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Oral Administration of Butylated Hydroxytoluene Induces Neuroprotection in a Streptozotocin-Induced Rat Alzheimer’S Disease Model Via Inhibition of Neuronal Ferroptosis Publisher Pubmed



Faraji P1, 2 ; Parandavar E1 ; Kuhn H2 ; Habibirezaei M3 ; Borchert A2 ; Zahedi E4 ; Ahmadian S1
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Authors Affiliations
  1. 1. Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
  2. 2. Department of Biochemistry, Charite - Universitatsmedizin Berlin, Corporate member of Freie Universitat Berlin and Humboldt Universitat zu Berlin, Chariteplatz 1, Berlin, D-10117, Germany
  3. 3. School of Biology, College of Science, University of Tehran, Tehran, Iran
  4. 4. Institute of Physiology, Tehran University of Medical Sciences, Tehran, Iran

Source: Molecular Medicine Published:2024


Abstract

Background: Alzheimer’s disease (AD) is the most common human neurodegenerative disorder worldwide. Owing to its chronic nature, our limited understanding of its pathophysiological mechanisms, and because of the lack of effective anti-AD drugs, AD represents a significant socio-economic challenge for all industrialized countries. Neuronal cell death is a key factor in AD pathogenesis and recent studies have suggested that neuronal ferroptosis may play a major patho-physiological role. Since ferroptosis involves free radical-mediated lipid peroxidation, we hypothesized that enteral administration of the radical scavenger butylated hydroxytoluene (BHT) might slow down or even prevent the development of AD-related symptoms in an in vivo animal AD model. Material and methods: To test this hypothesis, we employed the rat model of streptozotocin-induced AD and administered butylated hydroxytoluene orally at a dose of 120 mg/kg body weight. Following BHT treatment, neuronal cell death was induced by bilateral stereotactic intraventricular injection of streptozotocin at a dose of 3.0 mg/kg body weight. Three weeks after surgery, we assessed the learning capabilities and the short-term memory of three experimental groups using the conventional y-maze test: (i) streptozotocin-treated rats (BHT pre-treatment), (ii) streptozotocin-treated rats (no BHT pre-treatment), (iii) sham-operated rats (BHT pre-treatment but no streptozotocin administration). After the y-maze test, the animals were sacrificed, hippocampal tissue was prepared and several biochemical (malonyl dialdehyde formation, glutathione homeostasis, gene expression patterns) and histochemical (Congo-red staining, Nissl staining, Perls staining) readout parameters were quantified. Results: Intraventricular streptozotocin injection induced the development of AD-related symptoms, elevated the degree of lipid peroxidation and upregulated the expression of ferroptosis-related genes. Histochemical analysis indicated neuronal cell death and neuroinflammation, which were paralleled by aberrant intraneuronal iron deposition. The streptozotocin-induced alterations were significantly reduced and sometimes even abolished by oral BHT treatment. Conclusion: Our data indicate that oral BHT treatment attenuated the development of AD-related symptoms in an in vivo rat model, most probably via inhibiting neuronal ferroptosis. These findings suggest that BHT might constitute a promising candidate as anti-AD drug. However, more work is needed to explore the potential applicability of BHT in other models of neurodegeneration and in additional ferroptosis-related disorders. © The Author(s) 2024.