**1. Introduction**

Methyl jasmonate (MeJA) is a cyclopentanone widely spread over the plant kingdom where it functions as signaling molecule associated with biotic and abiotic stress [1]. It was first isolated from the flowers of jasmine (*Jasminum grandiflorum*), whose infusions have been traditionally used to relieve stress, depression, irritability and memory deficit [2]. MeJA has been reported to present anti-tumor activity without affecting healthy cells [3]. In fact, MeJA was revealed to be cytotoxic against various murine and human cancer cell lines [1,3]. In the cancer cells the compound mainly affects the mitochondria, where it detaches the outer membrane-bound hexokinase, stimulates the production of reactive oxygen species (ROS), depletes ATP and induces apoptosis [4,5].

MeJA shares structural similarity with anti-inflammatory prostaglandins and, therefore, has been lately investigated as a promising anti-inflammatory agent [3,6]. The compound itself and its synthetic derivatives inhibit the synthesis of tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), prostaglandin E and nitric oxide (NO) in murine macrophages (RAW264.7) stimulated by lipopolysaccharide (LPS) [6–8]. A recent study also showed that orally administered MeJA improves the systemic and articular inflammation in rats with adjuvant-induced arthritis, an experimental model of human severe rheumatoid arthritis [9]. Thus, MeJA emerges also as a promising agent for treatment of rheumatoid arthritis and other systemic inflammatory disorders.

Rheumatoid arthritis is a chronic and autoimmune inflammatory disease that can lead to progressive joint destruction and affects approximately 1.0% of the adult population worldwide [10,11]. An accentuated hyperplasia of the synovial membrane and cartilage and intense production of pro-inflammatory cytokines (TNFα, IL-1β and IL-6) are normally associated with rheumatoid arthritis [12]. The overproduction of reactive species and metalloproteinases are additionally stimulated by cytokines and mediate the tissue injury [13,14]. Rheumatoid arthritis is a systemic disease and in addition to affecting the joints, it evokes inflammatory and oxidative alterations in other organs, such as lungs, liver and heart [12]. In fact, the oxidative stress biomarkers are modified in the serum of patients with rheumatoid arthritis and in the extra-articular tissues of animal models of rheumatoid arthritis [14–19]. Metabolic alterations also occur in rheumatoid arthritis, as for example, the condition of muscle wasting known as rheumatoid cachexia [20]. The hepatic metabolism is also significantly modified in rats with adjuvant-induced arthritis, a phenomenon associated with pronounced oxidative stress in the organ [17,21–23].

Inflammation in rheumatoid arthritis also affects the brain where it causes fatigue and reduced cognitive function [12]. Cerebral atrophy and other structural modifications have been reported in patients with severe rheumatoid arthritis [24,25]. The levels of ROS, NO, lipoperoxides and protein carbonyl groups are increased in the brain of rats with adjuvant-induced arthritis, particularly in the mitochondria, where the transmembrane potential is also increased [26]. These alterations are accompanied by decreased levels of reduced glutathione (GSH) and diminished activities of antioxidant enzymes. Additionally, the activity of the pro-oxidant enzyme xanthine oxidase (XO) and the pro-inflammatory enzyme iNOS are increased in the brain of arthritic rats [26].

An earlier study has shown that intraperitoneally administered MeJA attenuates the memory dysfunction, decreases the levels of prostaglandin E, TNFα and IL-1 and suppresses the expression of COX-2 and iNOS in the brain of mice with LPS-induced neuroinflammation [27]. In addition, MeJA reverses in mice the memory impairment caused by scopolamine and unpredictable chronic mild stress (UCMS), phenomena that were associated with the improvement in the brain's levels of oxidative stress biomarkers, specifically lipoperoxides and GSH [28,29]. Considering these actions of MeJA on the cerebral tissue of mice, it is reasonable to hypothesize that MeJA will be capable of attenuating the inflammation and oxidative stress in the brain of arthritic rats. The present work was thus planned to investigate the effects of orally administered MeJA on inflammation and on the oxidative status of the brain of rats using the model of adjuvant-induced arthritis. Because orally administered MeJA stimulated ROS production in isolated hepatic mitochondria [9], this work has also evaluated the production of ROS in isolated brain mitochondria from healthy and arthritic rats as well as the activities of several mitochondrial dehydrogenases. Furthermore, the activity of hexokinase was also evaluated, as the liver of arthritic rats presents a considerably enhanced glucose phosphorylation capacity [30]. The data obtained in the current study should allow to infer about the possible actions of MeJA on the brain of patients with severe rheumatoid arthritis.
