A novel phosphodiesterase 5 inhibitor, RF26, improves memory impairment and ameliorates tau aggregation and neuroinflammation in the P301S tauopathy mouse model of Alzheimer's disease

Sara El-Desouky; Mohammad Abdel-Halim; Reem K Fathalla; Ashraf H Abadi; Gary A Piazza; Mohamed Salama; Sabry Ahmed El-Khodery; Mohamed A Youssef; Sara Elfarrash

doi:10.1016/j.expneurol.2024.115058

A novel phosphodiesterase 5 inhibitor, RF26, improves memory impairment and ameliorates tau aggregation and neuroinflammation in the P301S tauopathy mouse model of Alzheimer's disease

Exp Neurol. 2025 Feb:384:115058. doi: 10.1016/j.expneurol.2024.115058. Epub 2024 Nov 14.

Authors

Sara El-Desouky¹, Mohammad Abdel-Halim², Reem K Fathalla², Ashraf H Abadi², Gary A Piazza³, Mohamed Salama⁴, Sabry Ahmed El-Khodery⁵, Mohamed A Youssef⁵, Sara Elfarrash⁶

Affiliations

¹ Medical experimental research center (MERC), Faculty of Medicine, Mansoura University, 35116 Mansoura, Egypt.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo 11835, Egypt.
³ Department of Drug discovery and development, Harrison Collage of Pharmacy, Auburn University, Auburn, AL 36832, USA.
⁴ Institute of Global health and Human ecology, American University in Cairo, Egypt; Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Mansoura University, 35116 Mansoura, Egypt.
⁵ Department of internal medicine, Faculty of Veterinary Medicine, Mansoura University, 35116 Mansoura, Egypt.
⁶ Medical experimental research center (MERC), Faculty of Medicine, Mansoura University, 35116 Mansoura, Egypt; Department of Medical Physiology, Faculty of Medicine, Mansoura University, 35116 Mansoura, Egypt. Electronic address: [email protected].

PMID: 39549949
DOI: 10.1016/j.expneurol.2024.115058

Abstract

Phosphodiesterase-5 (PDE5) inhibitors are primarily used in the treatment of erectile dysfunction and pulmonary hypertension, but have also been reported to have a potential therapeutic effect for the treatment of Alzheimer's disease (AD). This is likely to be through stimulation of nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signaling by elevating cGMP, a secondary messenger involved in processes of neuroplasticity. In the present study, we evaluated the efficacy of a novel PDE5 inhibitor, RF26, using P301S tauopathy mice model. A body of experimental evidence suggests that the development of tau inclusions leads to the neurodegeneration observed in tauopathies, including AD, Frontotemporal dementia (FTD), Supranuclear palsy and others. RF26 successfully targeted NO/cGMP signaling pathway and showed a significant improvement of spatial memory task performance of P301S mice using Morris Water Maze and T-maze. Furthermore, RF26 -treated mice showed a significant reduction of phosphorylated tau load, gliosis and downregulated pro-inflammatory cytokines. The presented data support the efficacy of RF26 as a potent PDE5 inhibitor and calls for further investigation as a potential therapeutic drug for Alzheimer's and other tauopathy related neurological disorders.

Keywords: Alzheimer's disease; Memory impairment; Neuroinflammation; P301S; PDE5 inhibitors; Pyrazolines; Tau.

MeSH terms

Alzheimer Disease* / drug therapy
Alzheimer Disease* / metabolism
Alzheimer Disease* / pathology
Animals
Disease Models, Animal*
Male
Maze Learning / drug effects
Memory Disorders* / drug therapy
Memory Disorders* / etiology
Mice
Mice, Transgenic
Neuroinflammatory Diseases* / drug therapy
Phosphodiesterase 5 Inhibitors* / pharmacology
Tauopathies* / drug therapy
tau Proteins* / metabolism

Substances

tau Proteins
Phosphodiesterase 5 Inhibitors