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E pac and the high affinity rolipram binding conformer of PDE 4 modulate neurite outgrowth and myelination using an in vitro spinal cord injury model
Author(s) -
Boomkamp S D,
McGrath M A,
Houslay M D,
Barnett S C
Publication year - 2014
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12588
Subject(s) - rolipram , neurite , chemistry , forskolin , microbiology and biotechnology , pharmacology , in vitro , neuroscience , biology , phosphodiesterase , biochemistry , enzyme
Background and Purpose cAMP and pharmacological inhibition of PDE 4, which degrades it, are promising therapeutic targets for the treatment of spinal cord injury ( SCI ). Using our previously described in vitro SCI model, we studied the mechanisms by which cAMP modulators promote neurite outgrowth and myelination using enantiomers of the PDE 4‐specific inhibitor rolipram and other modulators of downstream signalling effectors. Experimental Approach Rat mixed neural cell myelinating cultures were cut with a scalpel and treated with enantiomers of the PDE 4‐specific inhibitor rolipram, E pac agonists and PKA antagonists. Neurite outgrowth, density and myelination were assessed by immunocytochemistry and cytokine levels analysed by qPCR . Key Results Inhibition of the high‐affinity rolipram‐binding state ( HARBS ), rather than the low‐affinity rolipram binding state ( LARBS ) PDE 4 conformer promoted neurite outgrowth and myelination. These effects were mediated through the activation of Epac and not through PKA. Expression of the chemokine CXCL10, known to inhibit myelination, was markedly elevated in astrocytes after Rho inhibition and this was blocked by inhibition of Rho kinase or PDE 4. Conclusions and Implications PDE 4 inhibitors targeted at the HARBS conformer or E pac agonists may provide promising novel targets for the treatment of SCI . Our study demonstrates the differential mechanisms of action of these compounds, as well as the benefit of a combined pharmacological approach and highlighting potential promising targets for the treatment of SCI . These findings need to be confirmed in vivo .