Acetylsalicylic Acid Suppresses Alcoholism-Induced Cognitive Impairment Associated with Atorvastatin Intake by Targeting Cerebral miRNA155 and NLRP3: In Vivo, and In Silico Study

Doaa I Mohamed; Dalia Alaa El-Din Aly El-Waseef; Enas S Nabih; Omnyah A El-Kharashi; Hanaa F Abd El-Kareem; Hebatallah H Abo Nahas; Basel A Abdel-Wahab; Yosra A Helmy; Samar Zuhair Alshawwa; Essa M Saied

doi:10.3390/pharmaceutics14030529

Acetylsalicylic Acid Suppresses Alcoholism-Induced Cognitive Impairment Associated with Atorvastatin Intake by Targeting Cerebral miRNA155 and NLRP3: In Vivo, and In Silico Study

Pharmaceutics. 2022 Feb 27;14(3):529. doi: 10.3390/pharmaceutics14030529.

Authors

Affiliations

¹ Department of Clinical Pharmacology and Therapeutics, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt.
² Department of Histology and Cell Biology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt.
³ Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt.
⁴ Zoology Department, Faculty of Science, Ain Shams University, Abbasseya, Cairo 11566, Egypt.
⁵ Zoology Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt.
⁶ Department of Medical Pharmacology, College of Medicine, Assiut University, Assiut 71111, Egypt.
⁷ Department of Pharmacology, College of Pharmacy, Najran University, Najran 1988, Saudi Arabia.
⁸ Department of Veterinary Science, College of Agriculture, Food, and Environment, University of Kentucky, Lexington, KY 40503, USA.
⁹ Department of Animal Hygiene, Zoonoses and Animal Ethology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia 41522, Egypt.
¹⁰ Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia.
¹¹ Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt.
¹² Institute for Chemistry, Humboldt Universität zu Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany.

Abstract

Alcoholism is one of the most common diseases that can lead to the development of several chronic diseases including steatosis, and cognitive dysfunction. Statins are lipid-lowering drugs that are commonly prescribed for patients with fatty liver diseases; however, the exact effect of statins on cognitive function is still not fully understood. In the present study, we have investigated the molecular and microscopic basis of cognitive impairment induced by alcohol and/or Atorvastatin (ATOR) administration to male Wistar albino rats and explored the possible protective effect of acetylsalicylic acid (ASA). The biochemical analysis indicated that either alcohol or ATOR or together in combination produced a significant increase in the nucleotide-binding domain-like receptor 3 (NLRP3), interleukin-1β (IL-1β) miRNA155 expression levels in the frontal cortex of the brain tissue. The histological and morphometric analysis showed signs of degeneration in the neurons and the glial cells with aggregations of inflammatory cells and a decrease in the mean thickness of the frontal cortex. Immunohistochemical analysis showed a significant increase in the caspase-8 immunoreaction in the neurons and glial cells of the frontal cortex. Interestingly, administration of ASA reversed the deleterious effect of the alcohol and ATOR intake and improved the cognitive function as indicated by biochemical and histological analysis. ASA significantly decreased the expression levels of miRNA155, NLRP3, and IL1B, and produced a significant decrease in caspase-8 immunoreaction in the neurons and glial cells of the frontal cortex with a reduction in the process of neuroinflammation and neuronal damage. To further investigate these findings, we have performed an extensive molecular docking study to investigate the binding affinity of ASA to the binding pockets of the NLRP3 protein. Our results indicated that ASA has high binding scores toward the active sites of the NLRP3 NACHT domain with the ability to bind to the NLRP3 pockets by a set of hydrophilic and hydrophobic interactions. Taken together, the present study highlights the protective pharmacological effect of ASA to attenuate the deleterious effect of alcohol intake and long term ATOR therapy on the cognitive function via targeting miRNA155 and NLRP3 proteins.

Keywords: NLRP3 inflammasomes; acetylsalicylic acid; alcoholism; atorvastatin; histopathology; miRNA155; molecular docking; statins.