The Potential Role of Peripheral Oxidative Stress on the Neurovascular Unit in Amyotrophic Lateral Sclerosis Pathogenesis: A Preliminary Report from Human and In Vitro Evaluations

Abstract

Oxidative stress, the alteration of mitochondrial function, and changes in the neurovascular unit (NVU) could play a role in Amyotrophic Lateral Sclerosis (ALS) pathogenesis. Our aim was to analyze the plasma redox system and nitric oxide (NO) in 25 ALS new-diagnosed patients and five healthy controls and the effects of plasma on the peroxidation/mitochondrial function in human umbilical cord-derived endothelial vascular cells (HUVEC) and astrocytes. In plasma, thiobarbituric acid reactive substances (TBARS), glutathione (GSH), and nitric oxide (NO) were analyzed by using specific assays. In HUVEC/astrocytes, the effects of plasma on the release of mitochondrial reactive oxygen species (mitoROS) and NO, viability, and mitochondrial membrane potential were investigated. In the plasma of ALS patients, an increase in TBARS and a reduction in GSH and NO were found. In HUVEC/astrocytes treated with a plasma of ALS patients, mitoROS increased, whereas cell viability and mitochondrial membrane potential decreased. Our results show that oxidative stress and NVU play a central role in ALS and suggest that unknown plasma factors could be involved in the disease pathogenesis. Quantifiable changes in ALS plasma related to redox state alterations can possibly be used for early diagnosis.

The “ON-OFF” Switching Response of Reactive Oxygen Species in Acute Normobaric Hypoxia: Preliminary Outcome

“…Finally, colorimetric assays are common methods for evaluating plasma TAC and TBARS, but their principal limitation is the non-specificity of the test. Nevertheless, various kits based on these methods are commercially available, and results have also been published recently [ 53 , 54 , 55 ]; they represent a reasonable compromise in terms of costs and reliability.…”

Patching Up the Permeability: The Role of Stem Cells in Lessening Neurovascular Damage in Amyotrophic Lateral Sclerosis

“…An in vitro model of human umbilical cord-derived endothelial vascular cells (HUVEC) and astrocytes treated with ALS plasma shows elevated mitochondrial ROS production. 83 ROS promote phosphorylation and ubiquination of tight junction occludin proteins, marking them for degradation and weakening the BCNSB. 84 Like inflammation, oxidative stress may induce or be induced by BCNSB damage.…”

“…In a sample of 25 patients, the plasma showed lipid peroxidation elevation and decreased anti-oxidants such as nitric oxide and reduced glutathione. 83 This oxidative damage may arise from erythrocyte infiltration into the CNS through gaps in the NVU barriers. Erythrocytes possess iron-containing hemoglobin and hemosiderin, both of which can induce oxidative stress through the Fenton reaction.…”

Is Dutasteride a Therapeutic Alternative for Amyotrophic Lateral Sclerosis?

“…This is why restoring mitochondrial alterations is closely linked to new therapeutic approaches for ALS, as these alterations are characterized by mitochondrial electron-transport-chain impairment [ 48 ], mitochondrial DNA deletions and reduced ATP levels [ 49 ], which are present in both patients with familial ALS (fALS) and sporadic ALS (sALS). These mitochondrial dysfunctions have linked oxidative-stress (OS) increases, antioxidant-defense decreases and inflammatory processes with the pathogenesis of ALS [ 50 ]. As a consequence, ALS patients have increased levels of OS markers, such as malondialdehyde or 8-hydroxy-2′-deoxyguanosine (8-OHdG), as well as proinflammatory cytokines, such as IL-6 and IL-8, which confirm the systemic alteration of the redox state and the inflammation in these patients [ 51 ].…”