Neuroprotective Role of Lazaroids Against Aluminium Chloride Poisoning
Aluminium (Al) is neurotoxic primarily because of its interference with biological enzymes in key mechanisms of metabolic pathways. Mitochondria being a major site of reactive oxygen species (ROS) production, it seems that the oxidative damage to mitochondrial proteins may underlie the pathogenesis of Al induced neurodegeneration. The present study investigates the effectiveness of the anti-oxidant property of lazaroids (U-74500A), a known lipid peroxidation inhibitor as neuroprotective agent against Al induced neurotoxicity. Al chloride was administered orally at a dose level of 100 mg/kg body wt/day in water and U-74500A was administered at a dose of 0.25 mg/kg body wt i.p. in citrate buffer for a period of 8 weeks on alternate days. Following Al exposure there was a significant increase in lipid peroxidation (LPO), ROS levels and reduction in the activity of mitochondrial complexes in all the three regions of rat brain, i.e., cerebral cortex, mid brain, and cerebellum. This decrease in the activities of electron transport complexes in turn affected the ATP synthesis and ATP levels adversely in the mitochondria. These alterations were also depicted in the histology which shows signs of hypoxia, paucity of neurons in cortical region and loosening of fibers in the white matter. U-74500A co-administration was able to restore alterations in the LPO, ROS levels as well as all the three mitochondrial complexes and caspase expression. Therefore, it is suggested that 21-aminosteroids (lazaroids), by attenuating LPO and mitochondrial dysfunction, holds a promise as an agent that can potentially reduce Al-induced adverse effects in brain.
KeywordsAluminium neurotoxicity Lipid peroxidation Oxidative phosphorylation Caspase expression Histopathology Lazaroids
Bovine serum albumin
Central nervous system
Deoxyribose nucleic acid
Ethylene diamine tricholoacetic acid
Ethylene glycol tetraacetic acid
Electron transport chain
Potassium dihydrogen phosphate
Mitochondrial transition permeability pore
Nicotinamide adenine dinucleotide reduced
Nicotinamide adenine dinucleotide phosphate reduced
Post mitochondrial fraction
Ribose nucleic acid
Reactive oxygen species
Sodium dodecyl sulphate
Sodium dodecyl sulphate poly acrylamide gel electrophoresis
- Tris HCl
Tricholro acetic acid
Financial support from ICMR in the form of Research fellowship to Ms Pooja Khanna is highly appreciated.
Compliance with Ethical Standards
Conflict of interest
The authors don’t have any conflicting interest in the manuscript.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were approved by Institutional Animal Ethics Committee (IAEC), Panjab University, Chandigarh, India and in general according to the NIH guidelines (Rule No. 23-85, as revised in 1985).
This article does not contain any studies with human participants performed by any of the authors.
- 14.King TE, Howard RL (1967) Preparation and properties of soluble NADH dehydrogenase from cardiac muscle. In: Colowick SP, Kaplan NO (eds) Methods in enzymology. Academic Press, New York, pp 275–276Google Scholar
- 15.King TS (1967) Preparation of succinate dehydrogenase and reconstitution of succinate oxidase. Methods in enzymology. Academic Press, New York, pp 322–325Google Scholar
- 20.Pearse AGE (1968) Histochemistry, theoretical and applied, vol 1; 3rd edn. Churchill Livingstone, London, p 660Google Scholar
- 21.Humanson GL (1961) Basic procedures—animal tissue technique, vol.1, pp 130–132Google Scholar
- 30.Maes M, Fisar Z, Medina M, Scapagnini G et al (2012) New drug targets in depression: inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant, and neuroprogressive pathways. And new drug candidates—Nrf2 activators and GSK-3 inhibitors. Inflammopharmacology 20:127–150CrossRefPubMedGoogle Scholar
- 32.Hroudova J, Singh N, Fisar Z (2014) BioMed Res Int. Article ID 175062, 9. doi: 10.1155/175062
- 33.Carpenter MB (1991) Textbook of neuroanatomy, 4th edn. Williams & Wilkins, BaltimoreGoogle Scholar
- 43.Dewitt DA, Hurd JA, Fox N, Townsend BE et al (2006) Peri-nuclear clustering of mitochondria is triggered during Al maltolate induced apoptosis. J Alzheimer Dis 9:195–205Google Scholar