Longitudinal PET Imaging of α7 Nicotinic Acetylcholine Receptors with [18F]ASEM in a Rat Model of Parkinson’s Disease
The nicotinic acetylcholine alpha-7 receptors (α7R) are involved in a number of neuropsychiatric and neurodegenerative brain disorders such as Parkinson’s disease (PD). However, their specific pathophysiologic roles are still unclear. In this context, we studied the evolution of these receptors in vivo by positron emission tomography (PET) imaging using the recently developed tracer 3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-[18F]fluorodibenzo[b,d]thiophene-5,5-dioxide) in a rat model mimicking early stages of PD.
PET imaging of α7R was performed at 3, 7, and 14 days following a partial striatal unilateral lesion with 6-hydroxydopamine in adult rats. After the last imaging experiments, the status of nigro-striatal dopamine neurons as well as different markers of neuroinflammation was evaluated on brain sections by autoradiographic and immunofluorescent experiments.
We showed an early and transitory rise in α7R expression in the lesioned striatum and substantia nigra, followed by over-expression of several gliosis activation markers in these regions of interest.
These findings support a longitudinally follow-up of α7R in animal models of PD and highlight the requirement to use a potential neuroprotective approach through α7R ligands at the early stages of PD.
Key wordsDopamine neurotransmission Neurodegeneration Neuroinflammation Microglia M1/M2 phenotype
We thank the Laboratories Cyclopharma for providing fluor-18 and Sylvie Bodard for technical assistance.
This work was supported by the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 278850 (INMiND), by Labex IRON (ANR-11-LABX-18-01), and by the Région Centre-Val de Loire project BIAlz (No. 2014 00091547).
Compliance with Ethical Standards
All procedures were conducted in accordance with the requirements of the European Community Council Directive 2010/63/EU for the care of laboratory animals and with the authorization of the Regional Ethical Committee (Authorization No. 2016.022218004689 and No. 00434.02).
Conflict of Interest
The authors declare that they have no conflict of interest.
- 9.Hillmer AT, Li S, Zheng MQ, Scheunemann M, Lin SF, Nabulsi N, Holden D, Pracitto R, Labaree D, Ropchan J, Teodoro R, Deuther-Conrad W, Esterlis I, Cosgrove KP, Brust P, Carson RE, Huang Y (2017) PET imaging of alpha7 nicotinic acetylcholine receptors: a comparative study of [18F]ASEM and [18F]DBT-10 in nonhuman primates, and further evaluation of [18F]ASEM in humans. Eur J Nucl Med Mol Imaging 44:1042–1050CrossRefGoogle Scholar
- 11.Wong DF, Kuwabara H, Horti AG, Roberts JM, Nandi A, Cascella N, Brasic J, Weerts EM, Kitzmiller K, Phan JA, Gapasin L, Sawa A, Valentine H, Wand G, Mishra C, George N, McDonald M, Lesniak W, Holt DP, Azad BB, Dannals RF, Kem W, Freedman R, Gjedde A (2018) Brain PET imaging of alpha7-nAChR with [18F]ASEM: reproducibility, occupancy, receptor density, and changes in schizophrenia. Int J Neuropsychopharmacol 21:656–667CrossRefGoogle Scholar
- 13.Chalon S, Garreau L, Emond P et al (1999) Pharmacological characterization of (E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4′-methylphenyl)nortropane as a selective and potent inhibitor of the neuronal dopamine transporter. J Pharmacol Exp Ther 291:648–654Google Scholar
- 14.Paxinos G, Watson C (2009) The rat brain in stereotaxic coordinates. Elsevier Academic Press, San DiegoGoogle Scholar
- 27.Casteels C, Vermaelen P, Nuyts J et al (2006) Construction and evaluation of multitracer small-animal PET probabilistic atlases for voxel-based functional mapping of the rat brain. J Nucl Med 47:1858–1866Google Scholar
- 32.Zhang Q, Lu Y, Bian H et al (2017) Activation of the alpha7 nicotinic receptor promotes lipopolysaccharide-induced conversion of M1 microglia to M2. Am J Transl Res 9:971–985Google Scholar
- 33.Ambrosi G, Kustrimovic N, Siani F, Rasini E, Cerri S, Ghezzi C, Dicorato G, Caputo S, Marino F, Cosentino M, Blandini F (2017) Complex changes in the innate and adaptive immunity accompany progressive degeneration of the nigrostriatal pathway induced by Intrastriatal injection of 6-hydroxydopamine in the rat. Neurotox Res 32:71–81CrossRefGoogle Scholar