Abstract
Oxidative stress is a key mediator of autoimmune/neurodegenerative disorders. The antioxidant/anti-inflammatory effect of a synthetic conjugated linoleic acid (CLA) mixture in MRL/MpJ-Faslpr mice (MRL/lpr), an animal model of neuropsychiatric lupus, was previously associated with the improvement of nuclear factor-E2-related factor 2 (Nrf2) defenses in the spleen and liver. However, little is known about the neuroprotective ability of a CLA mixture. This study investigated the age-dependent progression of oxidative stress and the hyperactivation of redox-sensitive compensatory pathways (macroautophagy, Nrf2) in old/diseased MRL/lpr mice brains and examines the effect produced by dietary CLA supplementation. Disrupted redox homeostasis was evidenced in the blood, liver, and brain of 21- to 22-week-old MRL/lpr (Old) mice compared with 8- to 10-week-old MRL/lpr (Young) animals. This alteration was associated with significant hyperactivation of compensatory mechanisms (macroautophagy, Nrf2, and astrocyte activation) in the brains of Old mice. Five-week daily supplementation with CLA (650 mg/kg−1 body weight) of 16-week-old (CLA+Old) mice diminished all the pathological hallmarks at a level comparable to Young mice or healthy controls (BALB/c). Such data demonstrated that MRL/lpr mice can serve as a valuable model for the evaluation of the effectiveness of neuroprotective drugs. Notably, the preventive effect provided by CLA supplementation against age-associated neuronal damage and hyperactivation of compensatory mechanisms suggests that the activation of an adaptive response is at least in part accountable for its neuroprotective ability.
Highlights
Oxidative stress is a key mediator of autoimmune/neurodegenerative disorders
They were significantly increased in old MRL/lpr (Old) mice in comparison with 8- to 10-week-old MRL/lpr (Young) samples (P < 0.01) and these modifications were almost completely inhibited by conjugated linoleic acid (CLA) pretreatment
Total GSH, Trolox-equivalent antioxidant capacity (TEAC), and carbonylated protein (PC) concentration were markedly altered in Old animals in comparison with Young mice (P < 0.05), while in CLA+Old animals, their values were similar to those measured in Young mice
Summary
Oxidative stress is a key mediator of autoimmune/neurodegenerative disorders. The antioxidant/antiinflammatory effect of a synthetic conjugated linoleic acid (CLA) mixture in MRL/MpJ-Faslpr mice (MRL/lpr), an animal model of neuropsychiatric lupus, was previously associated with the improvement of nuclear factor-E2-related factor 2 (Nrf2) defenses in the spleen and liver. Disrupted redox homeostasis was evidenced in the blood, liver, and brain of 21- to 22-week-old MRL/lpr (Old) mice compared with 8- to 10-week-old MRL/lpr (Young) animals This alteration was associated with significant hyperactivation of compensatory mechanisms (macroautophagy, Nrf, and astrocyte activation) in the brains of Old mice. MRL/lpr mice exhibit an accelerated form of lupus-like disease associated with behavioral manifestations/neurological signs [3, 4] and a marked increase of degenerating neurons [5], while no data indicating the occurrence of such pathological symptoms in age-matched MRL/+ mice are available For these reasons, MRL/lpr mice have been indicated as a useful animal model for the evaluation of neuroprotective drugs [6], but their utilization in such studies has so far been limited. The Nrf pathway has been implicated as a potential drug target in the prevention/ therapy of neurodegenerative conditions [14]
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