Prevention of autoimmune demyelination in non-human primates by a cAMP-specific phosphodiesterase inhibitor.

Abstract

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system that serves as a model for the human disease multiple sclerosis. We evaluated rolipram, a type IV phosphodiesterase inhibitor, for its efficacy in preventing EAE in the common marmoset Callithrix jacchus. In a blinded experimental design, clinical signs of EAE developed within 17 days of immunization with human white matter in two placebo-treated animals but in none of three monkeys that received rolipram (10 mg/kg s.c. every other day) beginning 1 week after immunization. In controls, signs of EAE were associated with development of cerebrospinal fluid pleocytosis and cerebral MRI abnormalities. In the treatment group, there was sustained protection from clinical EAE, transient cerebrospinal fluid pleocytosis in only one of three animals, no MRI abnormality, and marked reduction in histopathologic findings. Rolipram-treated and control animals equally developed circulating antibodies to myelin basic protein. Thus, inhibition of type IV phosphodiesterase, initiated after sensitization to central nervous system antigens, protected against autoimmune demyelinating disease.

Modulation of the cAMP signaling pathway after traumatic brain injury

“…These results are in accordance with previous results using rolipram as a therapeutic agent in spinal cord injury and transient global ischemia where lower doses were also more effective (Block et al, 1997, Nikulina et al, 2004. Rolipram has also been found to improve outcome in experimental allergic encephalomyelitis, Alzheimer disease, multiple sclerosis, ischemia, and striatal excitotoxicity (Genain et al, 1995, Navikas et al, 1998, Folcik et al, 1999, Gong et al, 2004, Demarch et al, 2007, Sasaki et al, 2007. Our results and the many studies assessing rolipram in models of neurological disorders suggest that use of a PDE IV antagonist may be a promising avenue of research as we search for a successful pharmacological therapy for TBI patients.…”

Gene therapy in nonhuman primate models of human autoimmune disease

“…55,56 Disease susceptibility was similar when EAE was induced with rhMOG or the encephalitogenic MOG peptide (14-36) that encompasses the specific CD4 cell epitope. Essentially, the same results were obtained by Genain et al 57 The beneficial effect of the phosphodiesterase inhibitor rolipram on myelininduced EAE supports the view that the pathogenic CD4 cells are of the Th1 type. 57 While autoreactive T cells were sufficient for the initiation of CNS inflammation, specific demyelination was dependent on the presence of anti- In T 2 -weighted brain MR-images of naïve animals, the white matter of a rat and a common marmoset appear as dark gray areas (arrow-head).…”

“…Essentially, the same results were obtained by Genain et al 57 The beneficial effect of the phosphodiesterase inhibitor rolipram on myelininduced EAE supports the view that the pathogenic CD4 cells are of the Th1 type. 57 While autoreactive T cells were sufficient for the initiation of CNS inflammation, specific demyelination was dependent on the presence of anti- In T 2 -weighted brain MR-images of naïve animals, the white matter of a rat and a common marmoset appear as dark gray areas (arrow-head). The picture illustrates that the common marmoset brain contains much more white matter than the rat brain.…”

Suppression of Astroglial Nitric Oxide Synthase Expression by Norepinephrine Results from Decreased NOS‐2 Promoter Activity

“…In rats, treatment of acute monophasic EAE with the /3-adrenergic agonist isoproterenol or of experimental allergic neuritis with terbutaline suppresses these diseases (Chelmicka-Shorr et al, 1989). More recently, the antidepressant rolipram, a type IV phosphodiesterase inhibitor, suppressed cytokine production and development of clinical symptoms in actively induced EAE in both rats (Sommer et al, 1995) and a nonhuman primate model (Genain et al, 1995), presumably due to increased cAMP levels. These observations raise the possibility that diminished levels of neurotransmitter such as NE that stimulate cAMP production could contribute to the causes and/ or exacerbation of autoimmune diseases by allowing normally restricted inflammatory responses to occur.…”