Pinhole SPECT imaging of dopamine transporters correlates with dopamine transporter immunohistochemical analysis in the MPTP mouse model of Parkinson's disease.
The in vivo analysis of dopaminergic degeneration in animal models of Parkinson's disease (PD), using pinhole single photon emission computed tomography (SPECT), ideally should afford a serial study design, enabling the analysis of the degenerative process as well as the potential neuroprotective and/or restorative properties of drugs over time in living animals. Previously, we demonstrated that striatal dopamine transporter (DAT) levels in rats could be analyzed reproducibly, using pinhole SPECT with the DAT probe [(123)I]N-omega-fluoropropyl-2beta-carbomethoxy-3beta-{4-iodophenyl}nortropane (FP-CIT). However, the capacity of this approach to accurately detect a range of striatal DAT levels in the most widely used animal model of PD, i.e., the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mouse, remains to be determined. For this purpose, various levels of DAT were induced by treating c57BL/6J mice for 1, 3, or 5 days with MPTP (25 mg/kg ip), respectively. [(123)I]FP-CIT SPECT scans were performed 5 days after the last MPTP injection. Mice were perfused 6 days after the last MPTP injection, and the SPECT data were compared to ex vivo striatal and nigral DAT levels as measured by immunohistochemistry within the same animals. The analysis of striatal DAT levels using SPECT and DAT immunohistochemistry yielded highly comparable results on the percentage of DAT reduction in each MPTP group. The in vivo data showed a decrease of specific striatal to non-specific binding ratios by 59%, 82%, and 76% in mice treated for 1, 3, and 5 days, respectively. Moreover, a strong, positive correlation was observed between the in vivo and ex vivo parameters. The present study provides the first evidence that [(123)I]FP-CIT pinhole SPECT allows the accurate detection of a range of striatal DAT (i.e., losses of approximately 60-80%) levels in mice. Since such large dopaminergic lesions could be detected, this SPECT method may at least be useful for analyzing neuroprotective treatment with a clear-cut positive (i.e., complete protection) or negative (i.e., not any protection) effect. Whether this method is also useful for analyzing more subtle effects of neuroprotective treatment (partial protection) remains to be established, by studying mice with small dopaminergic lesions.
Andringa
Gerda
G
Department of Medical Pharmacology, VU University Medical Center, Institute for Clinical and Experimental Neurosciences (ICEN), Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. G.andringa@vumc.nl
Drukarch
Benjamin
B
Bol
John G J M
JG
de Bruin
Kora
K
Sorman
Karolina
K
Habraken
Jan B A
JB
Booij
Jan
J
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D003042:Cocaine / Q000031:analogs & derivatives*; D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D007150:Immunohistochemistry; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000000981:diagnostic imaging / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000000981:diagnostic imaging* / Q000378:metabolism*; D019275:Radiopharmaceuticals; D013378:Substantia Nigra / Q000000981:diagnostic imaging / Q000378:metabolism; D015899:Tomography, Emission-Computed, Single-Photon
D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D019275:Radiopharmaceuticals; C493215:Slc6a3 protein, mouse; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D003042:Cocaine