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Patients with acquired brain injury (ABI) suffer from cognitive deficits that interfere significantly with their daily lives. These deficits are long-lasting and no treatment options are available. A better understanding of the mechanistic basis for these cognitive deficits is needed to develop novel treatments. Intracellular cyclic adenosine monophosphate (cAMP) levels are decreased in ABI. Herein, we focus on augmentation of cAMP by PDE4 inhibitors and the potentially synergistic mechanisms in traumatic brain injury. A major acute pathophysiological event in ABI is the breakdown of the blood-brain-barrier (BBB). Intracellular cAMP pathways are involved in the subsequent emergence of edema, inflammation and hyperexcitability. We propose that PDE4 inhibitors such as roflumilast can improve cognition by modulation of the activity in the cAMPPhosphokinase A-Ras-related C3 botulinum toxin substrate (RAC1) inflammation pathway. In addition, PDE4 inhibitors can also directly enhance network plasticity and attenuate degenerative processes and cognitive dysfunction by increasing activity of the canonical cAMP/phosphokinase- A/cAMP Responsive Element Binding protein (cAMP/PKA/CREB) plasticity pathway. Doublecourtin and microtubule-associated protein 2 are generated following activation of the cAMP/PKA/CREB pathway and are decreased or even absent after injury. Both proteins are involved in neuronal plasticity and may consist of viable markers to track these processes. It is concluded that PDE4 inhibitors may consist of a novel class of drugs for the treatment of residual symptoms in ABI attenuating the pathophysiological consequences of a BBB breakdown by their anti-inflammatory actions via the cAMP/PKA/RAC1 pathway and by increasing synaptic plasticity via the cAMP/PKA/CREB pathway. Roflumilast improves cognition in young and elderly humans and would be an excellent candidate for a proof of concept study in ABI patients.