NOS knockout or inhibition but not disrupting PSD-95-NOS interaction protect against ischemic brain damage

Kleinschnitz, Christoph; Mencl, Stine; Kleikers, Pamela W. M.; Schuhmann, Michael K.; López, Manuela G.; Casas, Ana I.; Sürün, Bilge; Reif, Andreas; Schmidt, Harald

doi:10.1177/0271678x16657094

Cited by 18 publications

(16 citation statements)

References 15 publications

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“…This outcome correlates with literature data on the efficacy of Tat-NR2B9c in a tMCAO mouse model, where a 3 nmol/g dose was ineffective, but 10 nmol/g reduced infarct size by 24-26% (Teves et al, 2016). Likewise, another study did not demonstrate any effects of 3 nmol/g Tat-NR2B9c on infarct size in their tMCAO mouse model, but that study also failed to show any effects of UCCB01-144 at the same dose (Kleinschnitz et al, 2016). It should be noted that our dose-response study is not conducted as a single experiment, but as four rounds of tests (Bach et al, 2012 and Fig.…”

Section: Discussionsupporting

confidence: 88%

Selectivity, efficacy and toxicity studies of UCCB01-144, a dimeric neuroprotective PSD-95 inhibitor

et al. 2019

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Inhibition of postsynaptic density protein-95 (PSD-95) decouples N-methyl-D-aspartate (NMDA) receptor downstream signaling and results in neuroprotection after focal cerebral ischemia. We have previously developed UCCB01-144, a potent dimeric PSD-95 inhibitor, which binds PSD-95 with high affinity and is neuroprotective in experimental stroke. Here, we investigate the selectivity, efficacy and toxicity of UCCB01-144 and compare with the monomeric drug candidate Tat-NR2B9c. Fluorescence polarization using purified proteins and pull-downs of mouse brain lysates showed that UCCB01-144 potently binds all four PSD-95-like membrane-associated guanylate kinases (MAGUKs). In addition, UCCB01-144 affected NMDA receptor signaling pathways in ischemic brain tissue. UCCB01-144 reduced infarct size in young and aged male mice at various doses when administered 30 min after permanent middle cerebral artery occlusion, but UCCB01-144 was not effective in young male mice when administered 1 hour post-ischemia or in female mice. Furthermore, UCCB01-144 was neuroprotective in a transient stroke model in rats, and in contrast to Tat-NR2B9c, high dose of UCCB01-144 did not lead to significant changes in mean arterial blood pressure or heart rate. Overall, UCCB01-144 is a potent MAGUK inhibitor that reduces neurotoxic PSD-95-mediated signaling and improves neuronal survival following focal brain ischemia in rodents under various conditions and without causing cardiovascular side effects, which encourages further studies towards clinical stroke trials.

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Section: Discussionsupporting

confidence: 88%

Selectivity, efficacy and toxicity studies of UCCB01-144, a dimeric neuroprotective PSD-95 inhibitor

et al. 2019

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“…Previously, NOX4 was thought to be primarily relevant in the vasculature. Neuronal autotoxicity in stroke, also termed excitotoxicity, was previously ascribed primarily to nitric oxide overproduction ( 27 ) and neurotrauma ( 28 ). However, both in vivo and also importantly in an ex vivo brain slice model free of BBB effects, neuronal NOX4 was clearly a major contributor to cellular autotoxicity upon ischemia or hypoxia.…”

Section: Discussionmentioning

confidence: 99%

NOX4-dependent neuronal autotoxicity and BBB breakdown explain the superior sensitivity of the brain to ischemic damage

Casas

Geuß

Kleikers

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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126

110

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SignificanceWhy the brain is uniquely sensitive to hypoxia and which cells are involved is incompletely understood. Here we identify that, upon ischemic stroke, in endothelial cells and neurons the reactive oxygen-forming NADPH oxidase 4 (NOX4) causes breakdown of the BBB and neuronal cell death. This mechanism is unique to the brain and not found in other forms of ischemia in the body. Genetic deletion of either cell type (endothelial or neuronal) or pharmacological inhibition of NOX4 leads to a significant reduction of infarct volume and direct neuroprotection. This mechanism explains the unique vulnerability of the hypoxic brain compared with other organs and provides a clear rationale for first-in-class neuroprotective therapies in stroke.

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“…Neurogenesis promotes brain recovery after ischemic stroke[1–5]. After stroke, the neural stem/progenitor cells that express glial fibrillary acidic protein (GFAP) and nestinin within the subventricular zone (SVZ) gradually differentiate into transit-amplifying cells that express mammalian achaete-scute homolog 1 (Mash1) and neuroblasts that express doublecortin (DCX) [6–8].…”

Section: Introductionmentioning

confidence: 99%

Alpha-7 Nicotinic Receptor Signaling Pathway Participates in the Neurogenesis Induced by ChAT-Positive Neurons in the Subventricular Zone

Wang

et al. 2017

Transl. Stroke Res.

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Choline acetyltransferase-positive (ChAT+) neurons within the subventricular zone (SVZ) have been shown to promote neurogenesis after stroke in mice by secreting acetylcholine (ACh); however, the mechanisms remain unclear. Receptors known to bind ACh include the nicotinic ACh receptors (nAChRs), which are present in the SVZ and have been shown to be important for cell proliferation, differentiation, and survival. In this study, we investigated the neurogenic role of the α7 nAChR in a mouse model of middle cerebral artery occlusion (MCAO) by using α7 nAChR inhibitor methyllycaconitine. Mice subjected to MCAO exhibited elevated expression of cytomembrane and nuclear fibroblast growth factor receptor 1 (FGFR1), as well as increased expression of PI3K, pAkt, doublecortin (DCX), polysialylated neuronal cell adhesion molecule (PSA-NCAM), and mammalian achaete-scute homolog 1 (Mash1). MCAO mice also had more GFAP/BrdU-positive cells and DCX-positive cells in the SVZ than did the sham-operated group. Methyllycaconitine treatment increased cytomembrane FGFR1 expression and GFAP/BrdU-positive cells, upregulated the levels of PI3K and pAkt, decreased nuclear FGFR1 expression, decreased the number of DCX-positive cells, and reduced the levels of DCX, PSA-NCAM, and Mash1 in the SVZ of MCAO mice compared with levels in vehicle-treated MCAO mice. MCAO mice treated with α7 nAChR agonist PNU-282987 exhibited the opposite effects. Our data show that α7 nAChR may decrease the proliferation of neural stem cells and promote differentiation of existing neural stem cells after stroke. These results identify a new mechanism of SVZ ChAT+ neuron-induced neurogenesis.

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NOS knockout or inhibition but not disrupting PSD-95-NOS interaction protect against ischemic brain damage

Cited by 18 publications

References 15 publications

Selectivity, efficacy and toxicity studies of UCCB01-144, a dimeric neuroprotective PSD-95 inhibitor

Selectivity, efficacy and toxicity studies of UCCB01-144, a dimeric neuroprotective PSD-95 inhibitor

NOX4-dependent neuronal autotoxicity and BBB breakdown explain the superior sensitivity of the brain to ischemic damage

Alpha-7 Nicotinic Receptor Signaling Pathway Participates in the Neurogenesis Induced by ChAT-Positive Neurons in the Subventricular Zone

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