatment groups were thus developed: LPS only, LPS/LXA4, LXA4 only, and Saline only. Animals were euthanized at 24 hours of LPS treatment and brain samples were processed for paraffin-embedded sections and immunohistochemistry. Sections comprising of hippocampus and cortical regions were selected for detection of impaired BBB as demonstrated by the extravasation of immunoglobulin G (IgG) and IBA1 (microgliosis marker). The area of the cerebral cortex and number of cortical blood vessels presenting with IgG extravasation were estimated and compared between treatment groups. Similarly, IBA1 immunoreactivity was quantified using Color Deconvolution V9 tool of Aperio ImageScope (Leica BIOSYSTEMS).

Results: LXA4 treatment following LPS injection demonstrated decrease in the extent of IgG leak compared to LPS only group. Likewise, we observed significant decrease in microgliosis in LPS-LXA4 group compared to LPS only.

Conclusion: These preliminary results demonstrate potential beneficial effects of LXA4 in reinstating BBB integrity and reducing neuroinflammation in rat model of acute BBB breach and inflammation.

Keywords

Blood-Brain Barrier, Brain Chemistry, Lipoxins, Neurodegenerative Diseases, Disease Models

Disciplines

Disease Modeling | Laboratory and Basic Science Research | Medical Neurobiology | Medicine and Health Sciences | Nervous System Diseases | Neurology | Neuroscience and Neurobiology

Document Type

Poster

DOI

10.31986/issn.2689-0690_rdw.stratford_research_day.146

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May 2nd, 12:00 AM

A Preliminary Report on the Role of Lipoxin A4 in Reinstating the Blood-Brain Barrier Integrity in a Rodent Model of Acute Inflammation with Impaired Cerebrovasculature

Background: The blood-brain barrier (BBB) is responsible for maintaining brain homeostasis and ultimately proper neuronal function. Disruption of the BBB, leading to increased BBB permeability, has been reported in several neurodegenerative diseases, including Alzheimer’s disease (AD) and traumatic brain injury (TBI). Lipoxins (LXs) are a class of arachidonate-derived eicosanoids, which are a class of specialized pro-resolving lipid mediators (SPMs). SPMs are known to inhibit immune response through inhibition of cellular infiltration, downregulation of pro-inflammatory mediators and upregulation of anti-inflammatory mediators. Hence, LXs are recognized as “breaking signals” in the inflammatory process. One form of LXs, Lipoxin A4 (LXA4), has been found to decreased production of proinflammatory mediators, inhibit neutrophils chemotaxis and infiltration to the site of injury, and promote the phagocytic clearance of debris by macrophages. Therefore, LXA4 serves a critical role in resolution of inflammatory process by regulating the activation of monocytes and modulating the generation of reactive oxygen species (ROS).

Hypothesis: LXA4 treatment reinstates the BBB integrity in a rodent model of acute BBB breakdown and inflammation.

Methods: Nine-month-old female Sprague Dawley rats were given an intravenous (IV) injection of 15 mg/kg lipopolysaccharide (LPS) through the tail for inducing acute inflammation and BBB breach. After three hours, the rats were injected with 9 µg/kg LXA4 or Saline (Vehicle control). Four treatment groups were thus developed: LPS only, LPS/LXA4, LXA4 only, and Saline only. Animals were euthanized at 24 hours of LPS treatment and brain samples were processed for paraffin-embedded sections and immunohistochemistry. Sections comprising of hippocampus and cortical regions were selected for detection of impaired BBB as demonstrated by the extravasation of immunoglobulin G (IgG) and IBA1 (microgliosis marker). The area of the cerebral cortex and number of cortical blood vessels presenting with IgG extravasation were estimated and compared between treatment groups. Similarly, IBA1 immunoreactivity was quantified using Color Deconvolution V9 tool of Aperio ImageScope (Leica BIOSYSTEMS).

Results: LXA4 treatment following LPS injection demonstrated decrease in the extent of IgG leak compared to LPS only group. Likewise, we observed significant decrease in microgliosis in LPS-LXA4 group compared to LPS only.

Conclusion: These preliminary results demonstrate potential beneficial effects of LXA4 in reinstating BBB integrity and reducing neuroinflammation in rat model of acute BBB breach and inflammation.

 

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