Upregulation of Uric Acid Production and Caspase 3 Signalling Mediates Rohypnol-Induced Cardiorenal Damage

Cardiovasc Toxicol. 2022 May;22(5):419-435. doi: 10.1007/s12012-022-09723-z. Epub 2022 Feb 1.

Abstract

The global prevalence of illicit drug use is on the increase with attendant complications like cardiorenal collapse. One such substance of abuse is rohypnol. Despite its ban in most countries, it remains a popular substance of abuse. Whether or not rohypnol induces cardiorenal injury and the associated mechanism is yet to be elucidated. Therefore, the present study investigated the effect of rohypnol on cardiorenal integrity and functions, and glucolipid metabolism. Forty-eight male Wistar rats randomized into six groups (n = 8/group) received (per os) vehicle, low-dose (2 mg/kg) and high-dose (4 mg/kg) rohypnol once daily for twenty eight days, with or without a cessation period. Data revealed that rohypnol exposure irreversibly caused insulin resistance, hyperglycaemia, and dyslipidaemia. This was accompanied by reduced cardiorenal mass and impaired cardiorenal cytoarchitecture and function. Furthermore, rohypnol treatment promoted oxidative stress, inflammation, genotoxicity, and decreased cardiorenal activities of Na+-K+-ATPase, Ca2+-ATPase, and Mg2+-ATPase. These alterations were associated with enhanced uric acid generation and caspase 3 activity in the cardiorenal complex. Thus, this study reveals that rohypnol exposure triggers cardiorenal toxicity with incident insulin resistance, glucolipid and cardiorenal proton pump dysregulation, altered redox state, and inflammation via enhancement of uric acid generation and caspase 3-dependent mechanism.

Keywords: Apoptosis; Benzodiazepines; Cardiometabolic disorder; Dyslipidaemia; Genotoxicity; Oxidative stress.

MeSH terms

  • Adenosine Triphosphatases / metabolism
  • Adenosine Triphosphatases / pharmacology
  • Animals
  • Caspase 3 / metabolism
  • Flunitrazepam / pharmacology
  • Inflammation
  • Insulin Resistance*
  • Male
  • Oxidative Stress
  • Rats
  • Rats, Wistar
  • Up-Regulation
  • Uric Acid* / metabolism
  • Uric Acid* / pharmacology

Substances

  • Uric Acid
  • Flunitrazepam
  • Caspase 3
  • Adenosine Triphosphatases