Abstract
Roflumilast, a selective inhibitor for PDE4, is approved by FDA as an anti-inflammation drug for treatment of chronic obstructive pulmonary disease (COPD). This study investigates the effects of roflumilast on cerebral inflammation in the rat SAH model. Here, we show that subcutaneous administration of roflumilast (3 mg/kg) significantly improved the neurological deficits. Measurement of evans blue extravasation and brain water content revealed a significant reduction of blood-brain barrier permeability and brain edema. Importantly, roflumilast treatment remarkably decreased levels of IL-1β, IL-6, and TNF-α and the number of apoptotic neurons in the brain after SAH. These results indicate that roflumilast is effective in treating cerebral inflammation following SAH.
Similar content being viewed by others
Change history
15 October 2022
A Correction to this paper has been published: https://doi.org/10.1007/s10753-022-01754-6
References
Miller, B.A., N. Turan, M. Chau, and G. Pradilla. 2014. Inflammation, vasospasm, and brain injury after subarachnoid hemorrhage. BioMed Research International 2014: 384342.
Pradilla, G., K.L. Chaichana, S. Hoang, J. Huang, and R.J. Tamargo. 2010. Inflammation and cerebral vasospasm after subarachnoid hemorrhage. Neurosurgery Clinics of North America 21 (2): 365–379.
Kaynar, M.Y., T. Tanriverdi, A.M. Kafadar, T. Kacira, H. Uzun, S. Aydin, K. Gumustas, A. Dirican, and C. Kuday. 2004. Detection of soluble intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in both cerebrospinal fluid and serum of patients after aneurysmal subarachnoid hemorrhage. Journal of Neurosurgery 101 (6): 1030–1036.
Horstmann, S., Y. Su, J. Koziol, U. Meyding-Lamade, S. Nagel, and S. Wagner. 2006. MMP-2 and MMP-9 levels in peripheral blood after subarachnoid hemorrhage. Journal of the Neurological Sciences 251 (1–2): 82–86.
Mocco, J., W.J. Mack, G.H. Kim, A.P. Lozier, I. Laufer, K.T. Kreiter, R.R. Sciacca, R.A. Solomon, S.A. Mayer, and E.S. Connolly Jr. 2002. Rise in serum soluble intercellular adhesion molecule-1 levels with vasospasm following aneurysmal subarachnoid hemorrhage. Journal of Neurosurgery 97 (3): 537–541.
Mathiesen, T., G. Edner, E. Ulfarsson, and B. Andersson. 1997. Cerebrospinal fluid interleukin-1 receptor antagonist and tumor necrosis factor-alpha following subarachnoid hemorrhage. Journal of Neurosurgery 87 (2): 215–220.
Dumont, A.S., R.J. Dumont, M.M. Chow, C.L. Lin, T. Calisaneller, K.F. Ley, N.F. Kassell, and K.S. Lee. 2003. Cerebral vasospasm after subarachnoid hemorrhage: putative role of inflammation. Neurosurgery 53 (1): 123–133 discussion 133-125.
Sehba, F.A., R.M. Pluta, and J.H. Zhang. 2011. Metamorphosis of subarachnoid hemorrhage research: from delayed vasospasm to early brain injury. Molecular Neurobiology 43 (1): 27–40.
Schaal, S.M., M.S. Garg, M. Ghosh, L. Lovera, M. Lopez, M. Patel, J. Louro, S. Patel, L. Tuesta, W.M. Chan, and D.D. Pearse. 2012. The therapeutic profile of rolipram, PDE target and mechanism of action as a neuroprotectant following spinal cord injury. PloS One 7 (9): e43634.
Atkins, C.M., A.A. Oliva Jr., Alonso OF, D.D. Pearse, H.M. Bramlett, and W.D. Dietrich. 2007. Modulation of the cAMP signaling pathway after traumatic brain injury. Experimental Neurology 208 (1): 145–158.
Gong, B., O.V. Vitolo, F. Trinchese, S. Liu, M. Shelanski, and O. Arancio. 2004. Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. The Journal of Clinical Investigation 114 (11): 1624–1634.
Zhang, H.T. 2009. Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs. Current Pharmaceutical Design 15 (14): 1688–1698.
Gonzalez-Garcia, C., B. Bravo, A. Ballester, R. Gomez-Perez, C. Eguiluz, M. Redondo, A. Martinez, C. Gil, and S. Ballester. 2013. Comparative assessment of PDE 4 and 7 inhibitors as therapeutic agents in experimental autoimmune encephalomyelitis. British Journal of Pharmacology 170 (3): 602–613.
Kraft, P., T. Schwarz, E. Gob, N. Heydenreich, M. Brede, S.G. Meuth, and C. Kleinschnitz. 2013. The phosphodiesterase-4 inhibitor rolipram protects from ischemic stroke in mice by reducing blood-brain-barrier damage, inflammation and thrombosis. Experimental Neurology 247: 80–90.
Hu, S., Q. Cao, P. Xu, W. Ji, G. Wang, and Y. Zhang. 2016. Rolipram stimulates angiogenesis and attenuates neuronal apoptosis through the cAMP/cAMP-responsive element binding protein pathway following ischemic stroke in rats. Experimental and Therapeutic Medicine 11 (3): 1005–1010.
Rabe, K.F. 2011. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease. British Journal of Pharmacology 163 (1): 53–67.
Chong, J., P. Poole, B. Leung, and P.N. Black. 2011. Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database of Systematic Reviews 5: CD002309.
Hatzelmann, A., E.J. Morcillo, G. Lungarella, S. Adnot, S. Sanjar, R. Beume, C. Schudt, and H. Tenor. 2010. The preclinical pharmacology of roflumilast—a selective, oral phosphodiesterase 4 inhibitor in development for chronic obstructive pulmonary disease. Pulmonary Pharmacology & Therapeutics 23 (4): 235–256.
Jabaris, S.G., H. Sumathy, R.S. Kumar, S. Narayanan, S. Thanikachalam, and C.S. Babu. 2015. Effects of rolipram and roflumilast, phosphodiesterase-4 inhibitors, on hypertension-induced defects in memory function in rats. European Journal of Pharmacology 746: 138–147.
Vanmierlo, T., P. Creemers, S. Akkerman, M. van Duinen, A. Sambeth, J. De Vry, T. Uz, A. Blokland, and J. Prickaerts. 2016. The PDE4 inhibitor roflumilast improves memory in rodents at non-emetic doses. Behavioural Brain Research 303: 26–33.
Zhang, Z.Y., M.F. Yang, T. Wang, D.W. Li, Y.L. Liu, J.H. Zhang, and B.L. Sun. 2015. Cysteamine alleviates early brain injury via reducing oxidative stress and apoptosis in a rat experimental subarachnoid hemorrhage model. Cellular and Molecular Neurobiology 35 (4): 543–553.
Zhang, Z.Y., M. Jiang, J. Fang, M.F. Yang, S. Zhang, Y.X. Yin, D.W. Li, L.L. Mao, X.Y. Fu, Y.J. Hou, X.T. Fu, C.D. Fan, and B.L. Sun. 2017. Enhanced therapeutic potential of nano-curcumin against subarachnoid hemorrhage-induced blood-brain barrier disruption through inhibition of inflammatory response and oxidative stress. Molecular Neurobiology 54 (1): 1–14.
Zhang, Z.Y., B.L. Sun, J.K. Liu, M.F. Yang, D.W. Li, J. Fang, S. Zhang, Q.L. Yuan, and S.L. Huang. 2015. Activation of mGluR5 attenuates microglial activation and neuronal apoptosis in early brain injury after experimental subarachnoid hemorrhage in rats. Neurochemical Research 40 (6): 1121–1132.
Acknowledgments
This work was supported by funds from the National Natural Science Foundation of China (Grant No. 81471212, 81271275, 81070947 to Baoliang Sun; 81671141 to Zongyong Zhang) and the Natural Science Foundation of Shandong, China (Grant No. ZR2012HZ006 to Baoliang Sun).
Contributors
BS and JK conceived the project and designed experiments. QW, LQ, HL, LM, MY, RX, and XY performed the experiments; BS and JW analyzed the results, ZZ and BS wrote the manuscript. All authors read and approved the final manuscript.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest
Additional information
Qingjian Wu and Lifeng Qi are co-first authors.
Rights and permissions
About this article
Cite this article
Wu, Q., Qi, L., Li, H. et al. Roflumilast Reduces Cerebral Inflammation in a Rat Model of Experimental Subarachnoid Hemorrhage. Inflammation 40, 1245–1253 (2017). https://doi.org/10.1007/s10753-017-0567-8
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10753-017-0567-8