PDE4A and major depressive disorder: Rolipram was also the first blood-brain-barrier (BBB) permeable PDE4 inhibitor, developed for ameliorating neuroinflammation which showed potent effectiveness in various animal models, including depression, neuropathic pain, Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis (Rose et al., 2005; Garcia-Osta et al., 2012; Pearse and Hughes, 2016).