Phosphodiesterase Inhibition

González-García C, Bravo B, Ballester A, Gómez-Pérez R, Eguiluz C, Redondo M, Martínez A, Gil C, Ballester S.Comparative assessment of phosphodiesterase 4 and 7 inhibitors as therapeutic agents in Experimental Autoimmune Encephalomyelitis. Br J Pharmacol. 2013 doi: 10.1111/bph.12308. [Epub ahead of print]
BACKGROUND AND PURPOSE:Phosphodiesterase 4 (PDE4) inhibition suppresses experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, side-effects hinder PDE4 inhibitors clinical use. PDE7 inhibition might constitute an alternative therapeutic strategy, but few data about the anti-inflammatory potential of PDE7 inhibitors are currently available. We have used the EAE model to perform a comparative evaluation of PDE4 and PDE7 inhibition as strategies for MS treatment.
EXPERIMENTAL APPROACH: Two PDE7 inhibitors, the sulfonamide derivative BRL50481 and the recently described quinazoline compound TC3.6, were assayed to modulate EAE in SJL mice, in comparison with the well-known PDE4 inhibitor Rolipram. We evaluated clinical signs, presence of inflammatory infiltrates in central nervous system (CNS) and anti-inflammatory markers. We also analyzed the effect of these inhbitors on the inflammatory profile of spleen cells in vitro.
KEY RESULTS: TC3.6 prevented EAE with efficacy similar to Rolipram, while BRL50481 had not effect on the disease. Differences between both PDE7 inhibitors are discussed. Data from Rolipram and TC3.6 showed that PDE4 and PDE7 inhibition work through both common and distinct pathways. Rolipram administration caused an increase in IL-10 and IL-27 expression which was not found after TC3.6 treatment. On the other hand, both inhibitors reduced IL-17 levels, prevented infiltration in CNS, and increased the expression of the T regulator cell marker Foxp3.
CONCLUSIONS AND IMPLICATIONS: These results provide new information about the effects of Rolipram on EAE, underline PDE7 inhibition as a new therapeutic target for inflammatory diseases, and show the value of TC3.6 to prevent EAE, with possible consequences for new therapeutic tools in MS.

This study is timely because it talks about Phosphodiesterase 4 (PDE4) inhibition. Ibudilast is a non-selective PDE4 inhibitor in planned trials.

Rolipram is a selective PDE-4, Rolipram inhibits the generation of EAE, many think it is because it inhibits tumour necrosis factor production…….oh no

Sommer N, Löschmann PA, Northoff GH, Weller M, Steinbrecher A, Steinbach JP, Lichtenfels R, Meyermann R, Riethmüller A, Fontana A, et al. The antidepressant rolipram suppresses cytokine production and prevents autoimmune encephalomyelitis. Nat Med. 1995; 1:244-8.

Jung S, Zielasek J, Köllner G, Donhauser T, Toyka K, Hartung HP.
Genain CP, Roberts T, Davis RL, Nguyen MH, Uccelli A, Faulds D, Li Y, Hedgpeth J, Hauser SL. Prevention of autoimmune demyelination in non-human primates by a cAMP-specific phosphodiesterase inhibitor. Proc Natl Acad Sci U S A. 1995; 92:3601-5.

Rolipram makes SPEAE transiently worse

Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Makriyannis A, Khanolkar A, Layward L, Fezza F, Bisogno T, Di Marzo V. Endocannabinoids control spasticity in a multiple sclerosis FASEB J. 2001;15(2):300-2.

Rolipram makes SPMS worse, seen 8 years later. Goes to show that neuros don’t pay attention to scientists or even talk to them half-the time.

Bielekova B, Richert N, Howard T, Packer AN, Blevins G, Ohayon J, McFarland HF, Stürzebecher CS, Martin R. Treatment with the phosphodiesterase type-4 inhibitor rolipram fails to inhibit blood–brain barrier disruption in multiple sclerosis. Mult Scler. 2009 Oct;15(10):1206-14

The trial was stopped prematurely because the drug was poorly tolerated and because of safety concerns: we observed an increase, rather than decrease, in the brain inflammatory activity measured by contrast-enhanced lesions on brain MRI.

Sicotte NL, Voskuhl RR.Onset of multiple sclerosis associated with anti-TNF therapy. Neurology. 2001 Nov 27;57(10):1885-8

Anti-TNF makes MS worse.

Sometimes we have to think what the biology tells us. 

Having activity outside PDE4 may have beneficialy effects, this current study shows that not all PDE inhibitors are created equal. Let’s hope so.

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