Function of Tat-NR2B9c in neuroprotection

2018-08-18

Introduction 

The peptide neuroprotectant Tat-NR2B9c, also known as NA-1, is a Tat peptide consisting of the nine C-terminal residues of the NR2B subunit. As a neuroprotective agent, Tat-NR2B9c peptide has shown clinical efficacy in acute stroke. It has similar and highly specific interactions with PDZ (postsynaptic density-95/Discs large/zona occludens-1) proteins, of which the strongest are with the PSD-95 (postsynaptic density-95 protein) family members. Therefore, Tat-NR2B9c is a promising compound that separates PSD-95 from neurotoxic signaling pathways. What's more, Tat-NR2B9C can also inhibit NMDA (N-methyl-D-aspartate) receptor-mediated excitotoxicity and has obvious neuroprotective effects.

Pharmacologic action

Tat-NR2B9c is a widely accepted drug for neuroprotection in stroke. It exhibits high-affinity binding to the second PDZ domain of PSD-95. Tat-NR2B9c works by perturbing NMDAR (NMDA-type glutamate receptors)/PSD-95 interactions and reducing neurons' vulnerability to excitotoxicity and ischemia. It has ability to inhibit native protein-protein interactions in an appropriate range. Some previous studies have demonstrated that the intravenous injection of Tat-NR2B9c into rats could reduce the vulnerability of neurons to focal cerebral ischemia at a dose of 3 nmol/g. These may be attributed to Tat-NR2B9c which can disrupt NR-PSD-95 interactions, that the peptide may be delivered tissues at effective concentrations.

Function

Tat-NR2B9c is the most advanced PSD-95 inhibitor in clinical trials, which is being developed for the treatment of ischemic brain damage after stroke and has recently successfully passed phase II clinical trials. At the same time, some experiments have shown that primates treated with Tat-NR2B9c after the onset of embolic strokes exhibited significantly reduced numbers and volumes of strokes, as visualized by diffusion and T2-weighted magnetic resonance imaging. Subsequently, several studies were conducted to demonstrate that Tat-NR2B9c indeed has neuroprotective effects in vivo, without affecting the synaptic activity of the receptor. Meanwhile, Tat-NR2B9c also blocks the interaction between nNOS (neuronal NO synthase) and PSD-95 with an IC50 of ∼0.2 μM, but shows no effect on the NMDA-induced JNK (c-Jun Nterminal Kinase) activation.

Pharmacokinetics and metabolism

In general, the pharmacokinetic profile of peptides is influenced in particular by enzymatic degradation, renal clearance, and hepatic metabolism. In vivo studies have shown that it has good metabolic and pharmacokinetics. Remarkably, in the tMCAO (transient MCA occlusion) model, a single dose of Tat-NR2B9C gave permanent maintenance of infarct size reduction and neurobehavioral improvement 3 hours after the onset of stroke, indicating that these drugs do not simply delay brain damage.

References:

1. J. Montaner, M. Campos, I. Cristobo, D. Giralt and M. Diaz-Guerra. Role of PSD-95 inhibitors in troke and neuroprotection: A systematic view on NA-1 (Tat-NR2B9c). Drugs of the Future, 2013, 38(7), 485-497.

2. Hong Cui, Amy Hayashi, Hong-Shuo Sun. PDZ protein interactions underlying NMDA receptor mediated excitotoxicity and neuroprotection by PSD-95 inhibitors. The Journal of Neuroscience, 2007, 27(37), 9901–9915.

3. Douglas J. Cook, Lucy Teves, Michael Tymianski, A translational paradigm for the preclinical evaluation of the stroke neuroprotectant Tat-NR2B9c in gyrencephalic nonhuman primates. ScienceTranslational Medicine, 2012, 4 (154), 133-154.

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