Small-molecule inhibitors at the PSD-95/nNOS interface attenuate MPP+-induced neuronal injury through Sirt3 mediated inhibition of mitochondrial dysfunction.

Abstract

Post-synaptic density protein 95 (PSD-95) links neuronal nitric oxide synthase (nNOS) with the N-methyl-D-aspartic acid (NMDA) receptor in the central nervous system, and this molecular complex has been implicated in regulating neuronal excitability in several neurological disorders. Here, small-molecule inhibitors of the PSD-95/nNOS interaction, IC87201 and ZL006 were tested for neuroprotective effects in an in vitro Parkinson's disease (PD) model. We now report that IC87201 and ZL006 reduced MPP(+)-induced neuronal injury and apoptotic cell death in a dose-dependent manner in cultured cortical neurons. These protective effects were associated with suppressed mitochondrial dysfunction, as evidenced by decreased reactive oxygen species (ROS) generation, cytochrome c release, mitochondrial membrane potential (MMP) collapse, and the preserved mitochondrial complex I activity and ATP synthesis. IC87201 and ZL006 also preserved intracellular homeostasis through mitigating mitochondrial Ca(2+) uptake and promoting mitochondrial Ca(2+) buffering capacity. Moreover, treatment with IC87201 and ZL006 significantly increased the expression of Sirt3 after MPP(+) exposure, and knockdown of Sirt3 using specific targeted small interfere RNA (siRNA) partially nullified the protective effects induced by these two inhibitors. These data strongly support the hypothesis that targeting the PSD-95/nNOS interaction produces neuroprotective effects and may represent a novel class of therapeutics for PD as well as other neurological diseases where detrimental NMDA receptor signaling plays a major role.

• Authors: Wei Hu, Lai-Shun Guan, Xing-Bo Dang, Peng-Yu Ren, Yue-Lin Zhang
• Journal: Neurochemistry international (Neurochem Int) Vol. 79 Pg. 57-64 (Dec 2014) ISSN: 1872-9754 [Electronic] England
• PMID: 25452082 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• 2-((1H-benzo(d)(1,2,3)triazol-5-ylamino)methyl)-4,6-dichlorophenol
• Chlorophenols
• Disks Large Homolog 4 Protein
• Dlg4 protein, rat
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• Neuroprotective Agents
• RNA, Small Interfering
• Receptors, N-Methyl-D-Aspartate
• Small Molecule Libraries
• Triazoles
• Nitric Oxide Synthase Type I
• Sirtuin 3
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Cells, Cultured
• Chlorophenols (therapeutic use)
• Disks Large Homolog 4 Protein
• Gene Knockdown Techniques
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors)
• MPTP Poisoning (drug therapy, pathology)
• Membrane Potential, Mitochondrial (drug effects)
• Membrane Proteins (antagonists & inhibitors)
• Mitochondria (drug effects, metabolism)
• Neurons (drug effects)
• Neuroprotective Agents (therapeutic use)
• Nitric Oxide Synthase Type I (antagonists & inhibitors)
• RNA, Small Interfering (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, N-Methyl-D-Aspartate (drug effects)
• Sirtuin 3 (antagonists & inhibitors, metabolism)
• Small Molecule Libraries
• Triazoles (therapeutic use)