PSD-95: An Effective Target for Stroke Therapy Using Neuroprotective Peptides

Lola Ugalde-Triviño, Margarita Díaz-Guerra, Lola Ugalde-Triviño, Margarita Díaz-Guerra

Abstract

Therapies for stroke have remained elusive in the past despite the great relevance of this pathology. However, recent results have provided strong evidence that postsynaptic density protein-95 (PSD-95) can be exploited as an efficient target for stroke neuroprotection by strategies able to counteract excitotoxicity, a major mechanism of neuronal death after ischemic stroke. This scaffold protein is key to the maintenance of a complex framework of protein interactions established at the postsynaptic density (PSD) of excitatory neurons, relevant to neuronal function and survival. Using cell penetrating peptides (CPPs) as therapeutic tools, two different approaches have been devised and advanced to different levels of clinical development. First, nerinetide (Phase 3) and AVLX-144 (Phase 1) were designed to interfere with the coupling of the ternary complex formed by PSD-95 with GluN2B subunits of the N-methyl-D-aspartate type of glutamate receptors (NMDARs) and neuronal nitric oxide synthase (nNOS). These peptides reduced neurotoxicity derived from NMDAR overactivation, decreased infarct volume and improved neurobehavioral results in different models of ischemic stroke. However, an important caveat to this approach was PSD-95 processing by calpain, a pathological mechanism specifically induced by excitotoxicity that results in a profound alteration of survival signaling. Thus, a third peptide (TP95414) has been recently developed to interfere with PSD-95 cleavage and reduce neuronal death, which also improves neurological outcome in a preclinical mouse model of permanent ischemia. Here, we review recent advancements in the development and characterization of PSD-95-targeted CPPs and propose the combination of these two approaches to improve treatment of stroke and other excitotoxicity-associated disorders.

Keywords: AVLV-144; NA-1; PSD-95; TP95414; calpain; cell-penetrating peptides; excitotoxicity; ischemia; nerinetide; neuroprotection; stroke.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 2
Figure 2
Heatmap showing amino acid conservation inside the different protein domains and interdomain linker sequences of DLG proteins. The location of four calpain-cleavage sites established by Edman sequencing in PSD-95 is also shown (numbered arrowheads). Mice protein sequences of PSD-95, PSD-93, SAP-97 and SAP-102 were compared using Clustal Omega. The percentage of conservation was calculated including identical amino acids and conservative changes, and a color code was assigned to each protein segment. The different DLG domains present a high level of conservation (70–90%), while linkers between them are less conserved, except for the PDZ3–SH3 sequence (94%). Notably, PSD-95 is processed by calpain inside this highly conserved sequence (arrowhead), while other DLG members are not. Substitution of S417 for G417 (blue) inside this highly conserved sequence of PSD-95 might have been determinant for creating a calpain-specific recognition sequence and cleavage of this particular DLG protein in excitotoxic conditions.
Figure 1
Figure 1
Diagram of PSD-95 protein domains, their organization in supramodules and some examples of their interacting proteins. From the N-terminal (Nt) to the C-terminal (Ct), PSD-95 is constituted by three PDZ (PDZ1 to 3) domains, a Src homology 3 (SH3) domain and a guanylate kinase-like (GK) domain. The PDZ1-2 and P-S-G supramodules, respectively formed by the PDZ1 and PDZ2 tandem or the three other protein domains, are indicated by dotted outlined rectangles.
Figure 3
Figure 3
(A). Structure of PSD-95-targeted peptides for stroke treatment. The three peptides share a Tat sequence (aa 47–57, italic). In nerinetide, this sequence is bound to the GluN2B C-terminus (dark green), containing the PDZ ligand, while AVLX-144 is a dimeric peptide with slightly different PDZ ligands (light green) that are more selective towards PDZ1 and PDZ2 over PDZ3. In TP95414, the Tat sequence is followed by a PSD-95 sequence (aa 414–427, purple) containing a calpain-cleavage site (arrowhead). (B). Model of PSD-95 regulation in excitotoxicity and action of PSD-95-targeted peptides. In excitotoxicity, without treatment, PSD-95 contributes to neuronal death by two different mechanisms: first, formation of a trimeric PSD-95–NMDAR–nNOS complex that produces nitric oxide (NO) upon massive calcium influx, and second, processing by calpain of PSD-95 that uncouples the two PSD-95 supramodules (dotted outlined rectangles) and partially cleaves P-S-G. Two different strategies have been developed to prevent these pathological mechanisms by means of brain-permeable neuroprotective peptides. Nerinetide and AVLX-144 are targeted to uncouple the trimeric complex and inhibit NO production while TP95414 prevents PSD-95 cleavage.

References

    1. Feigin V.L., Stark B.A., Johnson C.O., Roth G.A., Bisignano C., Abady G.G., Abbasifard M., Abbasi-Kangevari M., Abd-Allah F., Abedi V., et al. Global, regional, and national burden of stroke and its risk factors, 1990–2019: A systematic analysis for the global burden of disease study 2019. Lancet Neurol. 2021;20:795–820. doi: 10.1016/S1474-4422(21)00252-0.
    1. Goyal M., Menon B.K., van Zwam W.H., Dippel D.W., Mitchell P.J., Demchuk A.M., Davalos A., Majoie C.B., van der Lugt A., de Miquel M.A., et al. Endovascular thrombectomy after large-vessel ischaemic stroke: A meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387:1723–1731. doi: 10.1016/S0140-6736(16)00163-X.
    1. Prabhakaran S., Ruff I., Bernstein R.A. Acute stroke intervention: A systematic review. JAMA. 2015;313:1451–1462. doi: 10.1001/jama.2015.3058.
    1. McCarthy D.J., Diaz A., Sheinberg D.L., Snelling B., Luther E.M., Chen S.H., Yavagal D.R., Peterson E.C., Starke R.M. Long-term outcomes of mechanical thrombectomy for stroke: A meta-analysis. Sci. World J. 2019;2019:1–9. doi: 10.1155/2019/7403104.
    1. Chamorro A., Lo E.H., Renu A., van Leyen K., Lyden P.D. The future of neuroprotection in stroke. J. Neurol. Neurosurg. Psychiatry. 2021;92:129–135. doi: 10.1136/jnnp-2020-324283.
    1. Roth S., Liesz A. Stroke research at the crossroads—Where are we heading? Swiss Med. Wkly. 2016;146:w14329. doi: 10.4414/smw.2016.14329.
    1. Hill M.D., Goyal M., Menon B.K., Nogueira R.G., McTaggart R.A., Demchuk A.M., Poppe A.Y., Buck B.H., Field T.S., Dowlatshahi D., et al. Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): A multicentre, double-blind, randomised controlled trial. Lancet. 2020;395:878–887. doi: 10.1016/S0140-6736(20)30258-0.
    1. Zhou X.F. ESCAPE-NA1 trial brings hope of neuroprotective drugs for acute ischemic stroke: Highlights of the phase 3 clinical trial on nerinetide. Neurosci. Bull. 2021;37:579–581. doi: 10.1007/s12264-020-00627-y.
    1. Hankey G.J. Nerinetide before reperfusion in acute ischaemic stroke: Deja vu or new insights? Lancet. 2020;395:843–844. doi: 10.1016/S0140-6736(20)30316-0.
    1. Wu Q., Tymianski M. Targeting NMDA receptors in stroke: New hope in neuroprotection. Mol. Brain. 2018;11:15. doi: 10.1186/s13041-018-0357-8.
    1. Hardingham G. NMDA receptor C-terminal signaling in development, plasticity, and disease. F1000 Res. 2019;8:1547. doi: 10.12688/f1000research.19925.1.
    1. Papadia S., Soriano F.X., Leveille F., Martel M.A., Dakin K.A., Hansen H.H., Kaindl A., Sifringer M., Fowler J., Stefovska V., et al. Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses. Nat. Neurosci. 2008;11:476–487. doi: 10.1038/nn2071.
    1. Ivanov A., Pellegrino C., Rama S., Dumalska I., Salyha Y., Ben-Ari Y., Medina I. Opposing role of synaptic and extrasynaptic NMDA receptors in regulation of the extracellular signal-regulated kinases (ERK) activity in cultured rat hippocampal neurons. J. Physiol. 2006;572:789–798. doi: 10.1113/jphysiol.2006.105510.
    1. Papadia S., Stevenson P., Hardingham N.R., Bading H., Hardingham G.E. Nuclear Ca2+ and the cAMP response element-binding protein family mediate a late phase of activity-dependent neuroprotection. J. Neurosci. 2005;25:4279–4287. doi: 10.1523/JNEUROSCI.5019-04.2005.
    1. Tao X., Finkbeiner S., Arnold D.B., Shaywitz A.J., Greenberg M.E. Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron. 1998;20:709–726. doi: 10.1016/S0896-6273(00)81010-7.
    1. Lyons M.R., Schwarz C.M., West A.E. Members of the myocyte enhancer factor 2 transcription factor family differentially regulate BDNF transcription in response to neuronal depolarization. J. Neurosci. 2012;32:12780–12785. doi: 10.1523/JNEUROSCI.0534-12.2012.
    1. Deogracias R., Espliguero G., Iglesias T., Rodriguez-Pena A. Expression of the neurotrophin receptor TrkB is regulated by the cAMP/CREB pathway in neurons. Mol. Cell Neurosci. 2004;26:470–480. doi: 10.1016/j.mcn.2004.03.007.
    1. Lai T.W., Zhang S., Wang Y.T. Excitotoxicity and stroke: Identifying novel targets for neuroprotection. Prog. Neurobiol. 2014;115C:157–188. doi: 10.1016/j.pneurobio.2013.11.006.
    1. Adamec E., Mohan P., Vonsattel J.P., Nixon R.A. Calpain activation in neurodegenerative diseases: Confocal immunofluorescence study with antibodies specifically recognizing the active form of calpain 2. Acta Neuropathol. 2002;104:92–104. doi: 10.1007/s00401-002-0528-6.
    1. Vosler P.S., Brennan C.S., Chen J. Calpain-mediated signaling mechanisms in neuronal injury and neurodegeneration. Mol. Neurobiol. 2008;38:78–100. doi: 10.1007/s12035-008-8036-x.
    1. Ono Y., Saido T.C., Sorimachi H. Calpain research for drug discovery: Challenges and potential. Nat. Rev. Drug Discov. 2016;15:854–876. doi: 10.1038/nrd.2016.212.
    1. Vidaurre O.G., Gascón S., Deogracias R., Sobrado M., Cuadrado E., Montaner J., Rodríguez-Peña A., Díaz-Guerra M. Imbalance of neurotrophin receptor isoforms TrkB-FL/TrkB-T1 induces neuronal death in excitotoxicity. Cell Death Dis. 2012;3:e256. doi: 10.1038/cddis.2011.143.
    1. Gascon S., Sobrado M., Roda J.M., Rodriguez-Pena A., Diaz-Guerra M. Excitotoxicity and focal cerebral ischemia induce truncation of the NR2A and NR2B subunits of the NMDA receptor and cleavage of the scaffolding protein PSD-95. Mol. Psychiatry. 2008;13:99–114. doi: 10.1038/sj.mp.4002017.
    1. Ayuso-Dolado S., Esteban-Ortega G.M., Vidaurre O.G., Diaz-Guerra M. A novel cell-penetrating peptide targeting calpain-cleavage of PSD-95 induced by excitotoxicity improves neurological outcome after stroke. Theranostics. 2021;11:6746–6765. doi: 10.7150/thno.60701.
    1. Ge Y., Chen W., Axerio-Cilies P., Wang Y.T. NMDARs in cell survival and death: Implications in stroke pathogenesis and treatment. Trends Mol. Med. 2020;26:533–551. doi: 10.1016/j.molmed.2020.03.001.
    1. Choi D.W. Glutamate neurotoxicity and diseases of the nervous system. Neuron. 1988;1:623–634. doi: 10.1016/0896-6273(88)90162-6.
    1. Zhu J., Shang Y., Zhang M. Mechanistic basis of MAGUK-organized complexes in synaptic development and signalling. Nat. Rev. Neurosci. 2016;17:209–223. doi: 10.1038/nrn.2016.18.
    1. Kim E., Sheng M. PDZ domain proteins of synapses. Nat. Rev. Neurosci. 2004;5:771–781. doi: 10.1038/nrn1517.
    1. Sheng N., Bemben M.A., Diaz-Alonso J., Tao W., Shi Y.S., Nicoll R.A. LTP requires postsynaptic PDZ-domain interactions with glutamate receptor/auxiliary protein complexes. Proc. Natl. Acad. Sci. USA. 2018;115:3948–3953. doi: 10.1073/pnas.1800719115.
    1. Zhang J., Lewis S.M., Kuhlman B., Lee A.L. Supertertiary structure of the MAGUK core from PSD-95. Structure. 2013;21:402–413. doi: 10.1016/j.str.2012.12.014.
    1. Wang W., Weng J., Zhang X., Liu M., Zhang M. Creating conformational entropy by increasing interdomain mobility in ligand binding regulation: A revisit to N-terminal tandem PDZ domains of PSD-95. J. Am. Chem. Soc. 2009;131:787–796. doi: 10.1021/ja8076022.
    1. Christopherson K.S., Hillier B.J., Lim W.A., Bredt D.S. PSD-95 assembles a ternary complex with the N-methyl-D-aspartic acid receptor and a bivalent neuronal NO synthase PDZ domain. J. Biol. Chem. 1999;274:27467–27473. doi: 10.1074/jbc.274.39.27467.
    1. Picon-Pages P., Garcia-Buendia J., Munoz F.J. Functions and dysfunctions of nitric oxide in brain. Biochim. Biophys. Acta Mol. Basis Dis. 2019;1865:1949–1967. doi: 10.1016/j.bbadis.2018.11.007.
    1. Luo C.X., Lin Y.H., Qian X.D., Tang Y., Zhou H.H., Jin X., Ni H.Y., Zhang F.Y., Qin C., Li F., et al. Interaction of nNOS with PSD-95 negatively controls regenerative repair after stroke. J. Neurosci. 2014;34:13535–13548. doi: 10.1523/JNEUROSCI.1305-14.2014.
    1. Pan L., Chen J., Yu J., Yu H., Zhang M. The structure of the PDZ3-SH3-GuK tandem of ZO-1 protein suggests a supramodular organization of the membrane-associated guanylate kinase (MAGUK) family scaffold protein core. J. Biol. Chem. 2011;286:40069–40074. doi: 10.1074/jbc.C111.293084.
    1. Rademacher N., Kunde S.A., Kalscheuer V.M., Shoichet S.A. Synaptic MAGUK multimer formation is mediated by PDZ domains and promoted by ligand binding. Chem. Biol. 2013;20:1044–1054. doi: 10.1016/j.chembiol.2013.06.016.
    1. Zeng M., Ye F., Xu J., Zhang M. PDZ ligand binding-induced conformational coupling of the PDZ-SH3-GK tandems in PSD-95 family MAGUKs. J. Mol. Biol. 2018;430:69–86. doi: 10.1016/j.jmb.2017.11.003.
    1. Rademacher N., Kuropka B., Kunde S.-A., Wahl M.C., Freund C., Shoichet S.A. Intramolecular domain dynamics regulate synaptic MAGUK protein interactions. eLife. 2019;8:e41299. doi: 10.7554/eLife.41299.
    1. Omelchenko A., Menon H., Donofrio S.G., Kumar G., Chapman H.M., Roshal J., Martinez-Montes E.R., Wang T.L., Spaller M.R., Firestein B.L. Interaction between CRIPT and PSD-95 is required for proper dendritic arborization in hippocampal neurons. Mol. Neurobiol. 2020;57:2479–2493. doi: 10.1007/s12035-020-01895-5.
    1. Vallejo D., Codocedo J.F., Inestrosa N.C. Posttranslational modifications regulate the postsynaptic localization of PSD-95. Mol. Neurobiol. 2017;54:1759–1776. doi: 10.1007/s12035-016-9745-1.
    1. Tulodziecka K., Diaz-Rohrer B.B., Farley M.M., Chan R.B., Di Paolo G., Levental K.R., Waxham M.N., Levental I. Remodeling of the postsynaptic plasma membrane during neural development. Mol. Biol. Cell. 2016;27:3480–3489. doi: 10.1091/mbc.e16-06-0420.
    1. Pedersen S.W., Albertsen L., Moran G.E., Levesque B., Pedersen S.B., Bartels L., Wapenaar H., Ye F., Zhang M., Bowen M.E., et al. Site-specific phosphorylation of PSD-95 PDZ domains reveals fine-tuned regulation of protein-protein interactions. ACS Chem. Biol. 2017;12:2313–2323. doi: 10.1021/acschembio.7b00361.
    1. Glantz L.A., Gilmore J.H., Hamer R.M., Lieberman J.A., Jarskog L.F. Synaptophysin and postsynaptic density protein 95 in the human prefrontal cortex from mid-gestation into early adulthood. Neuroscience. 2007;149:582–591. doi: 10.1016/j.neuroscience.2007.06.036.
    1. Fromer M., Pocklington A.J., Kavanagh D.H., Williams H.J., Dwyer S., Gormley P., Georgieva L., Rees E., Palta P., Ruderfer D.M., et al. De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014;506:179–184. doi: 10.1038/nature12929.
    1. Purcell S.M., Moran J.L., Fromer M., Ruderfer D., Solovieff N., Roussos P., O’Dushlaine C., Chambert K., Bergen S.E., Kähler A., et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature. 2014;506:185–190. doi: 10.1038/nature12975.
    1. Coley A.A., Gao W.J. PSD95: A synaptic protein implicated in schizophrenia or autism? Prog. Neuro-Psychopharmacol. Biol. Psychiatry. 2018;82:187–194. doi: 10.1016/j.pnpbp.2017.11.016.
    1. Chen X., Levy J.M., Hou A., Winters C., Azzam R., Sousa A.A., Leapman R.D., Nicoll R.A., Reese T.S. PSD-95 family MAGUKs are essential for anchoring AMPA and NMDA receptor complexes at the postsynaptic density. Proc. Natl. Acad. Sci. USA. 2015;112:E6983–E6992. doi: 10.1073/pnas.1517045112.
    1. Gardoni F., Bellone C., Viviani B., Marinovich M., Meli E., Pellegrini-Giampietro D.E., Cattabeni F., Di Luca M. Lack of PSD-95 drives hippocampal neuronal cell death through activation of an alpha CaMKII transduction pathway. Eur. J. Neurosci. 2002;16:777–786. doi: 10.1046/j.1460-9568.2002.02141.x.
    1. Zhang J., Xu T.X., Hallett P.J., Watanabe M., Grant S.G., Isacson O., Yao W.D. PSD-95 uncouples dopamine-glutamate interaction in the D1/PSD-95/NMDA receptor complex. J. Neurosci. 2009;29:2948–2960. doi: 10.1523/JNEUROSCI.4424-08.2009.
    1. Dore K., Carrico Z., Alfonso S., Marino M., Koymans K., Kessels H.W., Malinow R. PSD-95 protects synapses from beta-amyloid. Cell Rep. 2021;35:109194. doi: 10.1016/j.celrep.2021.109194.
    1. Kurrikoff K., Langel U. Recent CPP-based applications in medicine. Expert Opin. Drug Deliv. 2019;16:1183–1191. doi: 10.1080/17425247.2019.1665021.
    1. Abdullahi W., Tripathi D., Ronaldson P.T. Blood-brain barrier dysfunction in ischemic stroke: Targeting tight junctions and transporters for vascular protection. Am. J. Physiol. Cell Physiol. 2018;315:C343–C356. doi: 10.1152/ajpcell.00095.2018.
    1. Vaslin A., Puyal J., Clarke P.G. Excitotoxicity-induced endocytosis confers drug targeting in cerebral ischemia. Ann. Neurol. Off. J. Am. Neurol. Assoc. Child Neurol. Soc. 2009;65:337–347. doi: 10.1002/ana.21584.
    1. Aarts M., Liu Y., Liu L., Besshoh S., Arundine M., Gurd J.W., Wang Y.T., Salter M.W., Tymianski M. Treatment of ischemic brain damage by perturbing NMDA receptor—PSD-95 protein interactions. Science. 2002;298:846–850. doi: 10.1126/science.1072873.
    1. Bratane B.T., Cui H., Cook D.J., Bouley J., Tymianski M., Fisher M. Neuroprotection by freezing ischemic penumbra evolution without cerebral blood flow augmentation with a postsynaptic density-95 protein inhibitor. Stroke. 2011;42:3265–3270. doi: 10.1161/STROKEAHA.111.618801.
    1. Sun H.S., Doucette T.A., Liu Y., Fang Y., Teves L., Aarts M., Ryan C.L., Bernard P.B., Lau A., Forder J.P., et al. Effectiveness of PSD95 inhibitors in permanent and transient focal ischemia in the rat. Stroke. 2008;39:2544–2553. doi: 10.1161/STROKEAHA.107.506048.
    1. Ballarin B., Tymianski M. Discovery and development of NA-1 for the treatment of acute ischemic stroke. Acta Pharmacol. Sin. 2018;39:661–668. doi: 10.1038/aps.2018.5.
    1. Cook D.J., Teves L., Tymianski M. Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain. Nature. 2012;483:213–217. doi: 10.1038/nature10841.
    1. Hill M.D., Martin R.H., Mikulis D., Wong J.H., Silver F.L., Terbrugge K.G., Milot G., Clark W.M., Macdonald R.L., Kelly M.E., et al. Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): A phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2012;11:942–950. doi: 10.1016/S1474-4422(12)70225-9.
    1. Docagne F., Parcq J., Lijnen R., Ali C., Vivien D. Understanding the functions of endogenous and exogenous tissue-type plasminogen activator during stroke. Stroke. 2015;46:314–320. doi: 10.1161/STROKEAHA.114.006698.
    1. Mayor-Nunez D., Ji Z., Sun X., Teves L., Garman J.D., Tymianski M. Plasmin-resistant PSD-95 inhibitors resolve effect-modifying drug-drug interactions between alteplase and nerinetide in acute stroke. Sci. Transl. Med. 2021;13:1844–1846. doi: 10.1126/scitranslmed.abb1498.
    1. Christensen N.R., Calyseva J., Fernandes E.F.A., Luchow S., Clemmensen L.S., Haugaard-Kedstrom L.M., Stromgaard K. PDZ domains as drug targets. Adv. Ther. 2019;2:1800143. doi: 10.1002/adtp.201800143.
    1. Bach A., Chi C.N., Olsen T.B., Pedersen S.W., Roder M.U., Pang G.F., Clausen R.P., Jemth P., Stromgaard K. Modified peptides as potent inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction. J. Med. Chem. 2008;51:6450–6459. doi: 10.1021/jm800836w.
    1. Bach A., Chi C.N., Pang G.F., Olsen L., Kristensen A.S., Jemth P., Stromgaard K. Design and synthesis of highly potent and plasma-stable dimeric inhibitors of the PSD-95-NMDA receptor interaction. Angew. Chem. Int. Ed. Engl. 2009;48:9685–9689. doi: 10.1002/anie.200904741.
    1. Bach A., Clausen B.H., Møller M., Vestergaard B., Chi C.N., Round A., Sørensen P.L., Nissen K.B., Kastrup J.S., Gajhede M., et al. A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage. Proc. Natl. Acad. Sci. USA. 2012;109:3317–3322. doi: 10.1073/pnas.1113761109.
    1. Teves L.M., Cui H., Tymianski M. Efficacy of the PSD95 inhibitor Tat-NR2B9c in mice requires dose translation between species. J. Cereb. Blood Flow Metab. 2016;36:555–561. doi: 10.1177/0271678X15612099.
    1. Bach A., Clausen B.H., Kristensen L.K., Andersen M.G., Ellman D.G., Hansen P.B.L., Hasseldam H., Heitz M., Ozcelik D., Tuck E.J., et al. Selectivity, efficacy and toxicity studies of UCCB01-144, a dimeric neuroprotective PSD-95 inhibitor. Neuropharmacology. 2019;150:100–111. doi: 10.1016/j.neuropharm.2019.02.035.
    1. Tejeda G.S., Esteban-Ortega G.M., San Antonio E., Vidaurre Ó.G.G., Díaz-Guerra M. Prevention of excitotoxicity-induced processing of BDNF receptor TrkB-FL leads to stroke neuroprotection. EMBO Mol. Med. 2019;11:e9950. doi: 10.15252/emmm.201809950.
    1. Zhang J., Petit C.M., King D.S., Lee A.L. Phosphorylation of a PDZ domain extension modulates binding affinity and interdomain interactions in postsynaptic density-95 (PSD-95) protein, a membrane-associated guanylate kinase (MAGUK) J. Biol. Chem. 2011;286:41776–41785. doi: 10.1074/jbc.M111.272583.
    1. Carmichael S.T. Rodent models of focal stroke: Size, mechanism, and purpose. NeuroRx. 2005;2:396–409. doi: 10.1602/neurorx.2.3.396.
    1. Meloni B.P., Chen Y., Harrison K.A., Nashed J.Y., Blacker D.J., South S.M., Anderton R.S., Mastaglia F.L., Winterborn A., Knuckey N.W., et al. Poly-arginine peptide-18 (R18) reduces brain injury and improves functional outcomes in a nonhuman primate stroke model. Neurotherapeutics. 2020;17:627–634. doi: 10.1007/s13311-019-00809-1.
    1. Meloni B.P., Mastaglia F.L., Knuckey N.W. Cationic arginine-rich peptides (CARPs): A novel class of neuroprotective agents with a multimodal mechanism of action. Front. Neurol. 2020;11:108. doi: 10.3389/fneur.2020.00108.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel