Abstract
Ischemic stroke is caused by a thromboembolic occlusion of a major cerebral artery, with the impaired blood flow triggering neuroinflammation and subsequent neuronal damage. Both the innate immune system (e.g., neutrophils, monocytes/macrophages) in the acute ischemic stroke phase and the adaptive immune system (e.g., T cells, B cells) in the chronic phase contribute to this neuroinflammatory process. Considering that the available therapeutic strategies are insufficiently successful, there is an urgent need for novel treatment options. It has been shown that increasing cAMP levels lowers neuroinflammation. By inhibiting cAMP-specific phosphodiesterases (PDEs), i.e., PDE4, 7, and 8, neuroinflammation can be tempered through elevating cAMP levels and, thereby, this can induce an improved functional recovery. This review discusses recent preclinical findings, clinical implications, and future perspectives of cAMP-specific PDE inhibition as a novel research interest for the treatment of ischemic stroke. In particular, PDE4 inhibition has been extensively studied, and is promising for the treatment of acute neuroinflammation following a stroke, whereas PDE7 and 8 inhibition more target the T cell component. In addition, more targeted PDE4 gene inhibition, or combined PDE4 and PDE7 or 8 inhibition, requires more extensive research.
Highlights
According to the World Stroke Organization, around 13.7 million individuals suffer a stroke each year [1]
Multiple effector proteins mediate these cyclic adenosine monophosphate (cAMP)-controlled biological functions including hyperpolarization-activated cyclic nucleotide regulated channels (HCN), cyclic nucleotide-gated channels (CNGC), exchange factor directly activated by cAMP (Epac), and protein kinase A (PKA)
A (PKA), hyperpolarization-activated cyclic nucleotide regulated channel (HCN), cyclic (HCN), cyclic nucleotide-gated channel (CNGC), and exchange factor directly activated by cAMP (Epac)
Summary
According to the World Stroke Organization, around 13.7 million individuals suffer a stroke each year [1]. Stroke can be described as neurological deficits that arise after the rapid onset of a focal lesion in the central nervous system (CNS) with vascular origin [7,8] This disorder can be classified into two types: hemorrhagic and ischemic stroke, with the latter. The elevated intracellular calcium levels trigger the production of free radicals by neuronal nitric oxide synthase, culminating in oxidative stress and mitochondrial dysfunction (Figure 1) This induces apoptotic and necrotic cell death, resulting in massive neuronal cell death, leading to severe neurological damage [9,15]. Endovascular therapy with a stent retriever (mechanical thrombectomy) have been approved as treatments of acute ischemic stroke [18,19] These therapies cause recanalization to salvage penumbral tissue [13,20]. Many stroke patients, even when treated successfully, suffer from residual neurological impairments [2,3,25]
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