Effect of Diazepam on Severity of Acute Pancreatitis: Possible Involvement of Peripheral Benzodiazepine Receptors

Abstract

Acute pancreatitis is a lethal inflammatory condition of pancreas with high mortality rate. There is a pressing need for research to explore active agents and novel mechanisms involving in the treatment of pancreatitis. Clinical studies have shown after the initial acinar cell injury plasma levels of pro-inflammatory cytokines are elevated in patients with acute pancreatitis and the degree of cytokine elevation correlates with disease severity. Diazepam may decrease interleukin release from macrophages, suppress neutrophil activities, and exhibit anti-inflammatory effects. So it is expected that in vivo pretreatment of acute pancreatitis with different doses of diazepam can attenuate its severity. Thus, we evaluated the effects of diazepam, intraperitoneally (5, 10, and 20 mg/kg i.p.), intracerebroventricularly (ICV 10 μg), and concurrently with flumazenil (1 mg/kg) on cerulein-induced acute pancreatitis in mice. Interestingly, the pretreatment with diazepam (5 mg/kg i.p.) reduced significantly the inflammatory response of acute pancreatitis by ameliorating pancreatic edema, amylase and lipase serum levels, myeloperoxidase activity, pancreatic TNF-alpha, and pathological alteration compared to control group. Diazepam i.c.v. was ineffective, suggesting that central benzodiazepine receptors have no significant role in this property. These results demonstrate that pretreatment with diazepam exhibits anti-inflammatory property in cerulein-induced acute pancreatitis possibly through peripheral benzodiazepine receptors.

Effects of Diazepam on Hematological and Histological Parameters in Rats / in Vivo and Unbiased Stereological Investigation

“…A signifi cant reduction in pancreatic lipase concentration in our study in diazepame-treated rats is in accordance with the literature. Decreased pancreatic lipase concentration has been described as a consequence of decreased physical activity in rats due to the sedative effect of diazepam [34,35]. Concentration of potassium ions was (p = 0.077) increased, while concentrations of sodium and calcium ions decreased insignifi cantly in our study after treating rats with diazepam.…”

Benzodiazepines and Z-Drugs: An Updated Review of Major Adverse Outcomes Reported on in Epidemiologic Research

“…A precise mechanism behind benzodiazepine- or Z-drug-induced pancreatitis remains elusive, though the authors of the previous studies have proposed direct noxious effects on pancreatic tissue from these drugs [ 101 – 103 ]. However, a pharmacological mouse-model study of cerulein-induced pancreatitis yielded anti-thetical results wherein pre-treatment diazepam 5 mg/kg (intra-peritoneal) was observed to produce anti-inflammatory effects; reducing pancreatic edema along with lipase and amylase serum levels compared with a negative control [ 104 ]. Recent review articles also make no mention of either benzodiazepines or Z-drugs as agents being associated with drug-induced pancreatitis [ 105 , 106 ].…”

Protective effects of tropisetron on cerulein-induced acute pancreatitis in mice

“…The serum amylase, lipase, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were determined using the commercially available kits (Pars-Azmun Co. Tehran, Iran) [22].…”