Efficacy of the PSD95 inhibitor Tat-NR2B9c in mice requires dose translation between species

Teves, Lucy; Cui, Hong; Tymianski, Michael

doi:10.1177/0271678x15612099

Cited by 35 publications

(29 citation statements)

References 36 publications

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“…As the highest 30 nmol/g dose was not effective, this study also seems to establish that the maximum effect of UCCB01-144 is within 37-40% infarct size reduction in this model. For Tat-NR2B9c, the 32% infarct reduction at 9 nmol/g confirms the well-documented neuroprotective properties of this compound (Aarts et al, 2002;Bell et al, 2013;Bratane et al, 2011;Cook et al, 2012a, b;Hill et al, 2012;Soriano et al, 2008;Sun et al, 2008;Teves et al, 2016). Given the previously reported lack of effect of 3 nmol/g Tat-NR2B9c (Bach et al, 2012) and high toxicity at 30 nmol/g, this indicates that the effective therapeutic window is narrower for Tat-NR2B9c (effective at 9 nmol/g, but not at 3 or 30 nmol/g) than for UCCB01-144 (effective at 3 and 9 nmol/g, but not at 1 or 30 nmol/g) in our pMCAO mouse model.…”

Section: Discussionsupporting

confidence: 67%

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: 67%

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

et al. 2019

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“…at reperfusion after 60 min of tMCAO using the filament technique neither altered stroke volumes nor neurological deficits between 6 and 72 h post-stroke (Figure 1(b) and Supplementary Figure 2) when compared with control animals. Even a high dose of NR2B (10 nmol/g), which recently has been reported to protect mice from acute ischemic stroke, 12 was ineffective in our hands (Supplementary Figure 1(a)). Blocking of PSD-95 also had no effect in female mice subjected to tMCAO or in a mouse model of permanent stroke (Supplementary Figure 2).…”

Section: Resultsmentioning

confidence: 56%

“…These novel substances have been reported to strongly lower the stroke infarct volume (up to mean cortical infarct volume 87.0 (4.4 SE)) 6 and improve functional outcome after ischemic stroke when compared to control groups in rodents and non-human primates. [6][7][8][9][10][11][12] Based on these reports, PSD-95i have entered into clinical development for multiple indications such as acute ischemic stroke and subarachnoid hemorrhage (www.nonoinc.ca) including a phase 2 human trial using Tat-NR2B9c in patients with procedurally induced brain ischemia.…”

Section: Introductionmentioning

confidence: 99%

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

Kleinschnitz

Mencl

Kleikers

et al. 2016

J Cereb Blood Flow Metab

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Promising results have been reported in preclinical stroke target validation for pharmacological principles that disrupt the N-methyl-D-aspartate receptor-post-synaptic density protein-95-neuronal nitric oxide synthase complex. However, post-synaptic density protein-95 is also coupled to potentially neuroprotective mechanisms. As post-synaptic density protein-95 inhibitors may interfere with potentially neuroprotective mechanisms and sufficient validation has often been an issue in translating basic stroke research, we wanted to close that gap by comparing post-synaptic density protein-95 inhibitors with NOS1 À/À mice and a NOS inhibitor. We confirm the deleterious role of NOS1 in stroke both in vivo and in vitro, but find three pharmacological post-synaptic density protein-95 inhibitors to be therapeutically ineffective.

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“…This peptide binds to PSD95 with high specificity and perturbs synaptic GluN2B:PSD95: nNOS complex, thereby protecting neurons against NMDAR-mediated excitotoxicity. Tat-NR2B9c has been shown to safely and efficiently attenuate ischemic brain damage in cynomolgus macaques and human beings [21,[37][38][39]. In this study, the neuroprotective effect of the Tat-NTS was observed in the OGD/R cell model and the MCAO animal model of stroke.…”

Section: Discussionmentioning

confidence: 72%

A novel cell-penetrating peptide protects against neuron apoptosis after cerebral ischemia by inhibiting the nuclear translocation of annexin A1

Zheng

Xiao

et al. 2018

Cell Death Differ

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Nuclear translocation of annexin A1 (ANXA1) has recently been reported to participate in neuronal apoptosis after cerebral ischemia. Prevention of the nuclear translocation of ANXA1 should therefore inhibit neuronal apoptosis and protect against cerebral stroke. Here, we found that, in the repeat III domain of ANXA1, the amino-acid residues from R228 to F237 function as a unique nuclear translocation signal (NTS) and are required for nuclear translocation of ANXA1. Intriguingly, we synthesized a cell-penetrating peptide derived by conjugating the trans-activator of transcription (Tat) domain to the NTS sequence. This Tat-NTS peptide specifically blocked the interaction of ANXA1 with importin β and, consequently, the nuclear translocation of ANXA1 without affecting the nucleocytoplasmic shuttling of other proteins. The Tat-NTS peptide inhibited the transcriptional activity of p53, decreased Bid expression, suppressed activation of the caspase-3 apoptosis pathway and improved the survival of hippocampal neurons subjected to oxygen-glucose deprivation and reperfusion in vitro. Moreover, using a focal brain ischemia animal model, we showed that the Tat-NTS peptide could be efficiently infused into the ischemic hippocampus and cortex by unilateral intracerebroventricular injection. Injection of the Tat-NTS peptide alleviated neuronal apoptosis in the ischemic zone. Importantly, further work revealed that administration of the Tat-NTS peptide resulted in a dramatic reduction in infarct volume and that this was correlated with a parallel improvement in neurological function after reperfusion. Interestingly, the effects of Tat-NTS were injury specific, with little impact on neuronal apoptosis or cognitive function in sham-treated nonischemic animals. In conclusion, based on its profound neuroprotective and cognitive-preserving effects, it is suggested that the Tat-NTS peptide represents a novel and potentially promising new therapeutic candidate for the treatment of ischemic stroke.

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Efficacy of the PSD95 inhibitor Tat-NR2B9c in mice requires dose translation between species

Cited by 35 publications

References 36 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

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

A novel cell-penetrating peptide protects against neuron apoptosis after cerebral ischemia by inhibiting the nuclear translocation of annexin A1

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