Rolipram Explained

Rolipram is a selective phosphodiesterase-4 inhibitor discovered and developed by Schering AG as a potential antidepressant drug in the early 1990s.^[1] It served as a prototype molecule for several companies' drug discovery and development efforts.^[2] Rolipram was discontinued after clinical trials showed that its therapeutic window was too narrow; it could not be dosed at high enough levels to be effective without causing significant gastrointestinal side effects.^[2]

Rolipram has several activities that make it a continuing focus for research. The etiology of many neurodegenerative diseases involves misfolded and clumped proteins which accumulate in the brain. Cells have a mechanism to dispose of such proteins called the proteasome. However, in Alzheimer's disease and some other conditions the activity of these proteasomes is impaired leading to a buildup of toxic aggregates. Research in mice suggests that rolipram has the ability to ramp up the activity of proteasomes and reduce the burden of these aggregates. Preliminary evidence suggests that this can improve spatial memory in mice engineered to have aggregate build-up.^[3] Rolipram continues to be used in research as a well-characterized PDE4 inhibitor.^[2] It has been used in studies to understand whether PDE4 inhibition could be useful in autoimmune diseases,^[4] Alzheimer's disease,^[5] cognitive enhancement,^[6] spinal cord injury,^[7] and respiratory diseases like asthma and COPD.^[8]

See also

• Roflumilast

Notes and References

1. Zhu J, Mix E, Winblad B . The antidepressant and antiinflammatory effects of rolipram in the central nervous system . CNS Drug Reviews . 7 . 4 . 387–398 . Winter 2001 . 11830756 . 6741679 . 10.1111/j.1527-3458.2001.tb00206.x .
2. Book: McKenna JM, Muller GW . Chapter 33: Medicinal Chemistry of PDE4 Inhibitors. . Cyclic Nucleotide Phosphodiesterases in Health and Disease . Beavo J, Francis SH, Houslay MD . CRC Press . December 2006 . 9781420020847.
3. Myeku N, Clelland CL, Emrani S, Kukushkin NV, Yu WH, Goldberg AL, Duff KE . Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling . Nature Medicine . 22 . 1 . 46–53 . January 2016 . 26692334 . 4787271 . 10.1038/nm.4011 .
4. Kumar N, Goldminz AM, Kim N, Gottlieb AB . Phosphodiesterase 4-targeted treatments for autoimmune diseases . BMC Medicine . 11 . 1 . 96 . April 2013 . 23557064 . 3616808 . 10.1186/1741-7015-11-96 . free .
5. García-Osta A, Cuadrado-Tejedor M, García-Barroso C, Oyarzábal J, Franco R . Phosphodiesterases as therapeutic targets for Alzheimer's disease . ACS Chemical Neuroscience . 3 . 11 . 832–844 . November 2012 . 23173065 . 3503343 . 10.1021/cn3000907 .
6. Normann C, Berger M . Neuroenhancement: status quo and perspectives . European Archives of Psychiatry and Clinical Neuroscience . 258 . Suppl 5 . 110–114 . November 2008 . 18985306 . 10.1007/s00406-008-5022-2 . 9733191 .
7. Hannila SS, Filbin MT . The role of cyclic AMP signaling in promoting axonal regeneration after spinal cord injury . Experimental Neurology . 209 . 2 . 321–332 . February 2008 . 17720160 . 2692909 . 10.1016/j.expneurol.2007.06.020 .
8. Huang Z, Mancini JA . Phosphodiesterase 4 inhibitors for the treatment of asthma and COPD . Current Medicinal Chemistry . 13 . 27 . 3253–3262 . 2006 . 17168849 . 10.2174/092986706778773040 .