Neuronal dysfunction, death and repair in the MPTP model of Parkinson's disease
Author: Delfani, Kioumars
Date: 2002-06-10
Location: Hillarpsalen, Retzius väg 8
Time: 9.00
Department: Institutionen för neurovetenskap / Department of Neuroscience
Abstract
We have used mouse and non-human primate models of Parkinson's Disease to analyze neuronal dysfunction, death and repair in the mammalian brain, utilizing the neurotoxin 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP).
In a series of experiments we assessed the effects of diethyIdithiocarbamate (DDC) on MPTP toxicity, analyzing striatal and midbrain dopamine levels as well as neuronal loss. We found that a single low dose of MPTP failed to produce any histological or neurochernical effects on the nigrostriatal dopamine system. However, in combination with MC the resulting degeneration was similar to a full-blown effect of a maximally tolerated MPTP dose, which may have clinical implications since DDC-like structures have been suggested to be linked to Parkinsonism.
Another study focused on the relation between MPTP-induced failure in energy metabolism and neuronal loss, evaluating the neuroprotective role of 7-nitroindazole (7-NI). Our results indicate a close relationship between initial striatal ATP loss within the first hours after toxin administration and nigral neuronal death. Although the mechanism of neuroprotection by 7-NI points to a possible involvement of neuronal nitric oxide synthase (nNOS) activity in nigral neuronal death, the results are also compatible with inhibition of the enzyme MAO-B that converts MPTP into its toxic metabolite MPP+, since lower levels of the substance inducing neuronal injury would lead to a less pronounced lesion.
In a non-human primate study we analyzed the dose-response effects on nigral nerve cell loss after a single dose of MPTP, in doses lower than those inducing clinical Parkinsonism in squirrel monkeys. The same animals were analyzed in vivo with PET and post mortem with biochemical methods studying the nerve terminal regions in the forebrain of the nigral projection neurons. Surprisingly, nigral nerve cell loss was found to occur before nerve terminal function was affected by the neurotoxin, which is contrary to the hypothesis the MPTP toxicity leads to neurons 'dying-back', i.e. that neurodegeneration starts at the nerve terminal region before nerve cells in the midbrain are affected.
The mechanism and time course of dopaminergic cell loss in substantia nigra after a single dose of MPTP was studied in detail in the mouse. We have found evidence for apoptotic-like mechanisms in the dying dopamine neurons, with an in vivo time course that is considerably slower than apoptosis in the embryonic brain or non- mammalian CNS. Further studies on these apoptotic mechanisms as well as on the functional implications of preventing neuronal apoptosis may lead to the development of new treatment strategies for human neurodegenerative disorders.
Interestingly, nigral nerve cell death through apoptosis can be seen also in adult mice during physiological conditions, although this phenomenon involves a small fraction of the entire dopaminergic nerve cell population in substantia nigra. The paradoxical finding that the size of the nigral nerve cell population remains constant during the life span of a mouse, led us to hypothesize that new neurons are added to match cell numbers. Most neurons have been thought to be generated before birth in mammals and neurogenesis has only been described in a few regions in the adult brain. In a manuscript we provide evidence for generation of dopaminergic projection neurons of the type that are lost in Parkinson's disease from stem cells in the adult rodent brain and show that the rate of neurogenesis is increased after a lesion. These data indicate that neurogenesis in the adult brain is more widespread than previously thought and may have implications for our understanding of the pathogenesis and treatment of neurodegenerative disorders such as Parkinson's disease.
The origin of newly generated dopaminergic neurons was further analyzed in a transplantation study. We grafted fetal ventral mesencephalic tissue from transgenic mice, where all cells express green fluorescent protein (EGFP+). The grafts where placed within the right lateral ventricle to allow interaction with putative adult neural stem cells in the ependymal layer in adult wild-type mice, after an MPTP-lesion of the host nigrostriatal dopamine system. Several weeks later, tyrosine hydroxylase inummoreactive (TH+) neurons not expressing the transgenic marker (EGFP-) were found within the graft. To address the possibility that the GFP signal may be down-regulated in TH+ neurons, we also used an inverted experimental design, i.e. wild-type fetal transplants in lesioned, adult transgenic mice. We propose that the host-derived neurons in the transplant originate from the lateral ventricular wall, triggered by the presence of factors promoting neurogenesis in the fetal midbrain transplant and the partial lesion of the host nigrostriatal dopamine system.
In a series of experiments we assessed the effects of diethyIdithiocarbamate (DDC) on MPTP toxicity, analyzing striatal and midbrain dopamine levels as well as neuronal loss. We found that a single low dose of MPTP failed to produce any histological or neurochernical effects on the nigrostriatal dopamine system. However, in combination with MC the resulting degeneration was similar to a full-blown effect of a maximally tolerated MPTP dose, which may have clinical implications since DDC-like structures have been suggested to be linked to Parkinsonism.
Another study focused on the relation between MPTP-induced failure in energy metabolism and neuronal loss, evaluating the neuroprotective role of 7-nitroindazole (7-NI). Our results indicate a close relationship between initial striatal ATP loss within the first hours after toxin administration and nigral neuronal death. Although the mechanism of neuroprotection by 7-NI points to a possible involvement of neuronal nitric oxide synthase (nNOS) activity in nigral neuronal death, the results are also compatible with inhibition of the enzyme MAO-B that converts MPTP into its toxic metabolite MPP+, since lower levels of the substance inducing neuronal injury would lead to a less pronounced lesion.
In a non-human primate study we analyzed the dose-response effects on nigral nerve cell loss after a single dose of MPTP, in doses lower than those inducing clinical Parkinsonism in squirrel monkeys. The same animals were analyzed in vivo with PET and post mortem with biochemical methods studying the nerve terminal regions in the forebrain of the nigral projection neurons. Surprisingly, nigral nerve cell loss was found to occur before nerve terminal function was affected by the neurotoxin, which is contrary to the hypothesis the MPTP toxicity leads to neurons 'dying-back', i.e. that neurodegeneration starts at the nerve terminal region before nerve cells in the midbrain are affected.
The mechanism and time course of dopaminergic cell loss in substantia nigra after a single dose of MPTP was studied in detail in the mouse. We have found evidence for apoptotic-like mechanisms in the dying dopamine neurons, with an in vivo time course that is considerably slower than apoptosis in the embryonic brain or non- mammalian CNS. Further studies on these apoptotic mechanisms as well as on the functional implications of preventing neuronal apoptosis may lead to the development of new treatment strategies for human neurodegenerative disorders.
Interestingly, nigral nerve cell death through apoptosis can be seen also in adult mice during physiological conditions, although this phenomenon involves a small fraction of the entire dopaminergic nerve cell population in substantia nigra. The paradoxical finding that the size of the nigral nerve cell population remains constant during the life span of a mouse, led us to hypothesize that new neurons are added to match cell numbers. Most neurons have been thought to be generated before birth in mammals and neurogenesis has only been described in a few regions in the adult brain. In a manuscript we provide evidence for generation of dopaminergic projection neurons of the type that are lost in Parkinson's disease from stem cells in the adult rodent brain and show that the rate of neurogenesis is increased after a lesion. These data indicate that neurogenesis in the adult brain is more widespread than previously thought and may have implications for our understanding of the pathogenesis and treatment of neurodegenerative disorders such as Parkinson's disease.
The origin of newly generated dopaminergic neurons was further analyzed in a transplantation study. We grafted fetal ventral mesencephalic tissue from transgenic mice, where all cells express green fluorescent protein (EGFP+). The grafts where placed within the right lateral ventricle to allow interaction with putative adult neural stem cells in the ependymal layer in adult wild-type mice, after an MPTP-lesion of the host nigrostriatal dopamine system. Several weeks later, tyrosine hydroxylase inummoreactive (TH+) neurons not expressing the transgenic marker (EGFP-) were found within the graft. To address the possibility that the GFP signal may be down-regulated in TH+ neurons, we also used an inverted experimental design, i.e. wild-type fetal transplants in lesioned, adult transgenic mice. We propose that the host-derived neurons in the transplant originate from the lateral ventricular wall, triggered by the presence of factors promoting neurogenesis in the fetal midbrain transplant and the partial lesion of the host nigrostriatal dopamine system.
List of papers:
I. Walters TL, Irwin I, Delfani K, Langston JW, Janson AM (1999). Diethyldithiocarbamate causes nigral cell loss and dopamine depletion with nontoxic doses of MPTP. Exp Neurol. 156(1): 62-70.
Pubmed
II. Royland JE, Delfani K, Langston JW, Janson AM, Di Monte DA (1999). 7-Nitroindazole prevents 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-induced ATP loss in the mouse striatum. Brain Res. 839(1): 41-8.
Pubmed
III. Yee RE, Irwin I, Milonas C, Stout DB, Huang SC, Shoghi-Jadid K, Satyamurthy N, Delanney LE, Togasaki DM, Farahani KF, Delfani K, Janson AM, Phelps ME, Langston JW, Barrio JR (2001). Novel observations with FDOPA-PET imaging after early nigrostriatal damage. Mov Disord. 16(5): 838-48.
Pubmed
IV. Delfani K, Janson AM (2002). The death and dying of neurons in a defined region of the lesioned adult mammalian brain. [Submitted]
V. Delfani K, Zhao M, Brismar H, Bjorklund LM, Janson AM (2002). Host-derived tyrosine hydroxylase immunoreactive neurons in fetal ventral mesencephalic grafts placed in the lateral ventricle of adult MPTP-lesioned C57BL/6 mice. [Manuscript]
VI. Zhao M, Momma S, Delfani K, Cassidy RM, Carlen M, Johansson CB, Brismar H, Frisen J, Janson AM (2002). Neurogenesis in the adult mammalian substantia nigra. [Submitted]
I. Walters TL, Irwin I, Delfani K, Langston JW, Janson AM (1999). Diethyldithiocarbamate causes nigral cell loss and dopamine depletion with nontoxic doses of MPTP. Exp Neurol. 156(1): 62-70.
Pubmed
II. Royland JE, Delfani K, Langston JW, Janson AM, Di Monte DA (1999). 7-Nitroindazole prevents 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-induced ATP loss in the mouse striatum. Brain Res. 839(1): 41-8.
Pubmed
III. Yee RE, Irwin I, Milonas C, Stout DB, Huang SC, Shoghi-Jadid K, Satyamurthy N, Delanney LE, Togasaki DM, Farahani KF, Delfani K, Janson AM, Phelps ME, Langston JW, Barrio JR (2001). Novel observations with FDOPA-PET imaging after early nigrostriatal damage. Mov Disord. 16(5): 838-48.
Pubmed
IV. Delfani K, Janson AM (2002). The death and dying of neurons in a defined region of the lesioned adult mammalian brain. [Submitted]
V. Delfani K, Zhao M, Brismar H, Bjorklund LM, Janson AM (2002). Host-derived tyrosine hydroxylase immunoreactive neurons in fetal ventral mesencephalic grafts placed in the lateral ventricle of adult MPTP-lesioned C57BL/6 mice. [Manuscript]
VI. Zhao M, Momma S, Delfani K, Cassidy RM, Carlen M, Johansson CB, Brismar H, Frisen J, Janson AM (2002). Neurogenesis in the adult mammalian substantia nigra. [Submitted]
Issue date: 2002-05-20
Publication year: 2002
ISBN: 91-7349-258-2
Statistics
Total Visits
Views | |
---|---|
Neuronal ...(legacy) | 287 |
Neuronal ... | 146 |
Total Visits Per Month
September 2023 | October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | |
---|---|---|---|---|---|---|---|
Neuronal ... | 0 | 5 | 1 | 0 | 2 | 0 | 1 |
Top country views
Views | |
---|---|
United States | 68 |
Sweden | 56 |
Germany | 48 |
China | 46 |
South Korea | 18 |
Ireland | 8 |
Finland | 6 |
France | 4 |
Canada | 3 |
Denmark | 3 |
Top cities views
Views | |
---|---|
Kiez | 15 |
Seoul | 11 |
Shenzhen | 10 |
Sunnyvale | 10 |
Beijing | 8 |
Dublin | 8 |
Norrköping | 5 |
Des Moines | 4 |
Frankfurt am Main | 4 |
Mountain View | 4 |