Delving into the Latest Updates on NS-102 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

NS-102

Target

AMPA receptor x GRIK

Action

antagonists

Mechanism

AMPA receptor antagonists(Glutamate receptor ionotropic AMPA antagonists), Kainate receptor antagonists

Therapeutic Areas-

Active Indication-

Inactive Indication-

Originator Organization

NTG Nordic Transport Group A/S

Active Organization

NTG Nordic Transport Group A/S

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC12H11N3O4

InChIKeySCDBMLHUXJBJSS-UHFFFAOYSA-N

CAS Registry136623-01-3

Efficient cytosolic delivery of RNA therapeutics remains a major challenge. In this study, we developed a polymer-incorporated lipid nanoparticle (p-LNP) platform by integrating a low-molecular-weight polyamine (NS102) into standard LNP formulations. Systematic evaluation revealed that the molecular weight and amine composition of the polymer significantly influenced the delivery performance and biocompatibility, with NS102 (Mw ∼1000 Da, exclusively tertiary amines) emerging as the optimal candidate. Incorporating 4.5 mol% NS102 into LNPs enhanced their pH-buffering capacity, endosomal escape, and RNA stability without altering key physicochemical properties. These improvements resulted in superior RNA delivery, evidenced by increased mRNA transfection efficiency and siRNA activity in mice following both intravenous and intramuscular administration. Specifically, the p-LNPs achieved up to a 100-fold increase in luciferase bioluminescence expression in the liver and reduced the effective dose (ED₅₀) of siRNA against factor VII produced by the liver by 50 %, compared to standard LNPs. Moreover, the p-LNP formulations exhibited excellent biocompatibility, with no significant cytotoxicity or liver toxicity in mice. These findings highlight the potential of the p-LNP platform for advancing RNA-based therapeutics, offering a promising strategy to overcome existing delivery barriers.

01 Oct 2023·Protein and peptide letters

Activation and Denitrosylation of Procaspase-3 in KA-induced Excitotoxicity

Article

Author: Lu, Feng ; Yan, Hui ; Cai, Yu-Ting ; Liu, Yong ; Liu, Ying-Kui ; Zhang, Jia ; Yin, Xiao-Hui ; Li, Chong

Background::

It has been reported that activation of glutamate kainate receptor subunit 2 (GluK2) subunit-containing glutamate receptors and the following Fas ligand(FasL) up-regulation, caspase-3 activation, result in delayed apoptosis-like neuronal death in hippocampus CA1 subfield after cerebral ischemia and reperfusion. Nitric oxide-mediated S-nitrosylation might inhibit the procaspase activation, whereas denitrosylation might contribute to cleavage and activation of procaspases.

Objectives::

The study aimed to elucidate the molecular mechanisms underlying procaspase-3 denitrosylation and activation following kainic acid (KA)-induced excitotoxicity in rat hippocampus.

Methods::

S-nitrosylation of procaspase-3 was detected by biotin-switch method. Activation of procaspase-3 was shown as cleavage of procaspase-3 detected by immunoblotting. FasL expression was detected by immunoblotting. Cresyl violets and TdT-mediated dUTP Nick-End Labeling (TUNEL) staining were used to detect apoptosis-like neuronal death in rat hippocampal CA1 and CA3 subfields.

Results::

KA led to the activation of procaspase-3 in a dose- and time-dependent manner, and the activation was inhibited by KA receptor antagonist NS102. Procaspase-3 was denitrosylated at 3 h after kainic acid administration, and the denitrosylation was reversed by SNP and GSNO. FasL ASODNs inhibited the procaspase-3 denitrosylation and activation. Moreover, thioredoxin reductase (TrxR) inhibitor auranofin prevented the denitrosylation and activation of procaspase-3 in rat hippocampal CA1 and CA3 subfields. NS102, FasL AS-ODNs, and auranofin reversed the KAinduced apoptosis and cell death in hippocampal CA1 and CA3 subfields.

Conclusions::

KA led to denitrosylation and activation of procaspase-3 via FasL and TrxR. Inhibition of procaspase-3 denitrosylation by auranofin, SNP, and GSNO played protective effects against KA-induced apoptosis-like neuronal death in rat hippocampal CA1 and CA3 subfields. These investigations revealed that the procaspase-3 undergoes an initial denitrosylation process before becoming activated, providing valuable insights into the underlying mechanisms and possible treatment of excitotoxicity.

01 Nov 2017·British journal of anaesthesiaQ1 · MEDICINE

Sevoflurane activates hippocampal CA3 kainate receptors (Gluk2) to induce hyperactivity during induction and recovery in a mouse model

Q1 · MEDICINE

Article

Author: Li, F ; Liao, D ; Huang, H ; Zhou, C ; Liu, J ; Liang, P

BACKGROUND:

In addition to general anaesthetic effects, sevoflurane can also induce hyperactive behaviours during induction and recovery, which may contribute to neurotoxicity; however, the mechanism of such effects is unclear. Volatile anaesthetics including isoflurane have been found to activate the kainate (GluK2) receptor. We developed a novel mouse model and further explored the involvement of kainate (GluK2) receptors in sevoflurane-induced hyperactivity.

METHODS:

Maximal speed, mean speed, total movement distance and resting percentage of C57BL/6 mice were quantitatively measured using behavioural tracking software before and after sevoflurane anaesthesia. Age dependence of this model was also analysed and sevoflurane-induced hyperactivity was evaluated after intracerebral injection of the GluK2 receptor blocker NS-102. Neurones from the hippocampal CA3 region were used to undertake in vitro electrophysiological measurement of kainate currents and miniature excitatory postsynaptic potential (mEPSP).

RESULTS:

Sevoflurane induced significant hyperactivities in mice under sevoflurane 1% anaesthesia and during the recovery period, characterized as increased movement speed and total distance. The hyperactivity was significantly increased in young mice compared with adults (P<0.01) and pre-injection of NS-102 significantly prevented this sevoflurane-induced hyperactivity. In electrophysiological experiments, sevoflurane significantly increased the frequency of mEPSP at low concentrations and evoked kainate currents at high concentrations.

CONCLUSIONS:

We developed a behavioural model in mice that enabled characterization of sevoflurane-induced hyperactivity. The kainate (GluK2) receptor antagonist attenuated these sevoflurane-induced hyperactivities in vivo, suggesting that kainate receptors might be the underlying therapeutic targets for sevoflurane-induced hyperactivities in general anaesthesia.

100 Deals associated with NS-102

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