Dihydrodiosgenin protects against experimental acute pancreatitis and associated lung injury through mitochondrial protection and PI3Kγ/Akt inhibition.

Abstract

Acute pancreatitis (AP) is a painful and distressing disorder of the exocrine pancreas with no specific treatment. Diosgenyl saponins extracted from from Dioscorea zingiberensis C. H. Wright have been reported to protect against experimental models of AP. Diosgenin, or its derivatives are anti-inflammatory in various conditions. However, the effects of diosgenin and its spiroacetal ring opened analogue, dihydrodiosgenin (Dydio), on AP have not been determined. Effects of diosgenin and Dydio on sodium taurocholate hydrate (Tauro)-induced necrosis were tested, using freshly isolated murine pancreatic acinar cells. Effects of Dydio on mitochondrial dysfunction in response to Tauro, cholecystokinin-8 and palmitoleic acid ethyl ester were also assessed. Dydio (5 or 10mg·kg-1 ) was administered after the induction in vivo of Tauro-induced AP (Wistar rats), caerulein-induced AP and palmitoleic acid plus ethanol-induced AP (Balb/c mice). Pancreatitis was assessed biochemically and histologically. Activation of pancreatic PI3Kγ/Akt was measured by immunoblotting. Dydio inhibited Tauro-induced activation of the necrotic cell death pathway and prevented pancreatitis stimuli-induced mitochondrial dysfunction. Therapeutic administration of Dydio ameliorated biochemical and histopathological responses in all three models of AP through pancreatic mitochondrial protection and PI3Kγ/Akt inactivation. Moreover, Dydio improved pancreatitis-associated acute lung injury through preventing excessive inflammatory responses. These data provide in vitro and in vivo mechanistic evidence that the diosgenin analogue, Dydio could be potential treatment for AP. Further medicinal optimization of diosgenin and its analogue might be a useful strategy for identifying lead candidates for inflammatory diseases.