Inhibition of phosphodiesterase IV enzyme improves locomotor and sensory complications of spinal cord injury via altering microglial activity: Introduction of Roflumilast as an alternative therapy

Authors

Kamyar Moradi, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Mohammadreza Golbakhsh, Department of Orthopedic Surgery, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran.
Farinaz Haghighi, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Khashayar Afshari, Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Rajan Nikbakhsh, Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Mohammad Mahdi Khavandi, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Shahriar Faghani, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Abolfazl Badripour, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Ali Etemadi, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Amir Ashraf-Ganjouei, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.
Sayna Bagheri, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Ahmad Reza Dehpour, Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: dehpour@yahoo.com.

Document Type

Article

Publication Title

International immunopharmacology

Abstract

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.

First Page

106743

DOI

10.1016/j.intimp.2020.106743

Publication Date

9-1-2020

Recommended Citation

Moradi, Kamyar; Golbakhsh, Mohammadreza; Haghighi, Farinaz; Afshari, Khashayar; Nikbakhsh, Rajan; Khavandi, Mohammad Mahdi; Faghani, Shahriar; Badripour, Abolfazl; Etemadi, Ali; Ashraf-Ganjouei, Amir; Bagheri, Sayna; and Dehpour, Ahmad Reza, "Inhibition of phosphodiesterase IV enzyme improves locomotor and sensory complications of spinal cord injury via altering microglial activity: Introduction of Roflumilast as an alternative therapy" (2020). Internal Medicine. 307.
https://scholar.bridgeporthospital.org/internal_medicine/307

Identifier

32619958 (pubmed); 10.1016/j.intimp.2020.106743 (doi); S1567-5769(20)30762-1 (pii)