Peripheral Phosphodiesterase 4 Inhibition Produced by 4-[2-(3,4-Bis-difluoromethoxyphenyl)-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-phenyl]-ethyl]-3-methylpyridine-1-oxide (L-826,141) Prevents Experimental Autoimmune Encephalomyelitis

Abstract

ABSTRACT

Elevated ATG5 expression in autoimmune demyelination and multiple sclerosis

“…Wild-type C57Bl/6 mice were immunized with 100 μg of myelin oligodendrocyte glycoprotein (MOG) peptide (amino acids 35–55) that was emulsified in complete Freund’s adjuvant (CFA) as described and employed in previous studies 37–39. Mice were evaluated daily for signs of EAE according to the following scale of clinical disability: 0—no signs of EAE; 1—flaccid tail; 2—hindlimb paresis; 3—unilateral hindlimb paralysis; 4—bilateral hindlimb paralysis; 5—moribund.…”

Critical role for PDE4 subfamilies in the development of experimental autoimmune encephalomyelitis

“…Activation/suppression of APCs and regulation of the cytokine environment are known to be controlled by cAMP levels (Fassbender et al, 2010;Kambayashi et al, 2001). Therefore the upregulation of PDE4B2 mRNA that we report here, in areas with high amount of cellular infiltrates and around the microvessels, together with the role of cAMP in the antigen presentation process (Fallarino et al, 2010) The amelioration of the clinical signs and delayed onset of EAE described after PDE4 inhibition (Folcik et al, 1999;Martinez et al, 1999;Moore et al, 2006;Sommer et al, 1995) T-cell populations that have a crucial role in the EAE model are Th1-and Th17-positive cells (Komiyama et al, 2006;Tzartos et al, 2008;Zamvil and Steinman 1990). These immune cells infiltrate and attack oligodendrocytes, activate resident microglia and astrocytes, leading to demyelination and axonal damage in the EAE model (Lassmann et al, 2001;Soulika et al, 2009).…”

“…In the EAE model, amelioration of the clinical signs and delayed onset is observed after PDE4 inhibition with rolipram (Folcik et al, 1999;Moore et al, 2006;Sommer et al, 1995). The PDE4B gene has been related to the inflammatory response in mouse monocytes and macrophages (Jin et al, 2005a) and previous publications by our group have shown that the PDE4B mRNA splice variant PDE4B2 is upregulated in cellular infiltrates of EAE rat brains (Reyes-Irisarri et al, 2007).…”

The Effect of Pulse Methylprednisolone Plus Theophylline Treatment on Clinical, Pulmonary and Inflammatory Markers in Relapses of Multiple Sclerosis

“…Phosphodiesterase inhibitors (PDEI) suppress the catabolism of cAMP and cGMP, thereby they increase intracellular levels of these cyclic nucleotides and modulate the cytokine secretion (7)(8)(9). Previous studies have shown that production of Thi cytokines especially TNF-alpha might be suppressed by PDEI (10)(11)(12)(13).…”