Objective: In the current study, we evaluated a newly developed compound with a 1,3,5-trisubstituted pyrazoline scaffold with an improved PDE5 inhibitory potency as a potential therapeutic agent using the P301S mice model. This included assessment of disease phenotype, biochemical and histopathological improvement following the treatment.

Background: Tauopathy is used to refer to the group of neurodegenerative diseases characterized by tau deposits in neurons or glia cells. Clinical symptoms of tauopathy disorders range from cognitive impairments like dementia up to the motor disorders. Many clinically diagnosed diseases are listed as tauopathies like, Picks disease, PSP and CBD, the list also include a more commonly studied Alzheimer’s disease. This had put tau pathology as a potential therapeutic target aiming for hindering of disease progression.

Method: A total of 28 mice were allocated into four groups as follows. 1) P301S receiving vehicle. 2) P301S receiving the novel PDE5i 15mg/kg. 3) B6 receiving vehicle and 4) B6 receiving the novel drug. Following the treatment of 35 days, all mice underwent 1)Morris water Maze 2) T-maze 3)Open field test. By the end of the behavioral tests, mice were sacrificed and brains were collected for biochemical and IHC. For biochemical analysis, ELISA, Western blotting, and qPCR were carried out as described earlier. For immunopathology assessment, antibodies against phosphorylated tau (AT8 and AT100), GFAP, and NeuN were evaluated.

Results: The preliminary data suggest that the drug had managed to hinder the phenotype of disease progression in P301S mice as seen in T maze and MWM. Open field showed that the drug-induced sedation is observed and reduced the locomotor activity of treated mice. Histopathological analysis, showed reduction of phosphorylated tau at the hippocampus and brain stem. Western blotting for CREB, VASP, Pvasp, and synaptophysin, in addition to ELISA level of cGMP is currently ongoing to evaluate the molecular mechanism of the behavioral and histopathological improvement.

Conclusion: The preliminary data suggest that our novel PDE5 inhibitor drug can be a promising therapeutic agent for hindering the progression of the tauopathy associated phenotype using P301S mice including the improvement of cognitive function and reduction of phosphorylated tau.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/evaluation-of-a-novel-phosphodiesterase-5-inhibitor-as-a-potential-therapeutic-agent-in-p301s-transgenic-mouse-model-of-tauopathy/