Browsing by Subject "NIGROSTRIATAL DOPAMINE SYSTEM"

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  • Huotarinen, Antti; Penttinen, Anna-Maija; Bäck, Susanne; Voutilainen, Merja H.; Julku, Ulrika; Piepponen, T. Petteri; Männistö, Pekka T.; Saarma, Mart; Tuominen, Raimo; Laakso, Aki; Airavaara, Mikko (2018)
    Several neurotrophic factors ( NTF) are shown to be neuroprotective and neurorestorative in pre-clinical animal models for Parkinson's disease ( PD), particularly in models where striatal dopamine neuron innervation partially exists. The results of clinical trials on late-stage patients have been modest. Subthalamic deep brain stimulation ( STN DBS) is a proven treatment for a selected group of advanced PD patients. The cerebral dopamine neurotrophic factor ( CDNF) is a promising therapeutic protein, but its effects in animal models of late-stage PD have remained under-researched. The interactions of NTF and STN DBS treatments have not been studied before. We found that a nigral CDNF protein alone had only a marginal effect on the behavioral deficits in a late-stage hemiparkinsonian rat model ( 6-OHDA MFB). However, CDNF improved the effect of acute STN DBS on front limb use asymmetry at 2 and 3 weeks after CDNF injection. STN lesion-modeling chronic stimulation-had an additive effect in reducing front limb use in the cylinder test and apomorphine-induced rotation. The combination of CDNF and acute STN DBS had a favorable effect on striatal tyrosine hydroxylase. This study presents a novel additive beneficial effect of NTF and STN DBS, which might be explained by the interaction of DBS-induced endogenous NTFs and exogenously injected CDNF. SNpc can be reached via similar trajectories used in clinical STN DBS, and this interaction is an important area for future studies. (C) 2018 The Authors. Published by Elsevier Ltd on behalf of IBRO. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).
  • Glerup, Simon; Lume, Maria; Olsen, Ditte; Nyengaard, Jens R.; Vaegter, Christian B.; Gustafsen, Camilla; Christensen, Erik I.; Kjolby, Mads; Hay-Schmidt, Anders; Bender, Dirk; Madsen, Peder; Saarma, Mart; Nykjaer, Anders; Petersen, Claus M. (2013)
  • Mätlik, Kärt; Võikar, Vootele; Vilenius, Carolina; Kulesskaya, Natalia; Andressoo, Jaan-Olle (2018)
    Glial cell line-derived neurotrophic factor (GDNF) promotes the survival of dopaminergic neurons in vitro and in vivo. For this reason, GDNF is currently in clinical trials for the treatment of Parkinson’s disease (PD). However, how endogenous GDNF influences dopamine system function and animal behavior is not fully understood. We recently generated GDNF hypermorphic mice that express increased levels of endogenous GDNF from the native locus, resulting in augmented function of the nigrostriatal dopamine system. Specifically, Gdnf wt/hyper mice have a mild increase in striatal and midbrain dopamine levels, increased dopamine transporter activity, and 15% increased numbers of midbrain dopamine neurons and striatal dopaminergic varicosities. Since changes in the dopamine system are implicated in several neuropsychiatric diseases, including schizophrenia, attention deficit hyperactivity disorder (ADHD) and depression, and ectopic GDNF delivery associates with side-effects in PD models and clinical trials, we further investigated Gdnf wt/hyper mice using 20 behavioral tests. Despite increased dopamine levels, dopamine release and dopamine transporter activity, there were no differences in psychiatric disease related phenotypes. However, compared to controls, male Gdnf wt/hyper mice performed better in tests measuring motor function. Therefore, a modest elevation of endogenous GDNF levels improves motor function but does not induce adverse behavioral outcomes.