Neuroinflammation in Ischemic Stroke: Inhibition of cAMP-Specific Phosphodiesterases (PDEs) to the Rescue

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.

Focus on the role of mitochondria in NLRP3 inflammasome activation: A prospective target for the treatment of ischemic stroke (Review)

“…Additionally, astrocytes that are activated by ischemia mediate inflammatory response to aggravate ischemic injury. However, they also limit the spread of inflammation by inhibiting excitotoxicity and secreting neurotrophic factors ( 65 , 66 ). Interestingly, NLRP3 inflammasome was found to play a key role in driving neuroinflammation in these cells during acute ischemic stroke, and early blockade of NLRP3 protects neurons from ischemia-reperfusion injury by mitigating inflammation ( 67 ).…”

The Role of PDE11A4 in Social Isolation-Induced Changes in Intracellular Signaling and Neuroinflammation

“…Various phosphodiesterase (PDE) families are known to influence social behaviors ( Sano et al, 2008 ; Grauer et al, 2009a ; Alexander et al, 2016 ; Gurney et al, 2017 ; Maurin et al, 2018 ; Enomoto et al, 2019 ) or neuroinflammation ( Sebastiani et al, 2006 ; Peixoto et al, 2015 ; Schwenkgrub et al, 2017 ; Tibbo and Baillie, 2020 ; Ponsaerts et al, 2021 ); but evidence suggests the PDE11A family may be a key regulator of both. Although there are four isoforms of PDE11A, PDE11A4 is the longest and only isoform found in the brain ( Yuasa et al, 2001a ; Yuasa et al, 2001b ).…”

Cdk5 mediates rotational force-induced brain injury

“…Interestingly, rTBI induced upregulation of known cell death dependent pathways linked to brain injury such as ferroptosis and phagosome formation 43 , 44 . We observed bidirectional alterations in homeostatic signaling pathways such as Protein Kinase A (PKA) and oxytocin signaling pathways, both of which have been observed to mediate injury in stroke and TBI 45 , 46 .…”