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

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

Longitudinal Neuropathological Consequences of Extracranial Radiation Therapy in Mice

“…The genes involved with astrocyte function including Amigo2 , Gfap , Al464131 , Hspb1 , and Nrcam were significantly changed between the mice prescribed ECRT and the control mice. Amigo2 is an A1-neurtoxic-associated gene in astrocytes and is involved in regulating cell survival, adhesion, neurite development, axon tract formation, and angiogenesis [ 69 , 70 , 71 ]. In a prior study, mice treated with brain irradiation had a significantly upregulated Amigo2 expression in the hippocampus from 24 h to 1 week post treatment [ 69 ].…”

Disease-Associated Neurotoxic Astrocyte Markers in Alzheimer Disease Based on Integrative Single-Nucleus RNA Sequencing

“…Each experiment ensured a value of E > 10(Charan and Kantharia 2013 ). Following previous research guidelines and setting a significance criterion at α = 0.05 and power at 0.80, the minimum required sample size with this effect size for a Wilcoxon-Mann Whitney test between two groups was determined to be N = 3 (Reid et al 2023 ). In order to bolster data robustness, 5–6 animals were included in each experimental group.…”

“…In order to bolster data robustness, 5–6 animals were included in each experimental group. According to existing literature (Reid et al 2023 ), the least sample size required is N = 4. Nevertheless, factoring in the diversity in effect size and data, it is postulated that a sample size of N = 6–7 per group would be adequate.…”

Ischemic Brain Injury: Involvement of Lipids in the Pathophysiology of Stroke and Therapeutic Strategies

“…NPD1 inhibits leukocyte infiltration mediated by brain ischemia–reperfusion, decreases proinflammatory gene expression, and increases neurogenesis [ 118 , 134 ]. The combination of resolvin D1 (RvD1) with NPD1 improves neuroprotection after focal cerebral ischemia in rats [ 135 ]. The exogenous supply of RvD2 via intraperitoneal injection, another derivative of ω-3 PUFAs, reversed cerebral ischemia–reperfusion injury caused by MCA occlusion by decreasing inflammation, brain edema, and neurological scores [ 136 , 137 ].…”