NPD1 Plus RvD1 Mediated Ischemic Stroke Penumbra Protection Increases Expression of Pro-homeostatic Microglial and Astrocyte Genes

Cellular and Molecular Neurobiology · 12 authors, 5 centres

AI SUMMARY

FIDELITY 100%

POPULATIONRats subjected to middle cerebral artery occlusion (MCAo) to model ischemic stroke.

INTERVENTIONCombination treatment with NPD1 and RvD1 at various doses and timepoints after MCAo.

COMPARISONSaline (vehicle) control.

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AGENT 01 · STRUCTURED SUMMARY

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TL;DR

This preclinical study in rats found that a combination of the specialized pro-resolving mediators NPD1 and RvD1, administered after a stroke, significantly reduced brain lesion volume and improved neurological function. The treatment also promoted a shift toward protective microglial and astrocyte gene expression in the ischemic penumbra.

Full summary

912 CHARS

This preclinical study used a rat model of transient middle cerebral artery occlusion (MCAo) to evaluate the neuroprotective effects of the lipid mediators NPD1 and RvD1, alone and in combination. The researchers first conducted a dose-response experiment to find an effective dose, then a therapeutic window study to determine how long after stroke onset the treatment remained effective. The central result was that the combination NPD1+RvD1, particularly at a moderate dose of 222 µg/kg, significantly improved neurological functional scores and reduced lesion volume when administered up to 6 hours after stroke. Mechanistic analysis of the ischemic penumbra at 24 hours showed the treatment increased expression of genes associated with homeostatic microglia (Fcrls, Tmem119) and reactive astrocytes (e.g., Osmr, Tm4sf1, Thbs2), suggesting a shift toward pro-survival and anti-inflammatory glial phenotypes.

PICO

PPOPULATION

Rats subjected to middle cerebral artery occlusion (MCAo) to model ischemic stroke.

IINTERVENTION

Combination treatment with NPD1 and RvD1 at various doses and timepoints after MCAo.

OOUTCOME

Neurological functional scores and T2-weighted MRI lesion volume.

STUDY TYPE

other

SPECIALTY

neurology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10477115

NPD1 Plus RvD1 Mediated Ischemic Stroke Penumbra Protection Increases Expression of Pro-homeostatic Microglial and Astrocyte Genes

Cellular and Molecular Neurobiology

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ABSTRACT

Abstract Neuroprotection to attenuate or block the ischemic cascade and salvage neuronal damage has been extensively explored for treating ischemic stroke. However, despite increasing knowledge of the physiologic, mechanistic, and imaging characterizations of the ischemic penumbra, no effective neuroprotective therapy has been found. This study focuses on the neuroprotective bioactivity of docosanoid mediators: Neuroprotectin D1 (NPD1), Resolvin D1 (RvD1), and their combination in experimental stroke. Molecular targets of NPD1 and RvD1 are defined by following dose–response and therapeutic window. We demonstrated that treatment with NPD1, RvD1, and combination therapy provides high-grade neurobehavioral recovery and decreases ischemic core and penumbra volumes even when administered up to 6 h after stroke. The expression of the following genes was salient: (a) Cd163, an anti-inflammatory stroke-associated gene, was the most differentially expressed gene by NPD1+RvD1, displaying more than a 123-fold upregulation in the ipsilesional penumbra (Lisi et al., Neurosci Lett 645:106–112, 2017); (b) 100-fold upregulation takes place in astrocyte gene PTX3 , a key regulator of neurogenesis and angiogenesis after cerebral ischemia (. Rodriguez-Grande et al., J Neuroinflammation 12:15, 2015); and (c) Tmem119 and P2y12 , two markers of homeostatic microglia, were found to be enhanced by ten- and fivefold, respectively (Walker et al. Int J Mol Sci 21:678, 2020). Overall, we uncovered that protection after middle cerebral artery occlusion (MCAo) by the lipid mediators elicits expression of microglia and astrocyte-specific genes ( Tmem119, Fcrls, Osmr, Msr1, Cd68, Cd163, Amigo2, Thbs1, and Tm4sf1 ) likely participating in enhancing homeostatic microglia, modulating neuroinflammation, promoting DAMP clearance, activating NPC differentiation and maturation, synapse integrity and contributing to cell survival. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s10571-023-01363-3. Keywords: Neuroprotection, Ischemic core, Lipid mediators, Apoptosis

CITATION EXPORT

Madigan M Reid, Marie-Audrey I Kautzmann, Gethein Andrew et al.. NPD1 Plus RvD1 Mediated Ischemic Stroke Penumbra Protection Increases Expression of Pro-homeostatic Microglial and Astrocyte Genes. Cellular and Molecular Neurobiology. (2023). https://doi.org/10.1007/s10571-023-01363-3

AUTHORS

12 · 5 CENTRES

Madigan M Reid, Marie-Audrey I Kautzmann, Gethein Andrew, Andre Obenaus, Pranab K Mukherjee, Larissa Khoutorova, Jeff X Ji, Cassia R Roque, Reinaldo B Oria, Bola F Habeb, Ludmila Belayev, Nicolas G Bazan

1Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112 USA
2Department of Pediatrics, School of Medicine, University of California, Irvine, CA 92618 USA
3Laboratory of the Biology of Tissue Healing, Ontogeny and Nutrition, Department of Morphology and Institute of Biomedicine, School of Medicine, Federal University of Ceara, Fortaleza, Brazil
4Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, Neuroscience Center of Excellence, 2020 Gravier Street, Suite D, New Orleans, LA 70112 USA
5Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, 2020 Gravier St, Suite 9B16, Room 935A, New Orleans, LA 70112 USA