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Repositioning Canagliflozin for Mitigation of Aluminium Chloride-Induced Alzheimer’s Disease: Involvement of TXNIP/NLRP3 Inflammasome Axis, Mitochondrial Dysfunction, and SIRT1/HMGB1 Signalling

  • Hemat A. Elariny
  • , Ahmed M. Kabel
  • , Heba Mohammed Refat M. Selim
  • , Azza I. Helal
  • , Doaa Abdelrahman
  • , Hany M. Borg
  • , Mennatallah A. Elkady
  • , Lamees M. Dawood
  • , Mohamed F. El-Badawy
  • , Haifa Faisal A. Almalawi
  • , El Shaimaa A. Arafa
  • , Shuruq E. Alsufyani
  • , Hany H. Arab
  • University of Hail
  • Al-Azhar University
  • Tanta University
  • Almaarefa University
  • Kafrelsheikh University
  • Princess Nourah Bint Abdulrahman University
  • University of Sadat City
  • King Faisal Medical Complex
  • Taif University

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Background and Objectives: Alzheimer’s disease (AD) is the most common neurodegenerative disorder in the world. Due to failure of the traditional drugs to produce a complete cure for AD, the search for new safe and effective lines of therapy has attracted the attention of ongoing research. Canagliflozin is an anti-diabetic agent with proven efficacy in the treatment of neurological disorders in which mitochondrial dysfunction, oxidative stress, apoptosis, and autophagy play a pathophysiological role. Elucidation of the potential effects of different doses of canagliflozin on AD induced by aluminium chloride in rats and exploration of the molecular mechanisms that may contribute to these effects were the primary objectives of the current study. Materials and Methods: In a rat model of AD, the effect of three different doses of canagliflozin on the behavioural, biochemical, and histopathological alterations induced by aluminium chloride was assessed. Results: Canagliflozin administered to aluminium chloride-treated animals induced dose-dependent normalisation in the behavioural tests, augmentation of the antioxidant defence mechanisms, inhibition of TXNIP/NLRP3 inflammasome signalling, modulation of the SIRT1/HMGB1 axis, interference with the pro-inflammatory and the pro-apoptotic mechanisms, and restoration of the mitochondrial functions and autophagy in the hippocampal tissues to approximately baseline values. In addition, canagliflozin exhibited an interesting dose-dependent ability to repress aluminium chloride-induced histopathological changes in the brain. Conclusions: The effects of canagliflozin on oxidative stress, mitochondrial functions, inflammatory pathways, and autophagy signals may open new gates towards the mitigation of the pathologic features of AD.

Original languageEnglish
Article number1805
JournalMedicina (Lithuania)
Volume60
Issue number11
DOIs
StatePublished - Nov 2024

Keywords

  • Alzheimer’s disease
  • aluminium chloride
  • behavioural changes
  • canagliflozin
  • rats
  • sirtuin-1

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