Metformin accelerates myelin recovery and ameliorates behavioral deficits in the animal model of multiple sclerosis via adjustment of AMPK/Nrf2/mTOR signaling and maintenance of endogenous oligodendrogenesis during brain self-repairing period

BACKGROUND: Multiple sclerosis (MS) is a devastating autoimmune disorder characterized by oligodendrocytes (OLGs) loss and demyelination. In this study, we have examined the effects of metformin (MET) on the oligodendrogenesis, redox signaling, apoptosis, and glial responses during a self-repairing period (1-week) in the animal model of MS. METHODS: For induction of demyelination, C57BL/6 J mice were fed a 0.2% cuprizone (CPZ) for 5 weeks. Thereafter, CPZ was removed for 1-week and molecular and behavioral changes were monitored in the presence or absence of MET (50 mg/kg body weight/day). RESULTS: MET remarkably increased the localization of precursor OLGs (NG2+/O4+ cells) and subsequently the renewal of mature OLGs (MOG+ cells) in the corpus callosum via AMPK/mammalian target of rapamycin (mTOR) pathway. Moreover, we observed a significant elevation in the antioxidant responses, especially in mature OLGs (MOG+/nuclear factor erythroid 2-related factor 2 (Nrf2+) cells) after MET intervention. MET also reduced brain apoptosis markers and lessened motor dysfunction in the open-field test. While MET was unable to decrease active astrogliosis (GFAP mRNA), it reduced microgliosis by down-regulation of Mac-3 mRNA a marker of pro-inflammatory microglia/macrophages. Molecular modeling studies, likewise, confirmed that MET exerts its effects via direct interaction with AMPK. CONCLUSIONS: Altogether, our study reveals that MET effectively induces lesion reduction and elevated molecular processes that support myelin recovery via direct activation of AMPK and indirect regulation of AMPK/Nrf2/mTOR pathway in OLGs. These findings facilitate the development of new therapeutic strategies based on AMPK activation for MS in the near future. KEYWORDS: AMPK; Cuprizone; Multiple sclerosis; Nrf2; mTO

Dalteparin as a Novel Therapeutic Agent to Prevent Diabetic Encephalopathy by Targeting Oxidative Stress and Inflammation

Introduction: Hepcidin is the main modulator of systemic iron metabolism, and its role in the brain has been clarified recently. Studies have shown that hepcidin plays an important role in neuronal iron load and inflammation. This issue is of significance because neuronal iron load and inflammation are pathophysiological processes that are highly linked to neurodegeneration. Moreover, the activity of hepcidin has recently been manipulated to recover the neuronal impairment caused by brain inflammation in animal models. Methods: Streptozotocin (STZ) was used to induce type 1 diabetes. Male Wistar rats (n = 40) with a weight range of 200–250 g were divided into control, diabetic, diabetic + insulin, and diabetic + dalteparin groups. Dalteparin (100 mg/kg IP) and insulin (100 mg/kg SC) were administered for 8 weeks. At the end of the experiment, Y-maze and passive avoidance tasks were carried out. The animals were perfused randomly and their hippocampal tissue was isolated for the analysis of markers such as lipid peroxidation like Malondialdehyde (MDA), hepcidin expression, iron, and ferritin. Blood samples were taken for the measurement of serum inflammatory cytokine Interleukin (IL)-6. Results: The findings indicated that treatment with dalteparin reduced IL-6, MDA, ferritin, and hepcidin expression in diabetic rats compared to treatment with insulin (P<0.05). Moreover, treatment with dalteparin did not decrease the iron level or prevented its decline. Conclusion: Treatment with dalteparin improved the cognitive dysfunctions and symptoms of Alzheimer disease in STZ-induced diabetic rats by appropriately modulating and reducing oxidative stress and neuroinflammation. This may enhance the existing knowledge of therapeutics to reduce cognitive impairment in diabetes and is suggested to be a potential therapeutic agent in diabetes

Bosutinib therapy through the TGF-ß1 signaling pathway activity can increase apoptosis of BCR-ABL oncogene positive cells

Abstract The authors have requested that this preprint be removed from Research Square.</jats:p