This study investigated the effects of pharmacological inhibition of phosphatidylinositol 3-kinase (PI3K)γ in the pruriceptive, inflammatory, and nociceptive responses induced by trypsin in mice. The animals were orally treated with the selective PI3Kγ inhibitor AS605240 (0.3-30 mg/kg) 30 minutes beforehand. In separate groups, AS605240 was given by intrathecal (i.t.) or intracerebroventricular (i.c.v.) routes. The control groups received saline at the same schedules. The effects of PI3K blocking were assessed in different experimental assays. The oral treatment with AS605240 produced a marked reduction of scratching behavior elicited by trypsin. Moreover, AS605240 (1mg/kg) was able to produce a partial but significant inhibition of the scratching bouts elicited by CP 48/80. Interestingly, the i.c.v. and i.t. injection of AS605240 also reduced trypsin-induced itching. The oral administration of AS605240 was found effective in producing a significant and dose-dependent reduction of trypsin-induced paw edema and tumor necrosis factor α production, as well as the neutrophil recruitment, according to myeloperoxidase activity assessment. Likewise, oral AS605240 (1mg/kg) promoted a significant reduction of spontaneous nociception induced by trypsin in the mouse paw. In contrast, the oral administration of AS605240 did not significantly modify capsaicin-evoked nociception, although this inhibitor was effective when dosed by i.c.v. route. Noteworthy, AS605240 (1mg/kg) was able to prevent c-Fos and phospho-Akt immunopositivity at the spinal cord of trypsin-injected mice, either into the back of the neck or the paws. To conclude, PI3Kγ inhibition might well represent a valuable alternative for treating inflammatory and painful conditions, as well as pruritus.

There is a current need for new therapeutic options for acetaminophen (APAP)-induced hepatotoxicity. Herein, we assessed the effects of prophylactic and therapeutic treatment with the angiotensin-converting enzyme (ACE) inhibitor, enalapril, on APAP-caused hepatotoxicity. Male and female C57BL/6 J mice were used, and hepatotoxicity was induced by a single application of APAP (400 mg/kg, i.p.). Macroscopic and histological liver alterations, serum alanine transaminase (ALT) and aspartate transaminase (AST) activity, liver catalase activity (CAT), reduced glutathione concentrations (GSH), hepatic measurement of neutrophil migration (myeloperoxidase, MPO activity), and caspase-3 liver expression were evaluated. The prophylactic and the therapeutic treatments with enalapril were able to markedly reduce the macroscopic and histological liver alterations as well as the caspase-3 immunopositivity. Both schedules of treatment were also effective in reducing GSH concentrations as well as neutrophil migration. Conversely, only the pre-treatment (but not the post-administration) with enalapril significantly reversed APAP-induced CAT decrease. Furthermore, the pre- or the post-treatment with enalapril largely reduced ALT and AST serum activity in APAP-intoxicated mice. The hepatoprotective effects of enalapril were comparable to those obtained with the clinically used compound N-acetylcysteine (NAC) when given in a therapeutic regimen. Data obtained with the prophylactic protocol of treatment might indicate that individuals under treatment with ACE inhibitors are less susceptible to the toxic effects of APAP. Additionally, the therapeutic approach allows us to suggest that enalapril might represent an innovative tool for treating APAP intoxication.