Tat-NR2B9c

Tat-NR2B9c is a 20-aa peptide, which acts as a postsynaptic density-95 (PSD-95) inhibitor, with an EC50 of 6.7 nM for PSD-95d2 (PSD-95 PDZ domain 2), and 670 nM for PSD-95d1; Tat-NR2B9c also reduces NMDA-induced p38 activation, and possesses neuroprotective efficacy.

Signaling Pathways >> MAPK/ERK Pathway >> p38 MAPK

Research Areas >> Neurological Disease

Peptides

EC50: 6.7 nM (PSD-95d2), 670 nM (PSD-95d1)[1] p38[2]

Tat-NR2B9c is a PSD-95 inhibitor, with an EC50 of 6.7 nM for PSD-95d2, representing a >100-fold higher affinity for this domain than for PSD-95d1 (EC50, 0.67 μM). Tat-NR2B9c inhibits NMDAR2A, NMDAR2B, and NMDAR2C binding to PSD-95, with IC50s of 0.5 μM, ∼8 μM, and 0.75 μM, respectively. Tat-NR2B9c also blocks the interaction between PSD-95 and nNOS with an IC50 of ∼0.2 μM[1]. Tat-NR2B9c reduces association of PSD-95 with GluN2B by ∼50% in the YAC128 striatum, decreases NMDA-induced p38 activation in YAC128 striatal tissue, but shows no effect on the NMDA-induced JNK activation[2].

Tat-NR2B9c (10 nM/g, i.v.) reduces infarction volume of male C57BL/6 mice, but has no effect at 3 nM/g[3].

Postnatal mono-cultured WT and YAC128 striatal neurons (DIV 9, due to the viability of these mono-cultured MSNs) are pretreated for 1 h with 200 nM Tat-NR2B9c, and/or SB-239063 (p38 inhibitor), and/or SP-600125 (JNK inhibitor), then incubated with or without 500 μM NMDA for 10 min. After NMDA treatment, striatal neurons are washed once with warm plating medium (PM) and then incubated in conditioned PM (without Tat peptides or p38, JNK inhibitors) for 24 h. Then cells are washed with PBS once and fixed with 4% paraformaldehyde (PFA) for 30 min[2].

Mice[3] In each study mice are randomly allocated to three treatment groups (0.0, 3.0, 10.0 nMole/g Tat-NR2B9c) or to sham treatment. The individual performing the experimental procedures, administering treatments and performing the analyses is blinded to the treatment assignments. Tat-NR2B9c is prepared at the indicated doses and administered intravenously via the tail vein using a pump in a volume of 1 µL/g over 5 min beginning at reperfusion[3].

[1]. Cui H, et al. PDZ protein interactions underlying NMDA receptor-mediated excitotoxicity and neuroprotection by PSD-95 inhibitors. J Neurosci. 2007 Sep 12;27(37):9901-15.

[2]. Fan J, et al. P38 MAPK is involved in enhanced NMDA receptor-dependent excitotoxicity in YAC transgenic mouse model of Huntington disease. Neurobiol Dis. 2012 Mar;45(3):999-1009.

[3]. Teves LM, et al. Efficacy of the PSD95 inhibitor Tat-NR2B9c in mice requires dose translation between species. J Cereb Blood Flow Metab. 2016 Mar;36(3):555-61.

[4]. Huang LE, et al. N-methyl D-aspartate receptor subtype 2B antagonist, Ro 25-6981, attenuates neuropathic pain by inhibiting postsynaptic density 95 expression. Sci Rep. 2018 May 18;8(1):7848.

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