Anxiolytic and antidepressant like effects of Zamzam water in STZ-induced diabetic rats, targeting oxidative stress, neuroinflammation, BDNF/ERK/CREP pathway with modulation of hypothalamo-pituitary-adrenal axis

Medhat Taha; Mohamed Ezzat Mahmoud; Abdullah G Al-Kushi; Anas Sarhan; Omer Abdelbagi; Tourki A S Baokbah; Omar Babateen; Ibrahim El-Shenbaby; Naeem F Qusty; Sara T Elazab

doi:10.3389/fnins.2023.1265134

Anxiolytic and antidepressant like effects of Zamzam water in STZ-induced diabetic rats, targeting oxidative stress, neuroinflammation, BDNF/ERK/CREP pathway with modulation of hypothalamo-pituitary-adrenal axis

Front Neurosci. 2023 Dec 1:17:1265134. doi: 10.3389/fnins.2023.1265134. eCollection 2023.

Authors

Affiliations

¹ Department of Anatomy and Embryology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
² Department of Anatomy, Al-Qunfudah Medical College, Umm Al-Qura University, Al-Qunfudah, Saudi Arabia.
³ Histology Department, Damietta Faculty of Medicine, Al-Azhar University, Damietta, Egypt.
⁴ Department of Human Anatomy, Faculty of Medicine, Umm Al-Qura University, Makkah, Makkah, Saudi Arabia.
⁵ Department of Internal Medicine, College of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia.
⁶ Department of Pathology, Qunfudah Faculty of Medicine, Umm-Al-Qura University, Al-Qunfudah, Saudi Arabia.
⁷ Department of Medical Emergency Services, College of Health Sciences-AlQunfudah, Umm Al-Qura University, Al-Qunfudah, Saudi Arabia.
⁸ Department of Physiology, Faculty of Medicine, Umm Al-Qura University, Makkah, Makkah, Saudi Arabia.
⁹ Clinical Pharmacology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
¹⁰ Medical Laboratories Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia.
¹¹ Department of Pharmacology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt.

Abstract

Introduction: Recent studies have reported a strong relationship between diabetes and anxiety- and depression-like behaviors; however, there is a lack of information on the underlying pathophysiology. Alkaline Zamzam water (ZW), which is rich in several trace elements, has neuroprotective properties. This study aimed to investigate the anxiolytic and antidepressant effects of ZW against diabetes-induced behavioral changes and shed light on the possible underlying mechanisms.

Methods: Forty-eight rats were divided into four experimental groups (n = 12): group I (control group), group II (Zamzam water group), group III (diabetic group), and group IV (diabetic + Zamzam water group). Diabetes was induced by an intraperitoneal injection of 60 mg/kg streptozotocin (STZ). At the end of the experiment, the forced swimming test (FST) was used to assess depression-like effects. The elevated plus maze test (EPMT) and open field test (OFT) were performed to evaluate anxiety-like behavior. Blood levels of the hypothalamic-pituitary-adrenal (HPA) axis were measured, and prefrontal cortex and hippocampal tissue samples were removed for histological, immunohistochemical, ELISA, and Q-PCR analyses.

Results: ZW significantly decreased the immobility time in the FST, indicating an antidepressant effect (p < 0.001). Additionally, ZW significantly improved the OFT and open field entry (OFE) percentages in the EPMT, increasing center crossing and decreasing grooming and fecal boli in the OFT. This indicated an anxiolytic-like effect in diabetic rats with histological improvement. Interestingly, ZW significantly increased prefrontal cortical and hippocampal levels of antioxidant enzymes and the Nrf2/HO-1 pathway. It also modulated the HPA axis by increasing cortisol and corticotropin-releasing hormone (CRH) levels, with a decrease in ACTH and an increase in monoamine neurotransmitters. Furthermore, diabetic rats that received ZW showed a decrease in the inflammatory markers TNF-α and GFAP by immunohistochemistry and in the mRNA levels of NFκB, IL-1β, and IL6. In addition, ZW downregulated the expression of the BDNF/ERK2/CREP pathway.

Conclusion: Our results suggested a neuroprotective effect of ZW against diabetes-induced anxiety- and depression-like behaviors and explored the underlying mechanisms. These findings suggest a promising therapeutic strategy for patients with diabetes who experience anxiety and depression.

Keywords: Zamzam water; anxiety; depression; diabetes; neuroinflammation; oxidative stress.

Grants and funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.