Ulcerative colitis (UC) is a form of
inflammatory bowel disease, which manifests as irritation or swelling and sores in the large intestine in a relapsing and remitting manner. In a
dextran sulfate sodium sulfate (DSS)-induced UC model in female mice, we found that the levels of cyclic
guanosine monophosphate (cGMP) are reduced, while the expression of
phosphodiesterase 9A (PDE9A) is highest among all
phosphodiesterase (
PDEs). Since PDE9 has the highest affinity toward cGMP, we evaluated the selective PDE9 inhibitor
PF-04447943 (PF) as a potential candidate for UC treatment. PF has been extensively studies in cognitive function and in
sickle cell disease, but not in models for
inflammatory bowel disease (IBD). Therefore, we used female C57BL/6 mice treated with 3% DSS alone or co-treated with PF or
sulfasalazine (SASP) to study the
body weight, colon length, histopathology, and measure
superoxide dismutase (SOD),
malondialdehyde (MDA), and cGMP level, as well as
cytokines such as
tumor necrosis factor-alpha (TNF-α),
interleukin-6 (IL-6),
interleukin-17 (IL-17),
interleukin-12/23 (
IL-12/23),
interleukin-10 (IL-10), and pathways including
nuclear factor kappa B (NF-κB),
signal transducer and activator of transcription 3 (STAT3), and
inflammasome activation. In addition, the number of dendritic cells (DC) and regulatory T cells (Treg cell) was assessed in the spleen, lymph node, and colon using flow cytometry. DSS reduced the number of goblet cells, decreased colon lengths and
body weights, all of them were attenuated by PF treatment. It also suppressed the elevated level of inflammatory
cytokines and increased level the anti-inflammatory
cytokine,
IL-10. PF treatment also reduced the DSS-induced
inflammation by suppressing oxidative stress, NF-κB, STAT3, and
inflammasome activation, by upregulating nuclear factor erythroid 2-related factor 2 (Nrf-2) and its downstream
proteins via
extracellular signal-regulated kinase (ERK) phosphorylation. Importantly, PF reversed imbalance in Treg/T helper 17 cells (Th17) cells ratio, possibly by regulating dendritic cells and Treg developmental process. In summary, this study shows the protective effect of a PDE9A inhibitor in
ulcerative colitis by suppressing oxidative stress and
inflammation as well as reversing the Treg/Th17 cells imbalance.