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  • Similarly results obtained in our lab using

    2023-01-31

    Similarly, results obtained in our lab using experimental diabetic encephalopathy induced by streptozotocin (STZ) in C57BL-6 mice showed that the hippocampus of the diabetic animals exhibited reactive gliosis, neuronal loss, NF-kB signaling activation as well as high levels of IL-1β and vascular endothelial growth factor (VEGF). T-maze test scores of these animals revealed a significantly poorer performance. Treatment with metformin reduced the expression of astrocyte and microglial markers (GFAP and Iba-1, respectively) and inflammation markers (p-Iκβ, IL-1 and VEGF), enhanced p-AMPK and eNOS levels and increased neuronal survival (Fox-1 and neuronal nuclear protein-NeuN). Treatment with metformin also improved the spatial memory scores of diabetic animals. In summary, metformin reduced neuroinflammation and decreased the loss of neurons in the hippocampus of diabetic animals, which could be related to the subsequent improvements in spatial memory (Oliveira et al., 2016). In contrast, a population-based, case-control study suggests that diabetic patients taking long-term metformin have a slightly increased risk of developing Alzheimer's than those taking other anti-diabetic drugs (Imfeld et al., 2012). Another epidemiological study also suggests that the administration of metformin in diabetic patients increases the risk of cognitive impairment (Moore et al., 2013). However, the evidence from this study was not sufficiently robust to establish that metformin causes cognitive deficit in diabetic patients, as the authors did not evaluate the duration and severity of diabetes, the length of treatment and the use of other hypoglycemic agents (Goodarzi, 2014). Barini et al. (2016) found that chronic treatment with metformin reduced tau phosphorylation in the cortex and hippocampus via AMPK/mTOR and PP2A in a P301S transgenic mouse model of tauopathy. However, metformin increased insoluble tau species (including tau oligomers) and the number of inclusions with β-sheet Fluconazole in the brain of P301S mice. These findings suggest that metformin may promote tau aggregation in vivo and indicate a possible risk for tauopathy in elderly diabetic patients. Jing et al. (2013) found that resveratrol attenuated hippocampal neurodegeneration in STZ-induced diabetic rats. Oral resveratrol treatment increased hippocampal p-AMPK levels and diminished both neurodegeneration and astrocytic activation. Resveratrol also reduced TNF-α and IL-6 transcripts as well as the expression of NF-kB, p38 and ERK1/2 phosphorylation/activation. According to the authors, this polyphenol treatment also reduced blood vessel permeability and VEGF expression and led to the recovery of capillary basement membrane thickness, thereby promoting the integrity and functionality of the brain-blood barrier (Jing et al., 2013). Recently, Moussa et al. (2017) described the effects of resveratrol on the brain-blood barrier in Alzheimer's patients. The authors examined banked cerebrospinal fluid and plasma samples from a subset of patients with mild to moderate Alzheimer's treated with resveratrol or a placebo and found a reduction in MMP9 reduction, suggesting that resveratrol may decrease central nervous system permeability, thereby limiting the infiltration of leukocytes and other inflammatory agents into the brain. Moreover, resveratrol-treated patients exhibited an increase in macrophage-derived chemokine (MDC) levels, which may facilitate the intracerebral homing of specific Th2 leukocytes and thus promote neuroprotection by mediating an adaptive immune response. Resveratrol also attenuated cognitive and functional declines (evaluated through mental state examination scores) as well as stabilized Aβ42 and Aβ40 levels in the cerebrospinal fluid. Moreover, resveratrol reduced plasma levels of inflammatory markers, such as IL-1R4, IL-12P40, IL-12P70, TNF-α and RANTES (CCL22). Using familial Alzheimer's double-transgenic mice (AβPPswe/PS1dE9), Porquet et al. (2014) found that treatment with resveratrol prevented memory loss (as measured by the object recognition test), reduced the amyloid burden and increased mitochondrial complex IV protein levels. These effects were mainly mediated by the increased activation of SIRT-1 and AMPK pathways.