Inflammation, Iron, Energy Failure, and Oxidative Stress in the Pathogenesis of Multiple Sclerosis

Abstract

Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system. Different trigger pathologies have been suggested by the primary cytodegenerative “inside-out” and primary inflammation-driven “outside-in” hypotheses. Recent data indicate that mitochondrial injury and subsequent energy failure are key factors in the induction of demyelination and neurodegeneration. The brain weighs only a few percent of the body mass but accounts for approximately 20% of the total basal oxygen consumption of mitochondria. Oxidative stress induces mitochondrial injury in patients with multiple sclerosis and energy failure in the central nervous system of susceptible individuals. The interconnected mechanisms responsible for free radical production in patients with multiple sclerosis are as follows: (i) inflammation-induced production of free radicals by activated immune cells, (ii) liberation of iron from the myelin sheets during demyelination, and (iii) mitochondrial injury and thus energy failure-related free radical production. In the present review, the different sources of oxidative stress and their relationships to patients with multiple sclerosis considering tissue injury mechanisms and clinical aspects have been discussed.

Hyperpolarized 13 C MR metabolic imaging can detect neuroinflammation in vivo in a multiple sclerosis murine model

“…For instance, after W6 of CPZ administration we observed a strong reduction of MPs in the corpus callosum. Although most of the remaining MPs still express PDK1 and there is a trend toward decreased PDH activity compared with CTRL, we did not detect a significantly increased production of HP [1][2][3][4][5][6][7][8][9][10][11][12][13] C]lactate at that time point, which may be explained by the limited sensitivity of HP 13 C MRSI to lower MP number. Furthermore, the lack of increase in the HP [1-13 C]lactate-topyruvate ratios in two of seven mice at W4 (Fig.…”

“…In the vast majority of cases, demyelinating lesions present a high inflammatory component, with elevated density of activated microglia/macrophages (mononuclear phagocytes, MPs) (4-6). Importantly, evidence suggests that proinflammatory MPs are one of the most abundant sources of reactive oxygen species (7), which mediate demyelination and axonal injury (8). Due to their central role in MS pathogenesis, noninvasive imaging of proinflammatory MPs would be of high importance for monitoring progression and response to antiinflammatory therapeutic approaches.…”

Elevated cerebrospinal fluid uric acid during relapse of neuromyelitis optica spectrum disorders

“…Neuromyelitis optica spectrum disorders (NMOSDs) comprise NMO, Asian optic‐spinal MS, optic neuritis or longitudinally extensive myelitis associated with systemic autoimmune disease, optic neuritis or myelitis associated with brain lesions typical of NMO (hypothalamic, corpus callosal, periventricular, or brainstem), and limited forms of NMO (idiopathic single or recurrent events of longitudinally extensive myelitis and recurrent or simultaneous bilateral optic neuritis) (Wingerchuk, Lennon, Lucchinetti, Pittock, & Weinshenker, 2007; Wingerchuk, Lennon, Pittock, Lucchinetti, & Weinshenker, 2006). Oxidative stress is also thought to be involved in NMO and MS (Gonsette, 2008; Haider, 2015; Lassmann & van Horssen, 2016; Penton‐Rol et al., 2009). Previous studies have focused more on serum UA in NMO/MS patients (Ashtari, Bahar, Aghaei, & Zahed, 2013; Liu et al., 2013; Min et al., 2012; Peng et al., 2008; Sotgiu et al., 2002), although cerebrospinal fluid (CSF) UA levels might more directly reflect CNS.…”

Iron chelation in the treatment of neurodegenerative diseases

“…Increased iron concentration was documented in the white matter lesions and deep gray matter structures [150][151][152][153][154][155]. Iron accumulates in the basal ganglia already in the very early stage of MS, i.e.…”