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Browsing by Subject "BDNF"

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  • Antila, Hanna (2012)
    Tissue plasminogen activator (tPA) is a serine protease that cleaves the inactive plasminogen to a broad-spectrum protease plasmin. Plasmin is involved in the degradation of blood clots by breaking down the fibrin network. In addition to it's role in the fibrinolytic system, tPA participates in the functions of the central nervous system. tPA is expressed in several brain areas and has been shown to be involved in neuronal plasticity. tPA's effects on brain plasticity are mediated in part via degradation of extracellular matrix proteins, but mainly via processing of brain-derived neurotrophic factor (BDNF). Plasmin cleaves pro-BDNF into BDNF that serves as primary endogenous ligand for TrkB neurotrophin receptor. TrkB signalling is strongly associated with the regulation of neuronal plasticity such as neurogenesis, synaptogenesis and long-term potentiation (LTP). On the contrary, pro-BDNF binds and activates p75 neurotrophin receptor that regulates many distinct, even opposite, effects on neuronal plasticity such as long-term depression and synapse refraction. Enhancement of brain plasticity is considered to be important for the therapeutic effects of antidepressant drugs and this is at least partially mediated via BDNF. Antidepressants activate TrkB receptors and increase BDNF protein levels in the rodent brain but the mechanism behind this remains obscure. Given that tPA is an important factor in the processing of BDNF, it is a possible mediator for antidepressants' neurotrophic effects. The effects of antidepressants on tPA activity have been previously studied only in the blood circulatory system. The aim of the experimental part of this Master's thesis was to examine the effects of antidepressant fluoxetine on tPA activity and protein levels in mouse hippocampus. Also the effects of fluoxetine on BDNF-TrkB signalling were studied. Fluoxetine was administered to mice acutely (30 mg/kg, i.p., 1 h) and chronically (0,08 mg/ml in drinking water, 3 weeks). tPA activity was studied using SDS-PAGE - and in situzymographies. TrkB activation, tPA and BDNF protein levels were measured using western blot. BDNF protein levels were also examined with ELISA method. No changes in tPA activity were found after acute fluoxetine treatment. In line with this result is the observation that also the BDNF levels remained unchanged. However, TrkB receptor activity was increased in fluoxetine treated mice. It seems possible that BDNF is not involved in the TrkB activation caused by acute fluoxetine treatment. Chronic fluoxetine treatment caused a significant increase in the BDNF protein levels compared to water-drinking control mice. This was not, however, associated with significant changes in TrkB activity. No changes in tPA activity were observed, which suggests that tPA is not involved in the increase of BDNF levels after chronic fluoxetine treatment. Interestingly, tPA antibody detected three distinct proteins in western blot of whose levels acute fluoxetine treatment regulated. However, more studies are needed to identify these proteins and to reveal the significance of such an effect of fluoxetine. According to this study, neither acute nor chronic fluoxetine treatment affects tPA activity in mouse hippocampus. However, environmental enrichment has been shown to enhance tPA activity and produce similar neurotrophic effects as chronic fluoxetine treatment. Therefore the result of this study concerning effect of chronic antidepressant treatment on tPA activity should be verified.
  • Rosenholm, Marko (2016)
    Pharmacologically induced neuronal plasticity holds unprecedented potential in treatment of several neurological disorders, such as depression. Several antidepressant drugs have been shown to induce neuronal plasticity by stimulating BDNF (brain-derived neurotrophic factor) receptor TrkB (tropomyosin receptor kinase B). Studies with rapid-acting antidepressant treatments suggest delta range slow wave EEG (electroencephalography) activity to function as a potential non-invasive biomarker for activation of TrkB-related neuroplastic signaling responses. A sedative GABAA-agonist THIP (gaboxadol) has been shown to induce slow wave EEG activity (SWA) and preliminary studies suggest it to activate TrkB signaling as well. The aim of the present study was to examine the potential connection between SWA, neuroplastic signaling responses and neuronal inhibition by utilizing EEG measurements and THIP administration in genetic and developmental mouse models. The pharmaco-EEG experiments showed acute THIP administration (6 mg/kg, i.p.) to increase SWA in wild-type but not in GABAA δ-subunit knockout mice. TrkB signaling responses from similar treatment groups showed a trend of increased TrkB-related protein phosphorylation in wild-type but not in GABAA δ-subunit knockout mice indicating a positive connection between SWA, neuronal inhibition and TrkB-related signaling response. Autophosphorylation response of TrkB and related proteins in mice of different age showed most TrkB phosphorylation in postnatal day 16 (P16) mouse pups, whereas phosphorylation response of CREB and p70S6k was the highest in postnatal day 8 (P8) mouse pups. Since SWA emerges during the second postnatal week in mice, the obtained result further supports the connection between SWA and TrkB signaling. Acute THIP administration caused no significant phosphorylation changes in P8 or P16 mouse pups. The results support the hypothesis of a positive connection between SWA, neuronal inhibition and TrkB-related signaling response. Further studies with different excitatory and inhibitory interventions are required to better understand the role of neuronal excitation and inhibition in TrkB signaling responses and corresponding EEG signatures.
  • Anttila, Jenni (2013)
    Brain-derived neurotrophic factor (BDNF) and the receptor mediating its effects, neurotrophin receptor TrkB, seem to have a role in the pathophysiology and treatment of mood disorders such as depression and mania. BDNF is a neurotrophin that regulates the differentiation and survival of neurons and mediates neuronal plasticity. Lithium and valproate are mood stabilizing agents that are commonly used to treat mania but their mechanism of action is still unclear. However, both acute and chronic lithium treatment have been shown to activate TrkB receptor in the rodent anterior cingulate cortex. It has also been shown that chronic lithium and valproate treatment increase the amount of BDNF in the rodent brain. The aim of the experimental part of this master's thesis was to find out what are the effects of lithium and valproate on TrkB receptor activation and on the amount of intracellular BDNF protein levels in vitro on embryonic day 18 (E18) rat primary cortical neurons. In addition, the possible role of neuronal maturation was investigated by conducting the experiments with neuronal cultures aged 7 and 21 days in vitro. The research methods included two different types of enzyme linked immunosorbent assays (ELISA), phospho-Trk ELISA and BDNF ELISA. Western blot was used to confirm the results. Therapeutically relevant concentration of lithiumchloride and valproate blocked BDNFinduced TrkB receptor phosphorylation in immature neurons aged 7 days in vitro. The effect of valproate was detected only with ELISA. In contrast, therapeutically relevant concentration of valproate increased TrkB receptor phosphorylation in immature neurons after one hour treatment. Lithium and valproate did not regulate TrkB receptor phosphorylation in mature neurons aged 21 days in vitro. However, therapeutically relevant concentration of lithium increased BDNF protein content in mature neurons after 24 hours treatment. Therapeutically relevant concentration of valproate did not alter BDNF protein levels. In conclusion, neuronal maturation does have a role on the effects of lithium and valproate on TrkB receptor activation and regulation of BDNF protein levels. It is possible that lithium and valproate are harmful to immature neurons through blocking BDNF-induced TrkB receptor phosphorylation. Since therapeutically relevant concentration of lithium did not activate TrkB receptor as has been shown previously in vivo it seems that certain developmental processes are essential for lithium-induced TrkB receptor activation.