Proteomic Assessment of C57BL/6 Hippocampi after Non-Selective Pharmacological Inhibition of Nitric Oxide Synthase Activity: Implications of Seizure-like Neuronal Hyperexcitability Followed by Tauopathy

Abstract

Nitric oxide (NO) is a small gaseous signaling molecule responsible for maintaining homeostasis in a myriad of tissues and molecular pathways in neurology and the cardiovasculature. In recent years, there has been increasing interest in the potential interaction between arterial stiffness (AS), an independent cardiovascular risk factor, and neurodegenerative syndromes given increasingly epidemiological study reports. For this reason, we previously investigated the mechanistic convergence between AS and neurodegeneration via the progressive non-selective inhibition of all nitric oxide synthase (NOS) isoforms with N(G)-nitro-L-arginine methyl ester (L-NAME) in C57BL/6 mice. Our previous results showed progressively increased AS in vivo and impaired visuospatial learning and memory in L-NAME-treated C57BL/6 mice. In the current study, we sought to further investigate the progressive molecular signatures in hippocampal tissue via LC–MS/MS proteomic analysis. Our data implicate mitochondrial dysfunction due to progressive L-NAME treatment. Two weeks of L-NAME treatment implicates altered G-protein-coupled-receptor signaling in the nerve synapse and associated presence of seizures and altered emotional behavior. Furthermore, molecular signatures implicate the cerebral presence of seizure-related hyperexcitability after short-term (8 weeks) treatment followed by ribosomal dysfunction and tauopathy after long-term (16 weeks) treatment.

Development of the correlation between mitophagy-related genes and epilepsy

“…In another study, RPL8 was signi cantly increased in mouse models of pentylenetetrazole (PTZ)-induced epilepsy [47] . Several studies have suggested the association of RPS23 with neurodevelopmental disorders [48][49][50] . In addition, RPL15 is differentially expressed across all brain regions in Parkinson's Disease and is thought to be closely associated with other brain diseases [51] .…”

Proteomics and Metabolomics in Biomedicine

“…The correlation between proteome or metabolome changes and drug perturbation was also explored in some of the selected papers. A proteomic snapshot of progressive molecular signatures was carried out in hippocampal mice tissue after pharmacological inhibition of nitric oxide synthase activity [46], whilst a proteomic analysis highlighted the effects of chitosan hydrogel supplemented with metformin on the neural differentiation of stem cells, with the final aim of employing them in the construction of biomimetic scaffolds for disease treatment [47].…”