Restoring nitric oxide/Peroxynitrite equilibrium in impaired human neural progenitor cells: Nanomedical approaches and their potential impact on neurodegenerative disease treatment

Abstract

Nitric oxide (NO), an essential inorganic signaling molecule, involved in many physiological processes and has promising therapeutic potential Its oxidation product, peroxynitrite (ONOO^¯), is cytotoxic, and elevated ONOO^¯ levels induce nitroxidative stress, a factor implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Through pharmacological modulation of NO and ONOO^¯ levels in human neural progenitor cell (hNPCs), this study explores the potential pharmaceutical interventions targeting the NO and the neuronal nitric oxide synthase (nNOS) pathway, (NO/nNOS), to prevent or reduce AD progression by restoring the [NO]/[ONOO^¯] balance. To achieve this, metalloporphyrin nanosensors have been effectively employed for real-time, in-situ measurement of NO and ONOO^¯ concentrations (200–300 nm diameter) were applied and precisely positioned 4–5 ± 1 μm from hNPCs membranes, enabling precise investigation of the [NO]/[ONOO^¯] ratio. The [NO]/[ONOO^¯] ratio emerged as a critical biomarker for the evaluation of nNOS coupling/uncoupling to the hNPC functioning/dysfunction. In healthy cells, this ratio was around 0.25 ± 0.005, While dysfunctional hNPCs treated to amyloid beta 42 (Aβ₄₂)—a hallmark of AD—caused a dramatic 94 % drop, signaling severe cellular dysfunction. Based on these findings, potential pharmacological interventions have been proposed to prevent or reduce AD progression by restoring the [NO]/[ONOO^¯] balance. Notably, a co-treatment of sepiapterin (SEP), a cofactor precursor for NO synthesis, with VAS 2870 (an NADPH oxidase inhibitor) partially restored the ratio to 0.1, indicating improved nNOS function.