Pregnenolone Inhibits Doxorubicin-Induced Cardiac Oxidative Stress, Inflammation, and Apoptosis—Role of Matrix Metalloproteinase 2 and NADPH Oxidase 1
The clinical usefulness of doxorubicin (DOX) is limited by its serious adverse effects, such as cardiotoxicity. Pregnenolone demonstrated both anti-inflammatory and antioxidant activity in animal models. The current study aimed to investigate the cardioprotective potential of pregnenolone against DO...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-04-01
|
| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/16/5/665 |
| _version_ | 1797598719709806592 |
|---|---|
| author | Mohamed A. Morsy Seham A. Abdel-Gaber Sahar A. Mokhemer Mahmoud Kandeel Wael F. Sedik Anroop B. Nair Katharigatta N. Venugopala Hany Ezzat Khalil Bandar E. Al-Dhubiab Mervat Z. Mohamed |
| author_facet | Mohamed A. Morsy Seham A. Abdel-Gaber Sahar A. Mokhemer Mahmoud Kandeel Wael F. Sedik Anroop B. Nair Katharigatta N. Venugopala Hany Ezzat Khalil Bandar E. Al-Dhubiab Mervat Z. Mohamed |
| author_sort | Mohamed A. Morsy |
| collection | DOAJ |
| description | The clinical usefulness of doxorubicin (DOX) is limited by its serious adverse effects, such as cardiotoxicity. Pregnenolone demonstrated both anti-inflammatory and antioxidant activity in animal models. The current study aimed to investigate the cardioprotective potential of pregnenolone against DOX-induced cardiotoxicity. After acclimatization, male Wistar rats were randomly grouped into four groups: control (vehicle-treated), pregnenolone (35 mg/kg/d, p.o.), DOX (15 mg/kg, i.p, once), and pregnenolone + DOX. All treatments continued for seven consecutive days except DOX, which was administered once on day 5. The heart and serum samples were harvested one day after the last treatment for further assays. Pregnenolone ameliorated the DOX-induced increase in markers of cardiotoxicity, namely, histopathological changes and elevated serum levels of creatine kinase-MB and lactate dehydrogenase. Moreover, pregnenolone prevented DOX-induced oxidative changes (significantly lowered cardiac malondialdehyde, total nitrite/nitrate, and NADPH oxidase 1, and elevated reduced glutathione), tissue remodeling (significantly decreased matrix metalloproteinase 2), inflammation (significantly decreased tumor necrosis factor-α and interleukin 6), and proapoptotic changes (significantly lowered cleaved caspase-3). In conclusion, these findings show the cardioprotective effects of pregnenolone in DOX-treated rats. The cardioprotection achieved by pregnenolone treatment can be attributed to its antioxidant, anti-inflammatory, and antiapoptotic actions. |
| first_indexed | 2024-03-11T03:25:40Z |
| format | Article |
| id | doaj.art-9fa69729efb9480dbde210f6f11d1777 |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-11T03:25:40Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-9fa69729efb9480dbde210f6f11d17772023-11-18T02:48:12ZengMDPI AGPharmaceuticals1424-82472023-04-0116566510.3390/ph16050665Pregnenolone Inhibits Doxorubicin-Induced Cardiac Oxidative Stress, Inflammation, and Apoptosis—Role of Matrix Metalloproteinase 2 and NADPH Oxidase 1Mohamed A. Morsy0Seham A. Abdel-Gaber1Sahar A. Mokhemer2Mahmoud Kandeel3Wael F. Sedik4Anroop B. Nair5Katharigatta N. Venugopala6Hany Ezzat Khalil7Bandar E. Al-Dhubiab8Mervat Z. Mohamed9Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi ArabiaDepartment of Pharmacology, Faculty of Medicine, Minia University, El-Minia 61511, EgyptDepartment of Histology and Cell Biology, Faculty of Medicine, Minia University, El-Minia 61511, EgyptDepartment of Biomedical Sciences, College of Veterinary Medicine, King Faisal University, Al-Ahsa 31982, Saudi ArabiaDepartment of Medical Biochemistry, Faculty of Medicine, Minia University, El-Minia 61511, EgyptDepartment of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi ArabiaDepartment of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi ArabiaDepartment of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi ArabiaDepartment of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi ArabiaDepartment of Pharmacology, Faculty of Medicine, Minia University, El-Minia 61511, EgyptThe clinical usefulness of doxorubicin (DOX) is limited by its serious adverse effects, such as cardiotoxicity. Pregnenolone demonstrated both anti-inflammatory and antioxidant activity in animal models. The current study aimed to investigate the cardioprotective potential of pregnenolone against DOX-induced cardiotoxicity. After acclimatization, male Wistar rats were randomly grouped into four groups: control (vehicle-treated), pregnenolone (35 mg/kg/d, p.o.), DOX (15 mg/kg, i.p, once), and pregnenolone + DOX. All treatments continued for seven consecutive days except DOX, which was administered once on day 5. The heart and serum samples were harvested one day after the last treatment for further assays. Pregnenolone ameliorated the DOX-induced increase in markers of cardiotoxicity, namely, histopathological changes and elevated serum levels of creatine kinase-MB and lactate dehydrogenase. Moreover, pregnenolone prevented DOX-induced oxidative changes (significantly lowered cardiac malondialdehyde, total nitrite/nitrate, and NADPH oxidase 1, and elevated reduced glutathione), tissue remodeling (significantly decreased matrix metalloproteinase 2), inflammation (significantly decreased tumor necrosis factor-α and interleukin 6), and proapoptotic changes (significantly lowered cleaved caspase-3). In conclusion, these findings show the cardioprotective effects of pregnenolone in DOX-treated rats. The cardioprotection achieved by pregnenolone treatment can be attributed to its antioxidant, anti-inflammatory, and antiapoptotic actions.https://www.mdpi.com/1424-8247/16/5/665pregnenolonedoxorubicincardiotoxicityMMP2NADPH oxidase 1caspase-3 |
| spellingShingle | Mohamed A. Morsy Seham A. Abdel-Gaber Sahar A. Mokhemer Mahmoud Kandeel Wael F. Sedik Anroop B. Nair Katharigatta N. Venugopala Hany Ezzat Khalil Bandar E. Al-Dhubiab Mervat Z. Mohamed Pregnenolone Inhibits Doxorubicin-Induced Cardiac Oxidative Stress, Inflammation, and Apoptosis—Role of Matrix Metalloproteinase 2 and NADPH Oxidase 1 Pharmaceuticals pregnenolone doxorubicin cardiotoxicity MMP2 NADPH oxidase 1 caspase-3 |
| title | Pregnenolone Inhibits Doxorubicin-Induced Cardiac Oxidative Stress, Inflammation, and Apoptosis—Role of Matrix Metalloproteinase 2 and NADPH Oxidase 1 |
| title_full | Pregnenolone Inhibits Doxorubicin-Induced Cardiac Oxidative Stress, Inflammation, and Apoptosis—Role of Matrix Metalloproteinase 2 and NADPH Oxidase 1 |
| title_fullStr | Pregnenolone Inhibits Doxorubicin-Induced Cardiac Oxidative Stress, Inflammation, and Apoptosis—Role of Matrix Metalloproteinase 2 and NADPH Oxidase 1 |
| title_full_unstemmed | Pregnenolone Inhibits Doxorubicin-Induced Cardiac Oxidative Stress, Inflammation, and Apoptosis—Role of Matrix Metalloproteinase 2 and NADPH Oxidase 1 |
| title_short | Pregnenolone Inhibits Doxorubicin-Induced Cardiac Oxidative Stress, Inflammation, and Apoptosis—Role of Matrix Metalloproteinase 2 and NADPH Oxidase 1 |
| title_sort | pregnenolone inhibits doxorubicin induced cardiac oxidative stress inflammation and apoptosis role of matrix metalloproteinase 2 and nadph oxidase 1 |
| topic | pregnenolone doxorubicin cardiotoxicity MMP2 NADPH oxidase 1 caspase-3 |
| url | https://www.mdpi.com/1424-8247/16/5/665 |
| work_keys_str_mv | AT mohamedamorsy pregnenoloneinhibitsdoxorubicininducedcardiacoxidativestressinflammationandapoptosisroleofmatrixmetalloproteinase2andnadphoxidase1 AT sehamaabdelgaber pregnenoloneinhibitsdoxorubicininducedcardiacoxidativestressinflammationandapoptosisroleofmatrixmetalloproteinase2andnadphoxidase1 AT saharamokhemer pregnenoloneinhibitsdoxorubicininducedcardiacoxidativestressinflammationandapoptosisroleofmatrixmetalloproteinase2andnadphoxidase1 AT mahmoudkandeel pregnenoloneinhibitsdoxorubicininducedcardiacoxidativestressinflammationandapoptosisroleofmatrixmetalloproteinase2andnadphoxidase1 AT waelfsedik pregnenoloneinhibitsdoxorubicininducedcardiacoxidativestressinflammationandapoptosisroleofmatrixmetalloproteinase2andnadphoxidase1 AT anroopbnair pregnenoloneinhibitsdoxorubicininducedcardiacoxidativestressinflammationandapoptosisroleofmatrixmetalloproteinase2andnadphoxidase1 AT katharigattanvenugopala pregnenoloneinhibitsdoxorubicininducedcardiacoxidativestressinflammationandapoptosisroleofmatrixmetalloproteinase2andnadphoxidase1 AT hanyezzatkhalil pregnenoloneinhibitsdoxorubicininducedcardiacoxidativestressinflammationandapoptosisroleofmatrixmetalloproteinase2andnadphoxidase1 AT bandarealdhubiab pregnenoloneinhibitsdoxorubicininducedcardiacoxidativestressinflammationandapoptosisroleofmatrixmetalloproteinase2andnadphoxidase1 AT mervatzmohamed pregnenoloneinhibitsdoxorubicininducedcardiacoxidativestressinflammationandapoptosisroleofmatrixmetalloproteinase2andnadphoxidase1 |