Abstract
Diabetes mellitus (DM) is a multisystem endocrine disorder affecting the brain. Mesenchymal stem cells (MSCs) pretreated with Melatonin have been shown to increase the potency of MSCs. This work aimed to compare Melatonin, stem cells, and stem cells pretreated with Melatonin on the cognitive functions and markers of synaptic plasticity in an animal model of type I diabetes mellitus (TIDM). Thirty-six rats represented the animal model; six rats for isolation of MSCs and 30 rats were divided into five groups: control, TIDM, TIDM + Melatonin, TIDM + Stem cells, and TIDM + Stem ex vivo Melatonin. Functional assessment was performed with Y-maze, forced swimming test and novel object recognition. Histological and biochemical evaluation of hippocampal Neuroligin 1, Sortilin, Brain-Derived Neurotrophic Factor (BDNF), inducible nitric oxide synthase (iNOS), toll-like receptor 2 (TLR2), Tumor necrosis factor-alpha (TNF-α), and Growth Associated Protein 43 (GAP43). The TIDM group showed a significant decrease of hippocampal Neuroligin, Sortilin, and BDNF and a significant increase in iNOS, TNF-α, TLR2, and GAP43. Melatonin or stem cells groups showed improvement compared to the diabetic group but not compared to the control group. TIDM + Stem ex vivo Melatonin group showed a significant improvement, and some values were restored to normal. Ex vivo melatonin-treated stem cells had improved spatial working and object recognition memory and depression, with positive effects on glucose homeostasis, inflammatory markers levels and synaptic plasticity markers expression.
Highlights
Diabetes mellitus (DM) is a systemic disease and may produce various adverse outcomes on the brain, such as neuronal damage, oxidative stress, decreased synaptic plasticity, glutamate neurotransmission changes, and dysfunction of astrocytes with abnormal neuronal activities (Arvanitakis et al, 2004; Son et al, 2015).Neurorestoration in Type I Diabetes MellitusBone marrow has two forms of stem cells: hematopoietic stem cells and mesenchymal stem cells (MSCs) (Krabbe et al, 2005)
The group treated with stem cells showed a significant (P values ≤ 0.05) increase in alternation score compared to the diabetic group and group treated with melatonin alone
Treatment with melatonin or stem cells alone or pretreatment of stem cells attenuated by melatonin significantly decreased (P-value ≤ 0.05) compared to the diabetic group with the best glucose homeostasis achieved in the group treated with stem cells attenuated by melatonin
Summary
Diabetes mellitus (DM) is a systemic disease and may produce various adverse outcomes on the brain, such as neuronal damage, oxidative stress, decreased synaptic plasticity, glutamate neurotransmission changes, and dysfunction of astrocytes with abnormal neuronal activities (Arvanitakis et al, 2004; Son et al, 2015).Neurorestoration in Type I Diabetes MellitusBone marrow has two forms of stem cells: hematopoietic stem cells and mesenchymal stem cells (MSCs) (Krabbe et al, 2005). Diabetes mellitus (DM) is a systemic disease and may produce various adverse outcomes on the brain, such as neuronal damage, oxidative stress, decreased synaptic plasticity, glutamate neurotransmission changes, and dysfunction of astrocytes with abnormal neuronal activities (Arvanitakis et al, 2004; Son et al, 2015). MSCs secrete cytokines and trophic factors, which activate neurogenesis, angiogenesis, and synaptogenesis that improve neural and cognitive functions (Lee et al, 2010). MSCs produce basal reactive oxygen species (ROS) to maintain cell proliferation and differentiation, which may cause DNA damage in MSCs and impair the normal function of MSCs (Jeong and Cho, 2016). The administration of Melatonin protects MSCs from oxidation, inflammation, apoptosis, ischemia, and aging and influences the differential activity of neural stem cells (Ma et al, 2013; Tang et al, 2014)
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