title: The therapeutic profile of rolipram, PDE target and mechanism of action as a neuroprotectant following spinal cord injury.
abstract: The extent of damage following spinal cord injury (SCI) can be reduced by various neuroprotective regimens that include maintaining levels of cyclic adenosine monophosphate (cyclic AMP), via administration of the phosphodiesterase 4 (PDE4) inhibitor Rolipram. The current study sought to determine the optimal neuroprotective dose, route and therapeutic window for Rolipram following contusive SCI in rat as well as its prominent PDE target and putative mechanism of protection. Rolipram or vehicle control (10% ethanol) was given subcutaneously (s.c.) daily for 2 wk post-injury (PI) after which the preservation of oligodendrocytes, neurons and central myelinated axons was stereologically assessed. Doses of 0.1 mg/kg to 1.0 mg/kg (given at 1 h PI) increased neuronal survival; 0.5 mg to 1.0 mg/kg protected oligodendrocytes and 1.0 mg/kg produced optimal preservation of central myelinated axons. Ethanol also demonstrated significant neuronal and oligo-protection; though the preservation provided was significantly less than Rolipram. Subsequent use of this optimal Rolipram dose, 1.0 mg/kg, via different routes (i.v., s.c. or oral, 1 h PI), demonstrated that i.v. administration produced the most significant and consistent cyto- and axo- protection, although all routes were effective. Examination of the therapeutic window for i.v. Rolipram (1.0 mg/kg), when initiated between 1 and 48 h after SCI, revealed maximal neuroprotection at 2 h post-SCI, although the protective efficacy of Rolipram could still be observed when administration was delayed for up to 48 h PI. Importantly, use of the optimal Rolipram regimen significantly improved locomotor function after SCI as measured by the BBB score. Lastly we show SCI-induced changes in PDE4A, B and D expression and phosphorylation as well as cytokine expression and immune cell infiltration. We demonstrate that Rolipram abrogates SCI-induced PDE4B1 and PDE4A5 production, PDE4A5 phosphorylation, MCP-1 expression and immune cell infiltration, while preventing post-injury reductions in IL-10. This work supports the use of Rolipram as an acute neuroprotectant following SCI and defines an optimal administration protocol and target for its therapeutic application.
authors.affiliation: The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Sandra Marie
authors.initials: SM
authors.lastname: Schaal
authors.forename: Maneesh Sen
authors.initials: MS
authors.lastname: Garg
authors.forename: Mousumi
authors.initials: M
authors.lastname: Ghosh
authors.forename: Lilie
authors.initials: L
authors.lastname: Lovera
authors.forename: Michael
authors.initials: M
authors.lastname: Lopez
authors.forename: Monal
authors.initials: M
authors.lastname: Patel
authors.forename: Jack
authors.initials: J
authors.lastname: Louro
authors.forename: Samik
authors.initials: S
authors.lastname: Patel
authors.forename: Luis
authors.initials: L
authors.lastname: Tuesta
authors.forename: Wai-Man
authors.initials: WM
authors.lastname: Chan
authors.forename: Damien Daniel
authors.initials: DD
authors.lastname: Pearse
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D009043:Motor Activity / Q000187:drug effects; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism; D010586:Phagocytes / Q000187:drug effects; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D020889:Rolipram / Q000008:administration & dosage / Q000494:pharmacology*; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D013997:Time Factors
chemical_list: D016207:Cytokines; D018696:Neuroprotective Agents; D058988:Phosphodiesterase 4 Inhibitors; D010727:Phosphoric Diester Hydrolases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram