A Potential Compensatory Role for Endogenous Striatal Tyrosine Hydroxylase-Positive Neurons in a Nonhuman Primate Model of Parkinson's Disease
The possibility of enhancing endogenous brain repair following neurological disorders, such as Parkinson's disease (PD), is of considerable recent interest. One such mechanism may exist in the striatum as an upregulated population of tyrosine hydroxylase (TH)-immunoreactive neurons that appear...
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doaj-4f2334f7ff554903ad2bf74aaa3b75b52020-11-25T03:24:08ZengSAGE PublishingCell Transplantation0963-68971555-38922015-04-012410.3727/096368915X687741A Potential Compensatory Role for Endogenous Striatal Tyrosine Hydroxylase-Positive Neurons in a Nonhuman Primate Model of Parkinson's DiseaseAndrew N. Bubak0D. Eugene Redmond1John D. Elsworth2Robert H. Roth3Timothy J. Collier4Kimberly B. Bjugstad5Barbara C. Blanchard6John R. Sladek7 Neuroscience Program, University of Colorado-Denver Anschutz Medical Campus, Denver, CO, USA Psychiatry and Neurosurgery, Yale University School of Medicine, New Haven, CT, USA Psychiatry, Yale University School of Medicine, New Haven, CT, USA Psychiatry, Yale University School of Medicine, New Haven, CT, USA Translational Science and Molecular Medicine, Michigan State University, East Lansing, MI, USA Department of Medicine, University of Colorado-Denver Anschutz Medical Campus, Denver, CO, USA Neurology and Pediatrics, University of Colorado-Denver Anschutz Medical Campus, Denver, CO, USA Neurology and Pediatrics, University of Colorado-Denver Anschutz Medical Campus, Denver, CO, USAThe possibility of enhancing endogenous brain repair following neurological disorders, such as Parkinson's disease (PD), is of considerable recent interest. One such mechanism may exist in the striatum as an upregulated population of tyrosine hydroxylase (TH)-immunoreactive neurons that appear after 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) lesions in nonhuman primates as well as in humans with PD. An intriguing possibility is that these endogenous neurons reflect a compensatory mechanism to mitigate the loss of striatal DA due to progressive destruction of the nigrostriatal pathway. The possibility of enhancing the number and function of this population is attractive; however, it is crucial to gain further information about these cells in order to comprehend more fully their possible therapeutic potential. The current research was designed to investigate the fate of this endogenous population in African green monkeys rendered parkinsonian by MPTP lesions. Specifically, we assessed changes in the numbers of striatal neurons expressing TH at differing stages of the toxin-induced behavioral disability and discovered a close relationship with symptom severity and striatal DA neuron numbers. Increased numbers of striatal TH-positive neurons were associated with MPTP treatment that produced parkinsonian symptoms compared to numbers of these neurons in MPTP-treated asymptomatic animals and untreated controls. Expression of striatal DA neurons peaked at the manifestation of symptoms in mild/moderate animals and remained stable in animals that were severely parkinsonian. Furthermore, in severely debilitated animals that improved after fetal dopaminergic grafts, we discovered a return to control levels of the endogenous population. Taken together, our results further support the concept that this population of DA neurons responds to variations in striatal DA tone and may serve as a compensatory mechanism to restore striatal DA levels in the context of significant depletion. Artificially manipulating this endogenous population could prove beneficial for PD treatment, especially for individuals in early disease stages.https://doi.org/10.3727/096368915X687741 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Andrew N. Bubak D. Eugene Redmond John D. Elsworth Robert H. Roth Timothy J. Collier Kimberly B. Bjugstad Barbara C. Blanchard John R. Sladek |
spellingShingle |
Andrew N. Bubak D. Eugene Redmond John D. Elsworth Robert H. Roth Timothy J. Collier Kimberly B. Bjugstad Barbara C. Blanchard John R. Sladek A Potential Compensatory Role for Endogenous Striatal Tyrosine Hydroxylase-Positive Neurons in a Nonhuman Primate Model of Parkinson's Disease Cell Transplantation |
author_facet |
Andrew N. Bubak D. Eugene Redmond John D. Elsworth Robert H. Roth Timothy J. Collier Kimberly B. Bjugstad Barbara C. Blanchard John R. Sladek |
author_sort |
Andrew N. Bubak |
title |
A Potential Compensatory Role for Endogenous Striatal Tyrosine Hydroxylase-Positive Neurons in a Nonhuman Primate Model of Parkinson's Disease |
title_short |
A Potential Compensatory Role for Endogenous Striatal Tyrosine Hydroxylase-Positive Neurons in a Nonhuman Primate Model of Parkinson's Disease |
title_full |
A Potential Compensatory Role for Endogenous Striatal Tyrosine Hydroxylase-Positive Neurons in a Nonhuman Primate Model of Parkinson's Disease |
title_fullStr |
A Potential Compensatory Role for Endogenous Striatal Tyrosine Hydroxylase-Positive Neurons in a Nonhuman Primate Model of Parkinson's Disease |
title_full_unstemmed |
A Potential Compensatory Role for Endogenous Striatal Tyrosine Hydroxylase-Positive Neurons in a Nonhuman Primate Model of Parkinson's Disease |
title_sort |
potential compensatory role for endogenous striatal tyrosine hydroxylase-positive neurons in a nonhuman primate model of parkinson's disease |
publisher |
SAGE Publishing |
series |
Cell Transplantation |
issn |
0963-6897 1555-3892 |
publishDate |
2015-04-01 |
description |
The possibility of enhancing endogenous brain repair following neurological disorders, such as Parkinson's disease (PD), is of considerable recent interest. One such mechanism may exist in the striatum as an upregulated population of tyrosine hydroxylase (TH)-immunoreactive neurons that appear after 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) lesions in nonhuman primates as well as in humans with PD. An intriguing possibility is that these endogenous neurons reflect a compensatory mechanism to mitigate the loss of striatal DA due to progressive destruction of the nigrostriatal pathway. The possibility of enhancing the number and function of this population is attractive; however, it is crucial to gain further information about these cells in order to comprehend more fully their possible therapeutic potential. The current research was designed to investigate the fate of this endogenous population in African green monkeys rendered parkinsonian by MPTP lesions. Specifically, we assessed changes in the numbers of striatal neurons expressing TH at differing stages of the toxin-induced behavioral disability and discovered a close relationship with symptom severity and striatal DA neuron numbers. Increased numbers of striatal TH-positive neurons were associated with MPTP treatment that produced parkinsonian symptoms compared to numbers of these neurons in MPTP-treated asymptomatic animals and untreated controls. Expression of striatal DA neurons peaked at the manifestation of symptoms in mild/moderate animals and remained stable in animals that were severely parkinsonian. Furthermore, in severely debilitated animals that improved after fetal dopaminergic grafts, we discovered a return to control levels of the endogenous population. Taken together, our results further support the concept that this population of DA neurons responds to variations in striatal DA tone and may serve as a compensatory mechanism to restore striatal DA levels in the context of significant depletion. Artificially manipulating this endogenous population could prove beneficial for PD treatment, especially for individuals in early disease stages. |
url |
https://doi.org/10.3727/096368915X687741 |
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