Cross talk between MSCs-extracellular vesicles and olea europaea leaf extract in encapsulated liposomal hydrogel: Attenuation of neuroinflammation and brain neurotransmitter and memory impairment associated with obesity induced High fat diet

Doaa Ibrahim^1*Ioan Pet²Hoda S Sherkawy³Haitham Eldoumani⁴Ola M Fathy⁵Aya Elgamal⁶Heba S A Gharib^7,8Asmaa A Muhammed⁹Aya Sh¹⁰Mirela Ahmadi¹¹Daniela Pușcașiu¹²Sherief Mohamed Abdel-Raheem¹³Ahmed Abdelfattah-Hassan¹⁴

• ¹Department of Nutrition and Clinical Nutrition, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
• ²Department of Biotechnology, Faculty of Bioengineering of Animals Resources, University of Life Sciences, Timisoara, Romania
• ³Department of medical biochemistry and Molecular Biology, Faculty of Medicine Aswan University, Aswan, Egypt
• ⁴Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
• ⁵Zagazig University Hospitals, Department of Biochemistry, Zagazig University, Zagazig, Egypt, Zagazig, Egypt
• ⁶Department of Animal Histology and Anatomy, Faculty of Veterinary Medicine, Badr University in Cairo (BUC), Cairo, Egypt, Cairo, Egypt
• ⁷Behaviour and management of animal, poultry and aquatics department, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
• ⁸Behaviour and management of animal, poultry and aquatics department, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Ecuador
• ⁹Department of Medical Physiology, Faculty of Medicine, Aswan University, Aswan, 81511, Egypt, Aswan, Egypt
• ¹⁰Department of Pharmacology, Faculty of Veterinary Medicine, Aswan University, Egypt, Aswan, Egypt
• ¹¹Department of Biotechnology, Faculty of Bioengineering of Animals Resources, University of Life Sciences “King Mihai I” from Timisoara, 300645 Timisoara, Romania, Timisoara, Romania
• ¹²Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy of Timisoara, E. Murgu, 2, Timisoara, 300041 Romania, Timisoara, Romania
• ¹³Department of Public Health, College of Veterinary Medicine, King Faisal University, Hofuf, Al-Ahsa31982, SaudiArabia, Hofuf, Saudi Arabia
• ¹⁴Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt, Zagazig, Egypt

Consumption of a high-fat diet (HFD) can trigger neuroinflammation, which may increase the risk of neurodegenerative disease progression, leading to memory impairment. In the current study, the curative impact of a novel therapy combing olea europaea leaf extract encapsulated a liposomal hydrogel (Lipo-OLE-Hydrogel) and mesenchymal stem cell derived-exosomes (MSCs-Exo) was evaluated against HFD‐induced brain dysfunction in a rat model. This assessment involved analyzing behavioral tasks, neurotransmitter levels, oxidative stress, neuroinflammation, endoplasmic reticulum-related markers, histopathological lesions, and immunostaining markers in brain tissues. The experimental groups were arranged for a 14-week study as follows: the first group received a control diet; second group was fed HFD; third group was fed HFD and treated with Lipo-OLE-Hydrogel, the fourth group was fed a HFD and treated with MSCs-Exo); and the fifth group was fed HFD and treated with both Lipo-OLE-Hydrogel and MSCs-Exo. he findings of this study demonstrated that the neuroprotective effect of the combined Lipo-OLE-Hydrogel and MSCs-Exo treatment reduced oxidative stress, as evidenced by the restoration of total antioxidant capacity and the marked decrease in oxidative biomarkers, including ROS, H₂O₂, and MDA. The HFD-fed group exhibited greater glucose intolerance and increased BWG; however, these effects were significantly reversed in the group treated with the combination of Lipo-OLE-Hydrogel and MSCs-Exo, even after long-term HFD induction. Impairments in behavioral tasks and memory were significantly improved in the group treated with the combined MSCs-Exo and Lipo-OLE-Hydrogel therapy, with the MSCs-Exo alone group showing moderate improvement. The excessive inflammatory response and expression of endoplasmic reticulum stress-related genes were markedly attenuated in Lipo-OLE-Hydrogel and MSCs-Exo. The severity of the histopathological changes in the brain tissues, including the development of neoplastic epithelium and the invasion of some neoplastic masses was significantly attenuated in the group treated with the combined Lipo-OLE-Hydrogel+MSCs-Exo therapy. Immunohistochemical staining displayed that Bcl-2 protein expression was significantly resorted to near normal level, while TNF-α expression was reduced in group treated with MSCs-Exo and Lipo-OLE-Hydrogel therapy. Taken together, these findings highlight a novel and promising therapeutic approach that combines a natural protective agent (Lipo-OLE-Hydrogel) with MSCs-Exo to effectively combat HFD-induced neuroinflammationprogression