The therapeutic profile of rolipram, PDE target and mechanism of action as a neuroprotectant following spinal cord injury.

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.

Systemic hypothermia improves histological and functional outcome after cervical spinal cord contusion in rats.

Hypothermia has been employed during the past 30 years as a therapeutic modality for spinal cord injury (SCI) in animal models and in humans. With our newly developed rat cervical model of contusive SCI, we investigated the therapeutic efficacy of transient systemic hypothermia (beginning 5 minutes post-injury for 4 hours, 33 degrees C) with gradual rewarming (1 degrees C per hour) for the preservation of tissue and the prevention of injury-induced functional loss. A moderate cervical displacement SCI was performed in female Fischer rats, and behavior was assessed for 8 weeks. Histologically, the application of hypothermia after SCI resulted in significant increases in normal-appearing white matter (31% increase) and gray matter (38% increase) volumes, greater preservation (four-fold) of neurons immediately rostral and caudal to the injury epicenter, and enhanced sparing of axonal connections from retrogradely traced reticulospinal neurons (127% increase) compared with normothermic controls. Functionally, a faster rate of recovery in open field locomotor ability (BBB score, weeks 1-3) and improved forelimb strength, as measured by both weight-supported hanging (43% increase) and grip strength (25% increase), were obtained after hypothermia. The current study demonstrates that mild systemic hypothermia is effective for retarding tissue damage and reducing neurological deficits following a clinically relevant contusive cervical SCI.