Inhibition of phosphodiesterase 7A ameliorates Concanavalin A-induced hepatitis in mice

Goto, Megumi; Tanaka, Yoshitaka; Murakawa, Masao; Kadoshima-Yamaoka, Kumiko; Inoue, Hidekazu; Murafuji, Hidenobu; Nagahira, Asako; Kanki, Satomi; Hayashi, Yasuhiko; Nagahira, Kazuhiro; Ogata, Atsuto; Miura, Kazuhiro; Nakatsuka, Takashi; Chamoto, Kenji; Fukuda, Yoshiaki; Nishimura, Takashi

doi:10.1016/j.intimp.2009.08.002

Cited by 11 publications

(9 citation statements)

References 25 publications

(41 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the present study, similar observations were made as rolipram reduced levels of TNF-α and decreased AST and ALT activities in serum of mice. In another study, a PDE inhibitor with a strong activity against PDE7A (IC 50 = 9 nM) has been investigated in the ConA-induced hepatitis model and it decreased ALT activity and TNF-α levels (34). Thus, it can be concluded that the observed effects of PDE inhibitors in ConA-induced hepatitis arise both from the inhibition of PDE4B and PDE7A.…”

Section: Discussionmentioning

confidence: 98%

Comparative Assessment of the New PDE7 Inhibitor – GRMS-55 and Lisofylline in Animal Models of Immune-Related Disorders: A PK/PD Modeling Approach

et al. 2020

View full text Add to dashboard Cite

Purpose This study aimed to assess the activity of two phosphodiesterase (PDE) inhibitors, namely GRMS-55 and racemic lisofylline ((±)-LSF)) in vitro and in animal models of immune-mediated disorders. Methods Inhibition of human recombinant (hr)PDEs and TNF-alpha release from LPS-stimulated whole rat blood by the studied compounds were assessed in vitro. LPS-induced endotoxemia, concanavalin A (ConA)-induced hepatitis, and collagen-induced arthritis (CIA) animal models were used for in vivo evaluation. The potency of the investigated compounds was evaluated using PK/PD and PK/PD/disease progression modeling. Results GRMS-55 is a potent hrPDE7A and hrPDE1B inhibitor, while (±)-LSF most strongly inhibits hrPDE3A and hrPDE4B. GRMS-55 decreased TNF-alpha levels in vivo and CIA progression with IC 50 of 1.06 and 0.26 mg/L, while (±)-LSF with IC 50 of 5.80 and 1.06 mg/L, respectively. Moreover, GRMS-55 significantly ameliorated symptoms of ConA-induced hepatitis. Conclusions PDE4B but not PDE4D inhibition appears to be mainly engaged in anti-inflammatory activity of the studied compounds. GRMS-55 and (±)-LSF seem to be promising candidates for future studies on the treatment of immunerelated diseases. The developed PK/PD models may be used to assess the anti-inflammatory and anti-arthritic potency of new compounds for the treatment of rheumatoid arthritis and other inflammatory disorders.

show abstract

Section: Discussionmentioning

confidence: 98%

Comparative Assessment of the New PDE7 Inhibitor – GRMS-55 and Lisofylline in Animal Models of Immune-Related Disorders: A PK/PD Modeling Approach

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Inhibition of PDE7A ameliorated degenerative changes in the mouse liver through suppression of natural killer T-cell (NKT) activation, and inhibition of PDE7A in these cells reduced FasL expression as well as reducing tumor necrosis factor alpha (TNFa) and IL4 production. IL4 production in NKT cells is thought to be the key mediator of ConA-induced liver injury in this model of viral and autoimmune hepatitis, and therefore PDE7A could be the key target for prevention of liver degeneration arising from such diseases [139]. Finally, another possible function for PDE7A in keratinocytes has been elucidated [140].…”

Section: Pde7mentioning

confidence: 89%

cAMP‐Specific Phosphodiesterases: Modulation, Inhibition, and Activation

Cameron

Baillie

2012

Therapeutic Targets

View full text Add to dashboard Cite

“…To our knowledge, this study showed for the first time that a selective PDE7 inhibitor effectively ameliorated liver damage in ConA-induced hepatitis. Other PDE7 inhibitors, which were investigated previously in this animal model of AIH, were not selective, but exhibited a significant PDE4-inhibitory activity [ 10 , 31 ]. Due to the relatively high PDE4-suppressing activity of the studied inhibitors, it was not clear if the observed pharmacological effect resulted from PDE7, PDE4, or dual PDE4/7 inhibition.…”

Section: Discussionmentioning

confidence: 99%

PK/PD Modeling of the PDE7 Inhibitor—GRMS-55 in a Mouse Model of Autoimmune Hepatitis

et al. 2021

View full text Add to dashboard Cite

This study aimed to assess the efficacy and explore the mechanisms of action of a potent phosphodiesterase (PDE)7A and a moderate PDE4B inhibitor GRMS-55 in a mouse model of autoimmune hepatitis (AIH). The concentrations of GRMS-55 and relevant biomarkers were measured in the serum of BALB/c mice with concanavalin A (ConA)-induced hepatitis administered with GRMS-55 at two dose levels. A semi-mechanistic PK/PD/disease progression model describing the time courses of measured biomarkers was developed. The emetogenicity as a potential side effect of the studied compound was evaluated in the α2-adrenoceptor agonist-induced anesthesia model. The results indicate that liver damage observed in mice challenged with ConA was mainly mediated by TNF-α and IFN-γ. GRMS-55 decreased the levels of pro-inflammatory mediators and the transaminase activities in the serum of mice with AIH. The anti-inflammatory properties of GRMS-55, resulting mainly from PDE7A inhibition, led to a high hepatoprotective activity in mice with AIH, which was mediated by an inhibition of pro-inflammatory signaling. GRMS-55 did not induce the emetic-like behavior. The developed PK/PD/disease progression model may be used in future studies to assess the potency and explore the mechanisms of action of new investigational compounds for the treatment of AIH.

show abstract

Inhibition of phosphodiesterase 7A ameliorates Concanavalin A-induced hepatitis in mice

Cited by 11 publications

References 25 publications

Comparative Assessment of the New PDE7 Inhibitor – GRMS-55 and Lisofylline in Animal Models of Immune-Related Disorders: A PK/PD Modeling Approach

Comparative Assessment of the New PDE7 Inhibitor – GRMS-55 and Lisofylline in Animal Models of Immune-Related Disorders: A PK/PD Modeling Approach

cAMP‐Specific Phosphodiesterases: Modulation, Inhibition, and Activation

PK/PD Modeling of the PDE7 Inhibitor—GRMS-55 in a Mouse Model of Autoimmune Hepatitis

Contact Info

Product

Resources

About