Browsing by Subject "NEUROPROTECTION"

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  • Leikas, Juuso V.; Kohtala, Samuel; Theilmann, Wiebke; Jalkanen, Aaro J.; Forsberg, Markus M.; Rantamaki, Tomi (2017)
    Parkinson's disease (PD) is a progressive neurodegenerative movement disorder primarily affecting the nigrostriatal dopaminergic system. The link between heightened activity of glycogen synthase kinase 3 beta (GSK313) and neurodegenerative processes has encouraged investigation into the potential disease-modifying effects of novel GSK3 beta inhibitors in experimental models of PD. Therefore, the intriguing ability of several anesthetics to readily inhibit GSK3 beta within the cortex and hippocampus led us to investigate the effects of brief isoflurane anesthesia on striatal GSK3 beta signaling in nave rats and in a rat model of early-stage PD. Deep but brief (20-min) isoflurane anesthesia exposure increased the phosphorylation of GSK3 beta at the inhibitory Ser9 residue, and induced phosphorylation of AKT(Thr308) (protein kinase B; negative regulator of GSK3 beta) in the striatum of naive rats and rats with unilateral striatal 6-hydroxydopamine (6-OHDA) lesion. The 6-OHDA protocol produced gradual functional deficiency within the nigrostriatal pathway, reflected as a preference for using the limb ipsilateral to the lesioned striatum at 2 weeks post 6-OHDA. Interestingly, such motor impairment was not observed in animals exposed to four consecutive isoflurane treatments (20-min anesthesia every 48 h; treatments started 7 days after 6-OHDA delivery). However, isoflurane had no effect on striatal or nigral tyrosine hydroxylase (a marker of dopaminergic neurons) protein levels. This brief report provides promising results regarding the therapeutic potential and neurobiological mechanisms of anesthetics in experimental models of PD and guides development of novel disease-modifying therapies.
  • Smedowski, Adrian; Akhtar, Saeed; Liu, Xiaonan; Pietrucha-Dutczak, Marita; Podracka, Lucia; Toropainen, Elisa; Alkanaan, Aljoharah; Ruponen, Marika; Urtti, Arto; Varjosalo, Markku; Kaarniranta, Kai; Lewin-Kowalik, Joanna (2020)
    Abstract Purpose To characterize newly discovered electrical synapses, formed by connexin (Cx) 36 and 45, between neighbouring axons within the optic nerve head. Methods Twenty-five Wistar rats were killed by CO2 inhalation. Proximal and distal optic nerve (ON) stumps were collected and processed for immunostainings, electron microscopy (EM) with immunogold labelling, PCR and Western blots (WB). Additional 15 animals were deeply anaesthetized, and flash visual evoked potentials (fVEP) after retrobulbar injection of saline (negative control) or 100 ?m meclofenamic acid solution (gap junctions? blocker) were recorded. Human paraffin cross-sections of eyeballs for immunostainings were obtained from the Human Eye Biobank for Research. Results Immunostainings of both rat and human ON revealed the presence of Cx45 and 36 colocalizing with ?3-tubulin, but not with glial fibrillary acidic protein (GFAP). In WB, Cx36 content in optic nerve was approximately halved when compared with retina (0.58 ± 0.005 in proximal stump and 0.44 ± 0.02 in distal stump), Cx45 showed higher levels (0.68 ± 0.01 in proximal stump and 0.9 ± 0.07 in distal stump). In immunogold-EM of optic nerve sections, we found electric synapses (formed mostly by Cx45) directly coupling neighbouring axons. In fVEP, blocking of gap junctions with meclofenamic acid resulted in significant prolongation of the latency of P1 wave up to 160% after 30 min (p 
  • Mahato, Arun Kumar; Kopra, Jaakko; Renko, Juho-Matti; Visnapuu, Tanel; Korhonen, Ilari; Pulkkinen, Nita; Bespalov, Maxim M.; Domanskyi, Andrii; Ronken, Eric; Piepponen, T. Petteri; Voutilainen, Merja H.; Tuominen, Raimo K.; Karelson, Mati; Sidorova, Yulia A.; Saarma, Mart (2020)
    Background Motor symptoms of Parkinson's disease (PD) are caused by degeneration and progressive loss of nigrostriatal dopamine neurons. Currently, no cure for this disease is available. Existing drugs alleviate PD symptoms but fail to halt neurodegeneration. Glial cell line-derived neurotrophic factor (GDNF) is able to protect and repair dopamine neurons in vitro and in animal models of PD, but the clinical use of GDNF is complicated by its pharmacokinetic properties. The present study aimed to evaluate the neuronal effects of a blood-brain-barrier penetrating small molecule GDNF receptor Rearranged in Transfection agonist, BT13, in the dopamine system. Methods We characterized the ability of BT13 to activate RET in immortalized cells, to support the survival of cultured dopamine neurons, to protect cultured dopamine neurons against neurotoxin-induced cell death, to activate intracellular signaling pathways both in vitro and in vivo, and to regulate dopamine release in the mouse striatum as well as BT13's distribution in the brain. Results BT13 potently activates RET and downstream signaling cascades such as Extracellular Signal Regulated Kinase and AKT in immortalized cells. It supports the survival of cultured dopamine neurons from wild-type but not from RET-knockout mice. BT13 protects cultured dopamine neurons from 6-Hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP+)-induced cell death only if they express RET. In addition, BT13 is absorbed in the brain, activates intracellular signaling cascades in dopamine neurons both in vitro and in vivo, and also stimulates the release of dopamine in the mouse striatum. Conclusion The GDNF receptor RET agonist BT13 demonstrates the potential for further development of novel disease-modifying treatments against PD. (c) 2019 International Parkinson and Movement Disorder Society