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Increased survival of nigrostriatal dopaminergic neurons following a toxic MPTP insult in the exercising primate: A [11C]DTBZ PET study
Abstracts / NeuroImage 41 (2008) T14–T57
T55
Oral Presentation No.: O42
Increased survival of nigrostriatal dopaminergic neurons following a toxic MPTP insult in the exercising primate: A [ 11 C]DTBZ PET study Brian J. Lopresti,a Z. Zhang,b M.J. Zigmond,c R.K. Leak,c C.A. Mathis,a and J.L. Camerond,e a
b
University of Pittsburgh Department of Radiology, Pittsburgh, PA, USA University of Kentucky Department of Anatomy and Neurobiology, Lexington, KY, USA c University of Pittsburgh Department of Neurology, Pittsburgh, PA, USA d University of Pittsburgh Department of Psychiatry, Pittsburgh, PA, USA e Oregon Health and Science University, Portland, OR, USA
Introduction: Existing therapies for the treatment of Parkinson's disease (PD) offer only symptomatic relief. Current research efforts are focused on understanding the processes that ultimately result in the destruction of dopamine (DA) neurons and modulators of these processes, as these could ultimately lead to disease-modifying treatments for PD. Rodent studies suggest that physical exercise can stimulate mechanisms of neuroprotection, neurogenesis, synaptogenesis, angiogenesis, and the production of trophic factors, and also mitigate the destruction of nigrostriatal neurons following exposure to DA neurotoxins. The goal of the present work is to investigate whether and to what degree physical exercise in primates leads to plastic changes in the brain that may mitigate loss of DA neurons in PD and animal models of PD. Methods: Three adult female rhesus monkeys (15–20 years of age) were trained to run on a treadmill in a manner similar to that recommended clinically to promote cardiovascular fitness. One monkey was exercised at 60% of its maximum heart rate (HR) and the second monkey at 80% max HR for 3 months (1 h/ day, 5 days/week). The third monkey was placed on the treadmill, but did not exercise (sedentary). After 3 months, the monkeys were administered a mild dose of the DA neurotoxin 1,2,3,6-methyl-phenyl-tetrahydropyridine (MPTP; 0.8 mg) via a unilateral carotid injection. Following MPTP injection, the monkeys resumed their exercise regimens or sat on the treadmill for a period of seven weeks. Frequent assessments were conducted to quantify the severity of Parkinsonian-associated motor symptoms before MPTP injection and for 7 weeks thereafter. At 5–6 days post-MPTP, PET scanning was performed using the VMAT2 selective radioligand [11C]DTBZ and a microPET P4 scanner. [11C]DTBZ BPND values for ipsi- and contralateral caudate and putamen were computed using the non-invasive Logan analysis (cerebellar reference). At 7 weeks post-MPTP striatal brain tissue was collected for histological analyses, which included western blots for DA transporter (DAT), VMAT2, and tyrosine hydroxylase (TH) immunoreactivity, and HPLC assays for the presence of DA and its metabolites (DOPAC, HVA). Results: Reductions in [11C]DTBZ binding in ipsilateral caudate and putamen (relative to contralateral; see table) were greatest in the sedentary animal (50– 75%). However, the 80% max HR animal showed comparatively mild reductions in ipsilateral striatum (15–30%) while reductions in the 60% max HR animal were intermediate. Behavioral assessments of locomotor function post-MPTP showed striking differences. The sedentary animal did not use the left hand during the 7 weeks post-MPTP, while the 60% max HR animal regained partial use. In contrast, the 80% max HR animal showed no quantifiable motor impairments after the first day post-MPTP. Post-mortem analyses revealed profound losses of DAT, VMAT2, and TH immunoreactivity in the ipsilateral striatum of the sedentary animal. A less severe loss of ipsilateral TH immunoreactivity was observed in the 60% max HR animal, while the 80% max HR level showed marked preservation of TH, VMAT2, and DAT immunoreactivity. HPLC measurement of DA showed 90–95% losses of DA in ipsilateral putamen of the sedentary and 60% max HR animals, but only a 56% loss in the 80% max HR animal. Assays of striatal DOPAC and HVA showed virtually no hemispheric asymmetry (− 3.2%) in the 80% max HR animal. Conclusion: These findings are consistent with a neuroprotective effect of exercise on dopaminergic projections from the substantia nigra following intracarotid injection of MPTP in a primate exercising at a level that is often undertaken by people to improve health and fitness. [11C]DTBZ BPND
[11C]DTBZ BPND 80% max HR
Caudate Putamen
60% max HR
Sedentary
Ipsi
Contra
%Diff
Ipsi
Contra
%Diff
Ipsi
Contra
%Diff
2.50 2.58
2.89 3.29
− 15.5
1.79 1.79
2.96 2.70
−39.6 −33.6
1.15 0.54
2.30 2.20
−50.0 −75.2
− 27.29
Acknowledgments: This work was supported by Grants from NINDS (R21 NS053471), U. Pittsburgh Udall Center of Excellence (P50 NS19608). doi:10.1016/j.neuroimage.2008.04.229
T55
Oral Presentation No.: O42
Increased survival of nigrostriatal dopaminergic neurons following a toxic MPTP insult in the exercising primate: A [ 11 C]DTBZ PET study Brian J. Lopresti,a Z. Zhang,b M.J. Zigmond,c R.K. Leak,c C.A. Mathis,a and J.L. Camerond,e a
b
University of Pittsburgh Department of Radiology, Pittsburgh, PA, USA University of Kentucky Department of Anatomy and Neurobiology, Lexington, KY, USA c University of Pittsburgh Department of Neurology, Pittsburgh, PA, USA d University of Pittsburgh Department of Psychiatry, Pittsburgh, PA, USA e Oregon Health and Science University, Portland, OR, USA
Introduction: Existing therapies for the treatment of Parkinson's disease (PD) offer only symptomatic relief. Current research efforts are focused on understanding the processes that ultimately result in the destruction of dopamine (DA) neurons and modulators of these processes, as these could ultimately lead to disease-modifying treatments for PD. Rodent studies suggest that physical exercise can stimulate mechanisms of neuroprotection, neurogenesis, synaptogenesis, angiogenesis, and the production of trophic factors, and also mitigate the destruction of nigrostriatal neurons following exposure to DA neurotoxins. The goal of the present work is to investigate whether and to what degree physical exercise in primates leads to plastic changes in the brain that may mitigate loss of DA neurons in PD and animal models of PD. Methods: Three adult female rhesus monkeys (15–20 years of age) were trained to run on a treadmill in a manner similar to that recommended clinically to promote cardiovascular fitness. One monkey was exercised at 60% of its maximum heart rate (HR) and the second monkey at 80% max HR for 3 months (1 h/ day, 5 days/week). The third monkey was placed on the treadmill, but did not exercise (sedentary). After 3 months, the monkeys were administered a mild dose of the DA neurotoxin 1,2,3,6-methyl-phenyl-tetrahydropyridine (MPTP; 0.8 mg) via a unilateral carotid injection. Following MPTP injection, the monkeys resumed their exercise regimens or sat on the treadmill for a period of seven weeks. Frequent assessments were conducted to quantify the severity of Parkinsonian-associated motor symptoms before MPTP injection and for 7 weeks thereafter. At 5–6 days post-MPTP, PET scanning was performed using the VMAT2 selective radioligand [11C]DTBZ and a microPET P4 scanner. [11C]DTBZ BPND values for ipsi- and contralateral caudate and putamen were computed using the non-invasive Logan analysis (cerebellar reference). At 7 weeks post-MPTP striatal brain tissue was collected for histological analyses, which included western blots for DA transporter (DAT), VMAT2, and tyrosine hydroxylase (TH) immunoreactivity, and HPLC assays for the presence of DA and its metabolites (DOPAC, HVA). Results: Reductions in [11C]DTBZ binding in ipsilateral caudate and putamen (relative to contralateral; see table) were greatest in the sedentary animal (50– 75%). However, the 80% max HR animal showed comparatively mild reductions in ipsilateral striatum (15–30%) while reductions in the 60% max HR animal were intermediate. Behavioral assessments of locomotor function post-MPTP showed striking differences. The sedentary animal did not use the left hand during the 7 weeks post-MPTP, while the 60% max HR animal regained partial use. In contrast, the 80% max HR animal showed no quantifiable motor impairments after the first day post-MPTP. Post-mortem analyses revealed profound losses of DAT, VMAT2, and TH immunoreactivity in the ipsilateral striatum of the sedentary animal. A less severe loss of ipsilateral TH immunoreactivity was observed in the 60% max HR animal, while the 80% max HR level showed marked preservation of TH, VMAT2, and DAT immunoreactivity. HPLC measurement of DA showed 90–95% losses of DA in ipsilateral putamen of the sedentary and 60% max HR animals, but only a 56% loss in the 80% max HR animal. Assays of striatal DOPAC and HVA showed virtually no hemispheric asymmetry (− 3.2%) in the 80% max HR animal. Conclusion: These findings are consistent with a neuroprotective effect of exercise on dopaminergic projections from the substantia nigra following intracarotid injection of MPTP in a primate exercising at a level that is often undertaken by people to improve health and fitness. [11C]DTBZ BPND
[11C]DTBZ BPND 80% max HR
Caudate Putamen
60% max HR
Sedentary
Ipsi
Contra
%Diff
Ipsi
Contra
%Diff
Ipsi
Contra
%Diff
2.50 2.58
2.89 3.29
− 15.5
1.79 1.79
2.96 2.70
−39.6 −33.6
1.15 0.54
2.30 2.20
−50.0 −75.2
− 27.29
Acknowledgments: This work was supported by Grants from NINDS (R21 NS053471), U. Pittsburgh Udall Center of Excellence (P50 NS19608). doi:10.1016/j.neuroimage.2008.04.229