PSD-95: An Effective Target for Stroke Therapy Using Neuroprotective Peptides
Abstract
:1. Introduction
2. Ischemic Stroke and Excitotoxicity
Dual Roles of NMDARs in Neuronal Survival and Death
3. PSD-95, a Protein Central to Neuronal Survival and Death
3.1. PSD-95 Structure and Function
3.2. Regulation of PSD-95 Location and Expression
3.3. PSD-95 Downregulation in Ischemia Models
4. Development of PSD-95-Targeted Cell-Penetrating Peptides for Stroke Treatment
4.1. Nerinetide, Renewed Hope for Neuroprotection in Human Stroke
4.2. AVLX-144, a High-Affinity Dimeric Peptide against Stroke
4.3. TP95414, a Novel Neuroprotective Approach for Preventing PSD-95 Processing
5. The Quest for Specificity in Stroke Therapies Based on PSD-95-Targeted Peptides
6. Potential of Combined Approaches for Stroke Neuroprotection Using PSD-95 Targets
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
- 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. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef]
- Prabhakaran, S.; Ruff, I.; Bernstein, R.A. Acute stroke intervention: A systematic review. JAMA 2015, 313, 1451–1462. [Google Scholar] [CrossRef] [PubMed]
- 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. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef]
- Roth, S.; Liesz, A. Stroke research at the crossroads—Where are we heading? Swiss Med. Wkly. 2016, 146, w14329. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef]
- Hankey, G.J. Nerinetide before reperfusion in acute ischaemic stroke: Deja vu or new insights? Lancet 2020, 395, 843–844. [Google Scholar] [CrossRef]
- Wu, Q.; Tymianski, M. Targeting NMDA receptors in stroke: New hope in neuroprotection. Mol. Brain 2018, 11, 15. [Google Scholar] [CrossRef]
- Hardingham, G. NMDA receptor C-terminal signaling in development, plasticity, and disease. F1000 Res. 2019, 8, 1547. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- 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. [Google Scholar] [CrossRef] [PubMed]
- 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. [Google Scholar] [CrossRef] [PubMed]
- 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. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef] [Green Version]
- 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. [Google Scholar] [CrossRef] [Green Version]
- 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. [Google Scholar] [CrossRef]
- Lai, T.W.; Zhang, S.; Wang, Y.T. Excitotoxicity and stroke: Identifying novel targets for neuroprotection. Prog. Neurobiol. 2014, 115C, 157–188. [Google Scholar] [CrossRef] [Green Version]
- 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. [Google Scholar] [CrossRef]
- Vosler, P.S.; Brennan, C.S.; Chen, J. Calpain-mediated signaling mechanisms in neuronal injury and neurodegeneration. Mol. Neurobiol. 2008, 38, 78–100. [Google Scholar] [CrossRef] [Green Version]
- Ono, Y.; Saido, T.C.; Sorimachi, H. Calpain research for drug discovery: Challenges and potential. Nat. Rev. Drug Discov. 2016, 15, 854–876. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef] [Green Version]
- 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. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef]
- Choi, D.W. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1988, 1, 623–634. [Google Scholar] [CrossRef]
- Zhu, J.; Shang, Y.; Zhang, M. Mechanistic basis of MAGUK-organized complexes in synaptic development and signalling. Nat. Rev. Neurosci. 2016, 17, 209–223. [Google Scholar] [CrossRef]
- Kim, E.; Sheng, M. PDZ domain proteins of synapses. Nat. Rev. Neurosci. 2004, 5, 771–781. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef] [Green Version]
- Zhang, J.; Lewis, S.M.; Kuhlman, B.; Lee, A.L. Supertertiary structure of the MAGUK core from PSD-95. Structure 2013, 21, 402–413. [Google Scholar] [CrossRef] [Green Version]
- 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. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef] [Green Version]
- 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. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef] [Green Version]
- 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. [Google Scholar] [CrossRef] [Green Version]
- 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. [Google Scholar] [CrossRef] [Green Version]
- 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. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef]
- Vallejo, D.; Codocedo, J.F.; Inestrosa, N.C. Posttranslational modifications regulate the postsynaptic localization of PSD-95. Mol. Neurobiol. 2017, 54, 1759–1776. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef] [PubMed]
- 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. [Google Scholar] [CrossRef] [PubMed]
- 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. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- 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. [Google Scholar] [CrossRef] [Green Version]
- 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. [Google Scholar] [CrossRef] [Green Version]
- Coley, A.A.; Gao, W.J. PSD95: A synaptic protein implicated in schizophrenia or autism? Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2018, 82, 187–194. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef] [Green Version]
- 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. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef]
- Kurrikoff, K.; Langel, U. Recent CPP-based applications in medicine. Expert Opin. Drug Deliv. 2019, 16, 1183–1191. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef] [Green Version]
- Ballarin, B.; Tymianski, M. Discovery and development of NA-1 for the treatment of acute ischemic stroke. Acta Pharmacol. Sin. 2018, 39, 661–668. [Google Scholar] [CrossRef] [Green Version]
- 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. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef] [Green Version]
- 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. [Google Scholar] [CrossRef] [PubMed]
- 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. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- 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. [Google Scholar] [CrossRef] [PubMed]
- 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. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef] [Green Version]
- 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. [Google Scholar] [CrossRef] [Green Version]
- 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. [Google Scholar] [CrossRef] [Green Version]
- 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. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef] [Green Version]
- Carmichael, S.T. Rodent models of focal stroke: Size, mechanism, and purpose. NeuroRx 2005, 2, 396–409. [Google Scholar] [CrossRef] [Green Version]
- 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. [Google Scholar] [CrossRef]
- 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. [Google Scholar] [CrossRef]
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Ugalde-Triviño, L.; Díaz-Guerra, M. PSD-95: An Effective Target for Stroke Therapy Using Neuroprotective Peptides. Int. J. Mol. Sci. 2021, 22, 12585. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212585
Ugalde-Triviño L, Díaz-Guerra M. PSD-95: An Effective Target for Stroke Therapy Using Neuroprotective Peptides. International Journal of Molecular Sciences. 2021; 22(22):12585. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212585
Chicago/Turabian StyleUgalde-Triviño, Lola, and Margarita Díaz-Guerra. 2021. "PSD-95: An Effective Target for Stroke Therapy Using Neuroprotective Peptides" International Journal of Molecular Sciences 22, no. 22: 12585. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212585