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.

HAMI 3379, a CysLT2 Receptor Antagonist, Attenuates Ischemia-Like Neuronal Injury by Inhibiting Microglial Activation

“…Inhibition of PDEs by montelukast may be beneficial to ischemic neuronal injury, because the resultant accumulation of cAMP protects neurons from ischemic brain injury (Tsukada et al, 2004;Lin et al, 2009) and inhibitors of PDE3 (cilostazol) and PDE4 (rolipram) have protective effects on neurons (Tanaka et al, 2010;Schaal et al, 2012). In addition, its inhibitory effects on P2Y receptors (Mamedova et al, 2005;Pugliese et al, 2009;Lau et al, 2011) may be protective, because downregulation of the novel P2Y-like receptor GPR17 protects from ischemic neuronal injury after focal cerebral ischemia in rats (Ciana et al, 2006;Zhao et al, 2012).…”

Peptide-functionalized polymeric nanoparticles for active targeting of damaged tissue in animals with experimental autoimmune encephalomyelitis

“…administration of functionalized NPs, anesthetized Dark Agouti rats underwent jugular vein exposure as described previously [13]. DiI laden, functionalized NPs (1.5 mg/ml concentration) were administered daily over a period of 2 min (100 l in PBS) starting at 7 days post-EAE induction for three consecutive days.…”

Immune-Based Therapies for Spinal Cord Injury

“…Extracellular molecules like cyto-and chemokines can be readily targeted by biological agents that demonstrate a high degree of specificity (Esposito and Cuzzocrea, 2011). For example, rolipram has been shown to prevent the reduction in cAMP levels after acute CNS injury as well as promote tissue protection, repair and functional recovery (Pearse et al, 2004;Atkins et al, 2006;Schaal et al, 2012). Additionally, a recent study described the benefits of utilizing a drugeluting microfibrous patch as means to deliver rolipram into the injured spinal cord and data indicated significant improvements in both functional and anatomical recovery (Downing et al, 2012).…”

“…Ideally, this will involve thoroughly investigating and harnessing the benefits of combinatorial therapies, optimization of the dosage and delivery mode and establishment of the best therapeutic window so that clinical feasibility can be examined (Rabchevsky et al, 2011;Schaal et al, 2012). …”