Suppression of neuroinflammation and immunomodulation by the acetylcholinesterase inhibitor rivastigmine
Introduction
Experimental autoimmune encephalomyelitis (EAE) is a widely used animal model for the study of the underlying pathology of MS that has also proved effective in the development of new therapies (Steinman and Zamvil, 2006). Using this model, previous work from our laboratory indicated the novel anti-inflammatory effect of acetylcholinesterase inhibitors (AChEIs) (Nizri et al., 2006), which was manifested as attenuation of the motor symptoms of EAE and inhibition of T-cell proliferation and cytokine secretion. This property of AChEIs depends on the activation of the α7 nicotinic acetylcholine receptors (nAChR) on T-cells. Accordingly, the α7 nAChR was recently identified as an anti-inflammatory target in macrophages (Borovikova et al., 2000, Wang et al., 2003), the activation of which reduced pro-inflammatory cytokine production and NF-кB-dependent transcription (Wang et al., 2004). The mechanism proposed for this novel function of AChEIs is the prevention of the hydrolysis of endogenous acetylcholine (ACh) thereby enhancing its interaction with α7 nAChR (Nizri et al., 2006). Indeed, nicotine was able to inhibit T-cell proliferation and the production of TNF-α and IL-1β (Nizri et al., 2006). Although it may seem practical to use nicotinic agonists to elicit the anti-inflammatory effect of the “immune cholinergic system” (Cloez-Tayarani and Changeux, 2007, Kawashima and Fujii, 2003), there are none currently in clinical use. Since the AChEI rivastigmine is already widely used for the treatment of cognitive dysfunction in Alzheimer's disease (AD) (Birks, 2006, Burns et al., 2006, Dantoine et al., 2006) it possesses an advantage for treatment of CNS diseases like MS in which inflammatory damage and cognitive dysfunction occur. Rivastigmine is a pseudo-irreversible AChEI that was shown to ameliorate cognitive dysfunction in AD (Cummings, 2004).
In the present study, we tested the efficacy of rivastigmine in a chronic EAE model induced by myelin oligodendrocyte glycoprotein (MOG) in C57BL\6 mice. Our results show that rivastigmine ameliorated clinical and pathological parameters of EAE. We also observed reduced reactivity of encephalitogenic T-cells, accompanied by diminished antigen presentation capability, indicating that this treatment had a multi-level influence on the immunologically-mediated autoimmune process. Rivastigmine also prevented the cognitive dysfunction associated with EAE, as judged from a spatial memory test. Thus AChEIs such as rivastigmine may induce an anti-inflammatory and disease modifying effect.
Section snippets
AChE inhibition in the CNS and in the periphery by rivastigmine
Female 8-week-old C57BL/6 mice received s.c. saline (n = 5) or rivastigmine 0.75 mg/kg (n = 8) and were sacrificed 45 min later. The time of sacrifice was chosen according to previous data from our laboratory showing that peak AChE inhibition in the brain occurs after this time (Wang et al., 2000). The brains (minus cerebellum) and tibialis muscles were rapidly removed and homogenized in 0.25 mM phosphate containing 1% Triton X-100. After centrifugation cholinesterase (ChE) activity was measured in
Amelioration of EAE by treatment with rivastigmine
To assess the influence of rivastigmine on CNS inflammation, we treated MOG-induced EAE mice from the day of induction with a dose of 0.75 mg/kg (s.c.). This inhibited ChE in brain by 56.1 ± 2.0% and in muscle by 42.4 ± 2.8%, 45 min after injection. Treatment with rivastigmine reduced disease severity and cumulative score by 50% and 54%, respectively (Fig. 1A and Table 1), and delayed disease onset by 3.5 days (p < 0.001). To substantiate our previous hypothesis that the anti-inflammatory activity of
Discussion
The major new finding in this study is that rivastigmine, an AChEI currently used for the treatment of cognitive impairment in AD, can ameliorate neurological dysfunction and memory deficits in a mouse model of multiple sclerosis. This effect resulted from its ability to down-regulate the inflammatory activation of immune cells through an increased level of ACh acting on nicotinic α7 receptors.
When administered by daily injection from the day of disease induction, rivastigmine (at 0.75 mg/kg)
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