Browsing by Subject "ISCHEMIC BRAIN-INJURY"

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  • Danilova, Tatiana; Lindahl, Maria (2018)
    Mesencephalic astrocyte-derived neurotrophic factor (MANF) was originally identified as a secreted trophic factor for dopamine neurons in vitro. It protects and restores damaged cells in rodent models of Parkinson's disease, brain and heart ischemia, spinocerebellar ataxia and retina in vivo. However, its exact mechanism of action is not known. MANF is widely expressed in most human and mouse organs with high levels in secretory tissues. Intracellularly, MANF localizes to the endoplasmic reticulum (ER) and ER stress increases it's expression in cells and tissues. Furthermore, increased MANF levels has been detected in the sera of young children with newly diagnosed Type 1 (T1D) diabetes and Type 2 (T2D) diabetic patients. ER stress is caused by the accumulation of misfolded and aggregated proteins in the ER. It activates a cellular defense mechanism, the unfolded protein response (UPR), a signaling cascade trying to restore ER homeostasis. However, if prolonged, unresolved ER stress leads to apoptosis. Unresolved ER stress contributes to the progressive death of pancreatic insulin-producing beta cells in both T1D and T2D. Diabetes mellitus is characterized by hyperglycemia, caused by the inability of the beta cells to maintain sufficient levels of circulating insulin. The current medications, insulin and antidiabetic drugs, alleviate diabetic symptoms but cannot reconstitute physiological insulin secretion which increases the risk of devastating vascular complications of the disease. Thus, one of the main strategies in improving current diabetes therapy is to define and validate novel approaches to protect beta cells from stress as well as activate their regeneration. Embryonic deletion of the Manf gene in mice led to gradual postnatal development of insulin-deficient diabetes caused by reduced beta cell proliferation and increased beta cell death due to increased and sustained ER stress. In vitro, recombinant MANF partly protected mouse and human beta cells from ER stress-induced beta cell death and potentiated mouse and human beta cell proliferation. Importantly, in vivo overexpression of MANF in the pancreas of T1D mice led to increased beta cell proliferation and decreased beta cell death, suggesting that MANF could be a new therapeutic candidate for beta cell protection and regeneration in diabetes.
  • Tseng, Kuan-Yin; Anttila, Jenni E.; Khodosevich, Konstantin; Tuominen, Raimo K.; Lindahl, Maria; Domanskyi, Andrii; Airavaara, Mikko (2018)
    Cerebral ischemia activates endogenous reparative processes, such as increased proliferation of neural stem cells (NSCs) in the subventricular zone (SVZ) and migration of neural progenitor cells (NPCs) toward the ischemic area. However, this reparative process is limited because most of the NPCs die shortly after injury or are unable to arrive at the infarct boundary. In this study, we demonstrate for the first time that endogenous mesencephalic astrocyte-derived neurotrophic factor (MANF) protects NSCs against oxygen-glucose-deprivation-induced injury and has a crucial role in regulating NPC migration. In NSC cultures, MANF protein administration did not affect growth of cells but triggered neuronal and glial differentiation, followed by activation of STAT3. In SVZ explants, MANF over expression facilitated cell migration and activated the STAT3 and ERK1/2 pathway. Using a rat model of cortical stroke, intracerebroventricular injections of MANF did not affect cell proliferation in the SVZ, but promoted migration of doublecortin (DCX)(+) cells toward the corpus callosum and infarct boundary on day 14 post-stroke. Long-term infusion of MANF into the per'-infarct zone increased the recruitment of DCX+ cells in the infarct area. In conclusion, our data demonstrate a neuroregenerative activity of MANF that facilitates differentiation and migration of NPCs, thereby increasing recruitment of neuroblasts in stroke cortex.
  • Mätlik, Kert; Anttila, Jenni E.; Kuan-Yin, Tseng; Smolander, Olli-Pekka; Pakarinen, Emmi; Lehtonen, Leevi; Abo-Ramadan, Usama; Lindholm, Päivi; Zheng, Congjun; Harvey, Brandon; Arumäe, Urmas; Lindahl, Maria; Airavaara, Mikko (2018)
    Stroke is the most common cause of adult disability in developed countries, largely because spontaneous recovery is often incomplete, and no pharmacological means to hasten the recovery exist. It was recently shown that mesencephalic astrocyte–derived neurotrophic factor (MANF) induces alternative or M2 activation of immune cells after retinal damage in both fruit fly and mouse and mediates retinal repair. Therefore, we set out to study whether poststroke MANF administration would enhance brain tissue repair and affect behavioral recovery of rats after cerebral ischemic injury. We used the distal middle cerebral artery occlusion (dMCAo) model of ischemia-reperfusion injury and administered MANF either as a recombinant protein or via adeno-associated viral (AAV) vector. We discovered that, when MANF was administered to the peri-infarct region 2 or 3 days after stroke, it promoted functional recovery of the animals without affecting the lesion volume. Further, AAV7-MANF treatment transiently increased the number of phagocytic macrophages in the subcortical peri-infarct regions. In addition, the analysis of knockout mice revealed the neuroprotective effects of endogenous MANF against ischemic injury, although endogenous MANF had no effect on immune cell–related gene expression. The beneficial effect of MANF treatment on the reversal of stroke-induced behavioral deficits implies that MANF-based therapies could be used for the repair of brain tissue after stroke.