Iyad Khamaysi, MD, Dalit Ben Hemo, PhD, Salim Haddad, PhD, Ahmad Fokra, PhD, Aviva Kabala, PhD, Israel Vlodavsky, PhD, Zaid Abassi, PhD Technion-Israel Institute of Technology, Haifa, Hefa, Israel
Introduction: The pathophysiology of acute pancreatitis (AP) is not well characterized. Previously, we have demonstrated that heparanase (Hpa) plays an important role in the pathogenesis of AP and that Hpa inhibitors mitigate AP in an animal model. Aspirin has been shown to inhibit Hpa activity in vivo and in vitro. Moreover, trehalose was shown to alleviate experimental AP via unknown mechanism. We hypothesize that a combination of Hpa inhibitors and aspirin or Trehalose can ameliorate AP more than each drug alone.
The current study examines whether combination of Pixatimod (PG545) or Roneparstat (SST0001), two inhibitors of Hpa with Aspirin or Trehalose, exerts additive or synergistic protective effect in cerulein-induced AP in mice.
Methods: Heparanase-overexpressing transgenic mice (Hpa-TG) and wild-type (WT) BALB/c mice (n= 6-20) were IP injected with either cerulein (50 mg/kg, 5 times, at 1 hour apart) or vehicle, with or without either PG545 (0.4 mg/mouse), Roneparstat (2 mg/mouse, Aspirin (250 mg/kg, sc), Trehalsoe (2.5 g/kg, ip) or combination of these drugs. The animals were sacrificed 24h following the induction of pancreatitis. The severity of AP was evaluated by amylase and lipase levels, inflammatory cytokines, pancreatic edema index, tissue inflammatory and autophagy response.
Results: Cerulein-induced AP in WT mice was associated with significant rises in the serum levels of amylase (X3) and lipase (X3.5), enhancement of pancreatic edema index, tissue inflammation, and autophagy response. All types of responses were more profound in Hpa-TG mice, as was evident by 4 and 7.5 fold increases in amylase and lipase levels, respectively. Importantly, pretreatment with PG545, Roneparstat, Aspirin or Trehalose reduced pancreatic inflammatory response, autophagy, along remarkable reduction in amylase and lipase serum levels in both WT and Hpa-Tg mice. Noteworthy, combination of Aspirin or Trehalose with either PG545 or Roneparstat completely abolished AP, as was evident by reversing the biochemical, inflammatory and histological perturbations in both subgroups of animals (figure).
Discussion: These findings suggest a fundamental role of Hpa in the pathogenesis of AP. Aspirin, Trehalose or Hpa inhibitor exerts protective effect against Cerulein-induced AP. Interestingly, combination of Aspirin or Trehalose and Hpa inhibitors dramatically ameliorate AP, providing a rational for their potential clinical use for prevention and treatment.
Figure: Effect of Trehalose given as monotherapy or in combination with Aspirin, PG545 or SST0001 and on cerulein -induced AP as evident by serum levels of amylase (A) lipase (B) and pancreatic index (Pancreas /Body weight ratio) (C) in WT mice and Hpa-Tg animals. *, p<0.05 compared to saline group; #, p<0.05 compared to cerulein group; $, p<0.05 compared to Combination group.
Iyad Khamaysi indicated no relevant financial relationships.
Dalit Ben Hemo indicated no relevant financial relationships.
Salim Haddad indicated no relevant financial relationships.
Ahmad Fokra indicated no relevant financial relationships.
Aviva Kabala indicated no relevant financial relationships.
Israel Vlodavsky indicated no relevant financial relationships.
Zaid Abassi indicated no relevant financial relationships.
Iyad Khamaysi, MD, Dalit Ben Hemo, PhD, Salim Haddad, PhD, Ahmad Fokra, PhD, Aviva Kabala, PhD, Israel Vlodavsky, PhD, Zaid Abassi, PhD. P1074 - Combination of Trehalose and Heparanase Inhibitors Treatment Ameliorates Cerulein-Induced Acute Pancreatitis in a Murine Model, ACG 2021 Annual Scientific Meeting Abstracts. Las Vegas, Nevada: American College of Gastroenterology.