Effects of Dimeric PSD-95 Inhibition on Excitotoxic Cell Death and Outcome After Controlled Cortical Impact in Rats

Sommer, Jens; Bach, Anders; Malá, Hana; Gynther, Mikko; Bjerre, Ann-Sofie; Gram, Marie Gajhede; Marschner, Linda; Strømgaard, Kristian; Mogensen, Jesper; Pickering, Darryl S.

doi:10.1007/s11064-017-2381-y

Cited by 5 publications

(3 citation statements)

References 84 publications

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“…Therefore, the interaction between glutamate receptors and postsynaptic scaffold proteins contributes to the modulation of neuronal injury after TBI. Disruption of the interaction between PSD-95 and NR2B, a NMDAR subunit, reduced brain damage and improved neurological dysfunction after TBI 4,10 . Furthermore, Homer 1a attenuated neuronal injury and brain damage after TBI by differentially regulating group I mGluRs 11 .…”

Section: Discussionmentioning

confidence: 99%

Preso regulates NMDA receptor-mediated excitotoxicity via modulating nitric oxide and calcium responses after traumatic brain injury

Luo

et al. 2019

Cell Death Dis

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Traumatic brain injury (TBI) has become a major health concern worldwide, and the poor outcome of TBI increases the need for therapeutic improvement. Secondary injuries following TBI, including excitotoxicity, lead to synaptic dysfunction and provide potential targets for intervention. Postsynaptic scaffold proteins, which are involved in the regulation of excitotoxicity after neuronal injury, play a crucial role in modulating synaptic function. Therefore, exploring the role of postsynaptic scaffold proteins in TBI might uncover new treatments. In this study, we demonstrated that downregulated expression of the postsynaptic scaffold protein Preso protects against neuronal injury after TBI in vitro and in vivo, and these effects are related to the inhibition of N-methyl-D-aspartate receptor (NMDAR) function. Further study showed that Preso facilitates signaling from NMDAR to nitric oxide (NO) and calcium (Ca 2+ ) responses. First, the complex constituting NMDAR, postsynaptic density-95 (PSD-95), and neuronal nitric oxide synthase (nNOS) was shown to be involved in the Preso regulation of the NO response. Uncoupling the linkage between Preso and PSD-95 attenuated the stability of this complex and suppressed the regulatory effect of Preso on the NO response. In addition, phosphorylation of NMDAR by cyclin-dependent kinase 5 (CDK5) was shown to be responsible for the Preso-mediated Ca 2+ response, which was dependent on the interaction between Preso and CDK5. These results suggested that the association of Preso with NMDAR signaling can serve as a target for neuroprotection against TBI.

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Section: Discussionmentioning

confidence: 99%

Preso regulates NMDA receptor-mediated excitotoxicity via modulating nitric oxide and calcium responses after traumatic brain injury

Luo

et al. 2019

Cell Death Dis

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“…Differences in the degree of BBB permeation could explain the differences between the in vitro and in vivo effects of Tat-NR2B9c and Tat- N -dimer. Tat- N -dimer delivery to the brain parenchyma has been verified quantitatively using fluorescent labels in mice [ 12 ] and rats [ 13 ]. The BBB permeation by fluorescently labelled Tat- N -dimer has also been qualitatively assessed in live mice by two-photon microscopy imaging [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Conjugation of Therapeutic PSD-95 Inhibitors to the Cell-Penetrating Peptide Tat Affects Blood–Brain Barrier Adherence, Uptake, and Permeation

et al. 2020

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Novel stroke therapies are needed. Inhibition of the interaction between the postsynaptic density-95 (PSD-95)/disc large/ZO-1 (PDZ) domains of PSD-95 and the N-methyl-D-aspartate (NMDA) receptor has been suggested as a strategy for relieving neuronal damage. The peptides NR2B9c and N-dimer have been designed to hinder this interaction; they are conjugated to the cell-penetrating peptide Tat to facilitate blood–brain barrier (BBB) permeation and neuronal uptake. Tat-N-dimer exhibits 1000-fold better target affinity than Tat-NR2B9c, but the same magnitude of improvement is not observed in terms of therapeutic effect. Differences in BBB permeation by Tat-NR2B9c and Tat-N-dimer may explain this difference, but studies providing a direct comparison of Tat-NR2B9c and Tat-N-dimer are lacking. The aim of the present study was therefore to compare the BBB uptake and permeation of Tat-NR2B9c and Tat-N-dimer. The peptides were conjugated to the fluorophore TAMRA and their chemical stability assessed. Endothelial membrane association and cell uptake, and transendothelial permeation were estimated using co-cultures of primary bovine brain capillary endothelial cells and rat astrocytes. In vivo BBB permeation was demonstrated in mice using two-photon microscopy imaging. Tissue distribution was evaluated in mice demonstrating brain accumulation of TAMRA-Tat (0.4% ID/g), TAMRA-Tat-NR2B9c (0.3% ID/g), and TAMRA-Tat-N-dimer (0.25% ID/g). In conclusion, we demonstrate that attachment of NR2B9c or N-dimer to Tat affects both the chemical stability and the ability of the resulting construct to interact with and permeate the BBB.

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“…Because other types of acute brain injury, such as traumatic brain injury, share similar pathophysiological mechanisms as stroke, the efficacy of the dimer inhibitor was tested in animals with traumatic brain injury. However, no neuroprotective effect by this inhibitor was found in two recent studies using different animal models of traumatic brain injury (Sommer et al, 2017a;Sommer et al, 2017b,c).…”

Section: Pdz Domain Inhibitors In Neuronal Disordersmentioning

confidence: 97%

Emerging Themes in PDZ Domain Signaling

Liu

Fuentes

2019

International Review of Cell and Molecular Biology

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Post-synaptic density-95, disks-large and zonula occludens-1 (PDZ) domains are small globular proteineprotein interaction domains widely conserved from yeast to humans. They are composed of w90 amino acids and form a classical two a-helical/six b-strand structure. The prototypical ligand is the C-terminus of partner proteins; however, they also bind internal peptide sequences. Recent findings indicate that PDZ domains also bind phosphatidylinositides and cholesterol. Through their ligand interactions, PDZ domain proteins are critical for cellular trafficking and the surface retention of various ion channels. In addition, PDZ proteins are essential for neuronal signaling, memory, and learning. PDZ proteins also contribute to cytoskeletal dynamics by mediating interactions critical for maintaining cellecell junctions, cell polarity, and cell migration. Given their important biological roles, it is not surprising that their dysfunction can lead to multiple disease states. As such, PDZ domainecontaining proteins have emerged as potential targets for the development of small molecular inhibitors as therapeutic agents. Recent data suggest that the critical binding function of PDZ domains in cell signaling is more than just glue, and their binding function can be regulated by phosphorylation or allosterically by other binding partners. These studies also provide a wealth of structural and biophysical data that are beginning to reveal the physical features that endow this small modular domain with a central role in cell signaling.

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Effects of Dimeric PSD-95 Inhibition on Excitotoxic Cell Death and Outcome After Controlled Cortical Impact in Rats

Cited by 5 publications

References 84 publications

Preso regulates NMDA receptor-mediated excitotoxicity via modulating nitric oxide and calcium responses after traumatic brain injury

Preso regulates NMDA receptor-mediated excitotoxicity via modulating nitric oxide and calcium responses after traumatic brain injury

Conjugation of Therapeutic PSD-95 Inhibitors to the Cell-Penetrating Peptide Tat Affects Blood–Brain Barrier Adherence, Uptake, and Permeation

Emerging Themes in PDZ Domain Signaling

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