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• There is ongoing effort to discover an efficient approach for management of spinal cord injury (SCI) complications. • Roflumilast is able to alleviate locomotor and sensory complications of SCI. • Roflumilast is a highly selective inhibitor of phosphodiesterase 4 and can enhance the intracellular cAMP level. • Roflumilast decreases the relative ratio of pro-inflammatory (M1) to anti-inflammatory (M2) microglia in the lesion site. • Roflumilast attenuates the secondary damage of SCI through reducing the neuroinflammation. Despite the great search for an effective approach to minimize secondary injury in spinal cord injury (SCI) setting, there have been limited advances. Roflumilast is a selective inhibitor of phosphodiesterase 4 with potent anti-inflammatory properties. Here, we sought to explore Roflumilast efficacy in the improvement of locomotor and sensory deficits of SCI. In an animal setting, 50 male rats were randomly assigned to five groups: an SCI group receiving Placebo, three SCI groups receiving Roflumilast at the doses of 0.25, 0.5, and 1 mg/kg prior to T9 vertebra laminectomy, and a sham-operated group. Locomotor, mechanical, and thermal activities were evaluated for 28 days. At the end of the study, spinal cord samples were taken to assess the relative ratio of microglial subtypes, including M1 and M2, histopathological changes, levels of pro-inflammatory (TNF-α and IL-1β) and anti-inflammatory (IL-10) biomarkers, and cAMP level. Repeated measure analysis revealed significant effect for time-treatment interaction on locomotion [ F (24, 270) = 280.7, p < 0.001], thermal sensitivity [ F (16, 180) = 4.35, p < 0.001], and mechanical sensitivity [ F (16, 180) = 7.96, p < 0.001]. As expected, Roflumilast significantly increased the expression of spinal cAMP. H&E staining exhibited lesser histopathological disruptions in Roflumilast-treated rodents. We also observed a significant reduction in the M1/M2 ratio (p values < 0.001) as well as in pro-inflammatory biomarkers following the administration of Roflumilast to the injured rats. Furthermore, IL-10 level was increased in rodents receiving 1 mg/kg of the reagent. In conclusion, the increased spinal cAMP following Roflumilast therapy might attenuate neuroinflammation via altering microglial activity; therefore, it could be considered as an alternative therapeutic agent for SCI complications. [ABSTRACT FROM AUTHOR]