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Review
. 2024 May;479(5):1267-1278.
doi: 10.1007/s11010-023-04793-1. Epub 2023 Jul 3.

The potential therapeutic effect of phosphodiesterase 5 inhibitors in the acute ischemic stroke (AIS)

Raed AlRuwaili #  1 , Hayder M Al-Kuraishy  2 , Mubarak Alruwaili  1 , Amira Karam Khalifa  3   4 , Athanasios Alexiou  5   6 , Marios Papadakis  7 , Hebatallah M Saad  8 , Gaber El-Saber Batiha  9
Affiliations
Review

The potential therapeutic effect of phosphodiesterase 5 inhibitors in the acute ischemic stroke (AIS)

Raed AlRuwaili et al. Mol Cell Biochem. 2024 May.

Abstract

Acute ischemic stroke (AIS) is a focal neurological disorder that accounts for 85% of all stroke types, due to occlusion of cerebral arteries by thrombosis and emboli. AIS is also developed due to cerebral hemodynamic abnormality. AIS is associated with the development of neuroinflammation which increases the severity of AIS. Phosphodiesterase enzyme (PDEs) inhibitors have neuro-restorative and neuroprotective effects against the development of AIS through modulation of the cerebral cyclic adenosine monophosphate (cAMP)/cyclic guanosine monophosphate (cGMP)/nitric oxide (NO) pathway. PDE5 inhibitors through mitigation of neuroinflammation may decrease the risk of long-term AIS-induced complications. PDE5 inhibitors may affect the hemodynamic properties and coagulation pathway which are associated with thrombotic complications in AIS. PDE5 inhibitors reduce activation of the pro-coagulant pathway and improve the microcirculatory level in patients with hemodynamic disturbances in AIS. PDE5 inhibitors mainly tadalafil and sildenafil improve clinical outcomes in AIS patients through the regulation of cerebral perfusion and cerebral blood flow (CBF). PDE5 inhibitors reduced thrombomodulin, P-selectin, and tissue plasminogen activator. Herein, PDE5 inhibitors may reduce activation of the pro-coagulant pathway and improve the microcirculatory level in patients with hemodynamic disturbances in AIS. In conclusion, PDE5 inhibitors may have potential roles in the management of AIS through modulation of CBF, cAMP/cGMP/NO pathway, neuroinflammation, and inflammatory signaling pathways. Preclinical and clinical studies are recommended in this regard.

Keywords: Acute ischemic stroke; Inflammatory signaling pathways; Neuroinflammation; PDE5 inhibitors.

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Conflict of interest statement

The authors declare no competing interests. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Fig. 1
Fig. 1
Role of phosphodiesterase enzymes (PDEs) in the metabolism of cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP). cGMP is synthesized from guanosine triphosphate (GTP) by the action of guanylate cyclases (GC) and then hydrolyzed by the PDE 5, 6 and 9 to GMP. cAMP is synthesized from adenosine triphosphate (ATP) by the action of Adenylate Cyclases (AC) and then hydrolyzed by the PDE 4, 7 and 8 to adenosine monophosphate (AMP). Additionally, PDE 1, 2, 3, 10 and 11 hydrolyze both cAMP and cGMP
Fig. 2
Fig. 2
Phosphodiesterase enzymes (PDEs) and nitric oxide (NO). NO penetrates smooth muscle cells and binds to guanylate cyclases (GC) resulting in the formation of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP). cGMP activates cGMP-dependent protein kinase leading to a decrease in intracellular calcium and relaxation of arterial smooth muscle subsequently
Fig. 3
Fig. 3
Mechanism of neural death following reduction of cerebral blood flow in ischemic stroke. During ischemic stroke, damage-associated molecular pattern (DAMP) is released from injured neurons which activates microglia to release various pro-inflammatory cytokines like interleukin (IL)-1β and tumor necrosis factor-alpha (TNF-α) in addition to reactive oxygen species (ROS) leading to weakness of blood–brain barrier with the subsequent lifting of astrocytic end feet from the basement membrane, cerebral edema and leukocytic infiltration to cerebral parenchyma, where they release proinflammatory mediators as IL-1 and monocyte chemotactic protein 1 (MCP-1) that exacerbate neuroinflammation
See this image and copyright information in PMC

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