The EAE-associated behavioral syndrome: II. Modulation by anti-inflammatory treatments
Introduction
EAE is an autoimmune disease of the central nervous system (CNS), in which CD4 Th1 cells are activated against self-myelin proteins and insult the myelin sheaths within the brain and spinal cord. This insult results in ascending motor and sensory deficits. The clinical episodes of EAE are associated with a behavioral syndrome consisting of anorexia and loss of body weight, reduced consumption of a sweet solution and decreased social investigation (Pollak et al., 2000). These behavioral alterations were termed EAE-associated behavioral syndrome or EBS (Pollak et al., 2002). Previous research revealed a correlation in time between phases of the EBS and the expression of the pro-inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis-factor α (TNF-α). Other EAE-related phenomena corresponded only partially to the behavioral phases, e.g., motor impairment began 1–2 days after the initiation of the behavioral alterations and sustained for several days after the behavioral recovery; onset of infiltration into the brain and of the increase in prostaglandin E2 (PGE2) production within several brain areas coincided with the onset of the behavioral syndrome, but both continued following behavioral recovery (Pollak et al., in this issue).
Sickness behavior is a common phenomenon accompanying infectious and inflammatory diseases, as demonstrated in animals and in humans by administration of lipopolysaccharide (LPS), Mycoplasma fermentans, HIV-gp120, influenza virus, as well as many other pathogens and toxins Kozak et al., 1997, Szechtman et al., 1997, Swiergiel et al., 1997, Connor and Leonard, 1998, Maier and Watkins, 1998, Yirmiya et al., 1999a, Yirmiya et al., 1999b, Dantzer, 2001, Barak et al., 2002. Pro-inflammatory mediators in general, and IL-1, TNF-α and PGE2 in particular, were implicated as mechanisms mediating sickness behavior in several models Connor and Leonard, 1998, Maier and Watkins, 1998, Yirmiya et al., 1999b, Yirmiya et al., 2000, Dantzer, 2001, Larson and Dunn, 2001. The aim of the present study was to further establish the role for these inflammatory mediators in the behavioral alterations associated with EAE. To this aim, we examined the EBS in mice that were treated with the steroid anti-inflammatory drug dexamethasone, which attenuates cytokine production (Barnes and Adcock, 1993), as well as more specific inhibitors of IL-1, TNF-α and PGE2, including IL-1 receptor antagonist (IL-1ra) which blocks the effects of IL-1 (Dinarello, 2000), pentoxifylline, which blocks the synthesis of TNF-α (Windmeier and Gressner, 1997), and indomethacin, which blocks the synthesis of prostaglandins from arachidonic acid by inhibiting cyclooxygenase (COX) (Lupulescu, 1996).
The most popular model of sickness behavior is the one induced by administration of LPS, the active component of gram-negative bacteria cell wall. Using this model, a role for pro-inflammatory cytokines and prostaglandins in mediating sickness behavior was established Connor and Leonard, 1998, Maier and Watkins, 1998, Yirmiya et al., 1999b, Dantzer, 2001, Larson and Dunn, 2001, Reichenberg et al., 2001. To enable a comparison between different models of sickness behavior, the protocols used to manipulate cytokine actions in EBS were subsequently examined in LPS-treated mice.
Section snippets
Subjects
Subjects were female SJL/J or C57Bl/6 mice (Harlan–Sprague–Dawley, USA), or C57Bl/6 mice with targeted deletion of the p55 TNF receptor gene (TNFR1−/−) (Jackson Laboratories). Mice (7–12/group) were 8–12 weeks in age. Animals were housed individually in constant room temperature (23±1 °C), and were provided with food, water and 2% sucrose solution ad libitum. Treatments and measurements were conducted during the dark phase of a reversed 12 h light–dark cycle (lights off at 8:30 AM).
Active induction and clinical evaluation of EAE
In most of
Effect of dexamethasone on the EBS
The effects of dexamethasone on the neurological score and the EBS were tested during 2 days of treatment (the day of disease onset and the following day). Dexamethasone produced a mild reduction in neurological score, which did not reach statistical significance (F(1,15)=1.57, p>0.05) (Fig. 1A). EAE-associated decrease in body weight was also not affected by dexamethasone (F(1,15)=3.18, p>0.05) (Fig. 1B).
EAE was associated with decreased food intake, which was significantly attenuated by the
Discussion
The results of the present study corroborate our previous report that EAE is associated with a behavioral syndrome, consisting of a reduction in food and sucrose intake and in social exploration (Pollak et al., 2000). Furthermore, using pharmacological treatments, we demonstrated here the critical role of inflammatory processes in mediating specific aspects of the EBS. Administration of PGE2 synthesis inhibitor or IL-1ra attenuated the several aspects of the behavioral syndrome.
Acknowledgments
The authors thank Orli Bar-Shalev, Shira Gur, Lior Friedman, Yael Perets, Meital Shahar, Michal Shlayer, Michal Shuker, and Gili Wolf for their excellent help in running the experiments. The research was supported by a grant from the Israel Science Foundation (No. 820/00) and in part by the Lena P. Harvey Endowment Fund for Neurological Research. RY is a member of the Eric Roland Center for Neurodegenerative Diseases at the Hebrew University of Jerusalem.
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