Neuroprotective Efficiency of Prodigiosins Conjugated with Selenium Nanoparticles in Rats Exposed to Chronic Unpredictable Mild Stress is Mediated Through Antioxidative, Anti-Inflammatory, Anti-Apoptotic, and Neuromodulatory Activities

Ashraf Albrakati,1 Khalaf F Alsharif,2 Naif E Al omairi,3 Walaa F Alsanie,2 Abdulraheem SA Almalki,4 Zakaria Y Abd Elmageed,5 Gehad E Elshopakey,6 Maha S Lokman,7,8 Amira A Bauomy,9 Ahmed E Abdel Moneim,8 Rami B Kassab8,10 1Department of Human Anatomy, College of Medicine, Taif University, Taif, Saudi Arabia; 2Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia; 3Department of Internal Medicine, College of Medicine, Taif University, Taif, Saudi Arabia; 4Department of Chemistry, Faculty of Science, Taif University, Taif, Saudi Arabia; 5Department of Pharmacology, Edward via College of Osteopathic Medicine, University of Louisiana at Monroe, Monroe, LA, USA; 6Department of Clinical Pathology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt; 7Biology Department, College of Science and Humanities, Prince Sattam bin Abdul Aziz University, Alkharj, Saudi Arabia; 8Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, Egypt; 9Department of Science Laboratories, College of Science and Arts, Qassim University, ArRassAl-Qassim, Saudi Arabia; 10Biology Department, Faculty of Science and Arts, Al Baha University, Al Makhwah Branch, Al Baha, Saudi ArabiaCorrespondence: Ahmed E Abdel MoneimDepartment of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, EgyptTel +20 1153322079Email aest1977@hotmail.comPurpose: Depression is a mood disorder accompanied by intensive molecular and neurochemical alterations. Currently, available antidepressant therapies are not fully effective and are often accompanied by several adverse impacts. Accordingly, the ultimate goal of this investigation was to clarify the possible antidepressant effects of prodigiosins (PDGs) loaded with selenium nanoparticles (PDGs-SeNPs) in chronic unpredictable mild stress (CUMS)-induced depression-like behavior in rats.Methods: Sixty Sprague Dawley rats were randomly allocated into six groups: control, CUMS group (depression model), fluoxetine (Flu, 10 mg/kg)+CUMS, PDGs+CUMS (300 mg/kg), sodium selenite (Na2SeO3, 400 mg/kg)+CUMS, and PDGs-SeNPs+CUMS (200 mg/kg). All treatments were applied orally for 28 consecutive days.Results: PDGs-SeNPs administration prevented oxidative insults in hippocampal tissue, as demonstrated by decreased oxidant levels (nitric oxide and malondialdehyde) and elevated innate antioxidants (glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase), in addition to the upregulated expression of nuclear factor erythroid 2-related factor 2 and heme oxygenase-1 in rats exposed to CUMS. Additionally, PDGs-SeNPs administration suppressed neuroinflammation in hippocampal tissue, as determined by the decreased production of pro-inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1β, and interleukin-6), increased anti-inflammatory cytokine interleukin-10, and decreased inflammatory mediators (prostaglandin E2, cyclooxygenase-2, and nuclear factor kappa B). Moreover, PDGs-SeNPs administration in stressed rats inhibited neuronal loss and the development of hippocampal apoptosis through enhanced levels of B cell lymphoma 2 and decreased levels of caspase 3 and Bcl-2-associated X protein. Interestingly, PDGs-SeNPs administration improved hormonal levels typically disrupted by CUMS exposure and significantly modulated hippocampal levels of monoamines, brain-derived neurotrophic factor, monoamine oxidase, and acetylcholinesterase activities, in addition to upregulating the immunoreactivity of glial fibrillary acidic protein in CUMS model rats.Conclusion: PDGs-SeNPs may serve as a prospective antidepressant candidate due to their potent antioxidant, anti-inflammatory, and neuroprotective potential.Keywords: chronic unpredictable mild stress, prodigiosin-loaded selenium nanoparticles, oxidative stress, neuroinflammation, apoptosis, neurochemical markers