Vol.:(0123456789) 1 3 Cell and Tissue Research (2023) 392:443–466 https://doi.org/10.1007/s00441-022-03735-5 REGULAR ARTICLE Caffeine protects against hippocampal alterations in type 2 diabetic rats via modulation of gliosis, inflammation and apoptosis Manal A. Othman 1,2  · Raouf Fadel 1,3  · Yasin Tayem 4  · Ahmed Jaradat 5  · Aisha Rashid 1  · Ayesha Fatima 1  · Ali E. Al‑Mahameed 6  · Wael Amin Nasr El‑Din 1,3 Received: 23 June 2022 / Accepted: 21 December 2022 / Published online: 29 December 2022 © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022 Abstract Type 2 diabetes (T2D) is implicated in the injury of several organs, including the brain resulting in neuronal damage, which may lead to cognitive impairment and dementia. Additionally, it is linked to infammation, cytokine release, apoptosis and various degenerative conditions. Astrocytes and microglia might have a role in mediating these processes. Cafeine, a psychoactive beverage, has been shown to reduce the risk of cognitive and memory impairment. This study proposes anti- infammatory and anti-apoptotic role of cafeine, which can be mediated via microglia/astrocyte activation and overexpression of pro-infammatory molecules. T2D was induced in rats by feeding with high fat high sugar diet and injecting a single low dose streptozotocin (STZ) intraperitoneally. Other diabetic rats were given cafeine orally (in two doses) for 5 weeks, start- ing 1 week before STZ injection. Measurement of plasma cytokines, TNFα and IL6, was performed using enzyme-linked immunosorbent assay (ELISA) technique. After sacrifcing animals, brains were obtained and processed for histological evaluation. Immunohistochemistry was also performed using the following primary antibodies, anti-astrocyte marker GFAP, anti-microglia marker CD11b and apoptotic marker (anti-cleaved caspase-3). There was upregulation of IL6 and TNF-α in diabetic rats. Additionally, histological evaluation of the hippocampus of diabetic rats revealed cellular degeneration. There was increased immunostaining of GFAP, CD11b and cleaved caspase-3 in diabetic rats. Pretreatment with cafeine to diabetic rats, resulted in improvement of structural changes and decrease in cytokine levels and immuno-markers, expres- sion, and this was in a dose-dependent manner. In conclusion, cafeine had an ameliorative role in enhancing hippocampal degenerative changes in T2D. Keywords Type 2 diabetes · Hippocampus · Gliosis · Inflammation · Apoptosis Introduction Type 2 diabetes (T2D) is a very common metabolic disease and is usually linked to lifestyle changes as high caloric food intake and sedentary life (reviewed in: Yuan and Larsson 2020). The occurrence of insulin resistance, in T2D, is aggra- vated by the consumption of high fat, and sugar diets (Soliman et al. 2016; Li et al. 2017; Qiao et al. 2020). The high calorie diet with low dose of streptozotocin (STZ) is being used to create a rodent model of insulin resistance and T2D (Buettner et al. 2006; Zhou et al. 2018). Current evidence suggests its correlation with variable neurodegenerative diseases includ- ing diabetic encephalopathy. It might lead to various health consequences such as defects in cognitive functions, memory impairment, brain atrophy and many structural abnormalities (Park et al. 2019; Qiao et al. 2020). The hippocampus is the major part of the brain that is concerned with memory function and cognitive behavior * Wael Amin Nasr El-Din waela@agu.edu.bh 1 Department of Anatomy, College of Medicine and Medical Sciences, Arabian Gulf University, P.O. Box 26671, Manama, Bahrain 2 Department of Histology and Cell Biology, Faculty of Medicine, Assiut University, Assiut, Egypt 3 Department of Human Anatomy and Embryology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt 4 Department of Pharmacology, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain 5 Department of Family and Community Medicine, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain 6 Department of Microbiology, Immunology & Infectious Diseases, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain Content courtesy of Springer Nature, terms of use apply. Rights reserved.