Skip to main content
Erschienen in: Molecular Imaging and Biology 2/2020

08.07.2019 | Research Article

Longitudinal PET Imaging of α7 Nicotinic Acetylcholine Receptors with [18F]ASEM in a Rat Model of Parkinson’s Disease

Erschienen in: Molecular Imaging and Biology | Ausgabe 2/2020

Einloggen, um Zugang zu erhalten

Abstract

Purpose

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.

Procedures

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.

Results

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.

Conclusions

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.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat Thomsen MS, Hansen HH, Timmerman DB, Mikkelsen JD (2010) Cognitive improvement by activation of alpha7 nicotinic acetylcholine receptors: from animal models to human pathophysiology. Curr Pharm Des 16:323–343CrossRef Thomsen MS, Hansen HH, Timmerman DB, Mikkelsen JD (2010) Cognitive improvement by activation of alpha7 nicotinic acetylcholine receptors: from animal models to human pathophysiology. Curr Pharm Des 16:323–343CrossRef
2.
Zurück zum Zitat Dineley KT, Pandya AA, Yakel JL (2015) Nicotinic ACh receptors as therapeutic targets in CNS disorders. Trends Pharmacol Sci 36:96–108CrossRef Dineley KT, Pandya AA, Yakel JL (2015) Nicotinic ACh receptors as therapeutic targets in CNS disorders. Trends Pharmacol Sci 36:96–108CrossRef
3.
Zurück zum Zitat Fan H, Gu R, Wei D (2015) The alpha7 nAChR selective agonists as drug candidates for Alzheimer’s disease. Adv Exp Med Biol 827:353–365CrossRef Fan H, Gu R, Wei D (2015) The alpha7 nAChR selective agonists as drug candidates for Alzheimer’s disease. Adv Exp Med Biol 827:353–365CrossRef
4.
Zurück zum Zitat Quik M, Zhang D, McGregor M, Bordia T (2015) Alpha7 nicotinic receptors as therapeutic targets for Parkinson’s disease. Biochem Pharmacol 97:399–407CrossRef Quik M, Zhang D, McGregor M, Bordia T (2015) Alpha7 nicotinic receptors as therapeutic targets for Parkinson’s disease. Biochem Pharmacol 97:399–407CrossRef
5.
Zurück zum Zitat Kalkman HO, Feuerbach D (2016) Modulatory effects of alpha7 nAChRs on the immune system and its relevance for CNS disorders. Cell Mol Life Sci 73:2511–2530CrossRef Kalkman HO, Feuerbach D (2016) Modulatory effects of alpha7 nAChRs on the immune system and its relevance for CNS disorders. Cell Mol Life Sci 73:2511–2530CrossRef
6.
Zurück zum Zitat Brust P, Peters D, Deuther-Conrad W (2012) Development of radioligands for the imaging of alpha7 nicotinic acetylcholine receptors with positron emission tomography. Curr Drug Targets 13:594–601CrossRef Brust P, Peters D, Deuther-Conrad W (2012) Development of radioligands for the imaging of alpha7 nicotinic acetylcholine receptors with positron emission tomography. Curr Drug Targets 13:594–601CrossRef
7.
Zurück zum Zitat Chalon S, Vercouillie J, Guilloteau D, Suzenet F, Routier S (2015) PET tracers for imaging brain alpha7 nicotinic receptors: an update. Chem Commun (Camb) 51:14826–14831CrossRef Chalon S, Vercouillie J, Guilloteau D, Suzenet F, Routier S (2015) PET tracers for imaging brain alpha7 nicotinic receptors: an update. Chem Commun (Camb) 51:14826–14831CrossRef
8.
Zurück zum Zitat Gao Y, Kellar KJ, Yasuda RP, Tran T, Xiao Y, Dannals RF, Horti AG (2013) Derivatives of dibenzothiophene for positron emission tomography imaging of alpha7-nicotinic acetylcholine receptors. J Med Chem 56:7574–7589CrossRef Gao Y, Kellar KJ, Yasuda RP, Tran T, Xiao Y, Dannals RF, Horti AG (2013) Derivatives of dibenzothiophene for positron emission tomography imaging of alpha7-nicotinic acetylcholine receptors. J Med Chem 56:7574–7589CrossRef
9.
Zurück zum Zitat 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 44:1042–1050CrossRef 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 44:1042–1050CrossRef
10.
Zurück zum Zitat Coughlin JM, Du Y, Rosenthal HB et al (2018) The distribution of the alpha7 nicotinic acetylcholine receptor in healthy aging: an in vivo positron emission tomography study with [18F]ASEM. Neuroimage 165:118–124CrossRef Coughlin JM, Du Y, Rosenthal HB et al (2018) The distribution of the alpha7 nicotinic acetylcholine receptor in healthy aging: an in vivo positron emission tomography study with [18F]ASEM. Neuroimage 165:118–124CrossRef
11.
Zurück zum Zitat 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 21:656–667CrossRef 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 21:656–667CrossRef
12.
Zurück zum Zitat Sérrière S, Doméné A, Vercouillie J et al (2015) Assessment of the protection of dopaminergic neurons by an α7 nicotinic receptor agonist, PHA543613 using [18F]LBT-999 in a Parkinson’s disease rat model. Front Med 2:61CrossRef Sérrière S, Doméné A, Vercouillie J et al (2015) Assessment of the protection of dopaminergic neurons by an α7 nicotinic receptor agonist, PHA543613 using [18F]LBT-999 in a Parkinson’s disease rat model. Front Med 2:61CrossRef
13.
Zurück zum Zitat 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 291:648–654PubMed 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 291:648–654PubMed
14.
Zurück zum Zitat Paxinos G, Watson C (2009) The rat brain in stereotaxic coordinates. Elsevier Academic Press, San Diego Paxinos G, Watson C (2009) The rat brain in stereotaxic coordinates. Elsevier Academic Press, San Diego
15.
Zurück zum Zitat Bertrand D, Chih-Hung LL, Flood D et al (2015) Therapeutic potential of α7 nicotinic acetylcholine receptors. Pharmacol Rev 67:1025–1073CrossRef Bertrand D, Chih-Hung LL, Flood D et al (2015) Therapeutic potential of α7 nicotinic acetylcholine receptors. Pharmacol Rev 67:1025–1073CrossRef
16.
Zurück zum Zitat Bertrand D, Terry AV (2018) The wonderland of neuronal nicotinic acetylcholine receptors. Biochem Pharmacol 151:214–225CrossRef Bertrand D, Terry AV (2018) The wonderland of neuronal nicotinic acetylcholine receptors. Biochem Pharmacol 151:214–225CrossRef
17.
Zurück zum Zitat Bordia T, McGregor M, Papke RL, Decker MW, Michael McIntosh J, Quik M (2015) The α7 nicotinic receptor agonist ABT-107 protects against nigrostriatal damage in rats with unilateral 6-hydroxydopamine lesions. Exp Neurol 263:277–284CrossRef Bordia T, McGregor M, Papke RL, Decker MW, Michael McIntosh J, Quik M (2015) The α7 nicotinic receptor agonist ABT-107 protects against nigrostriatal damage in rats with unilateral 6-hydroxydopamine lesions. Exp Neurol 263:277–284CrossRef
18.
Zurück zum Zitat Horti AG (2015) Development of [18F]ASEM, a specific radiotracer for quantification of the α7-nAChR with positron-emission tomography. Biochem Pharmacol 97:566–575CrossRef Horti AG (2015) Development of [18F]ASEM, a specific radiotracer for quantification of the α7-nAChR with positron-emission tomography. Biochem Pharmacol 97:566–575CrossRef
19.
Zurück zum Zitat Clarke PB, Schwartz RD, Paul SM, Pert CB, Pert A (1985) Nicotinic binding in rat brain autoradiographic comparison of [3H]acetylcholine, [3H]nicotine, and [125I]-alpha-bungarotoxin. J Neurosci 5:1307–1345CrossRef Clarke PB, Schwartz RD, Paul SM, Pert CB, Pert A (1985) Nicotinic binding in rat brain autoradiographic comparison of [3H]acetylcholine, [3H]nicotine, and [125I]-alpha-bungarotoxin. J Neurosci 5:1307–1345CrossRef
20.
Zurück zum Zitat Whiteaker P, Davies AR, Marks MJ et al (1999) An autoradiographic study of the distribution of binding sites for the novel alpha7-selective nicotinic radioligand [3H]-methyllycaconitine in the mouse brain. Eur J Neurosci 11:2689–2696CrossRef Whiteaker P, Davies AR, Marks MJ et al (1999) An autoradiographic study of the distribution of binding sites for the novel alpha7-selective nicotinic radioligand [3H]-methyllycaconitine in the mouse brain. Eur J Neurosci 11:2689–2696CrossRef
21.
Zurück zum Zitat Vetel S, Serriere S, Vercouillie J et al (2019) Extensive exploration of a novel rat model of Parkinson’s disease using partial 6-hydroxydopamine lesion of dopaminergic neurons suggests new therapeutic approaches. Synapse 73:e22077CrossRef Vetel S, Serriere S, Vercouillie J et al (2019) Extensive exploration of a novel rat model of Parkinson’s disease using partial 6-hydroxydopamine lesion of dopaminergic neurons suggests new therapeutic approaches. Synapse 73:e22077CrossRef
22.
Zurück zum Zitat Vingill S, Connor-Robson N, Wade-Martins R (2017) Are rodent models of Parkinson’s disease behaving as they should? Behav Brain Res 352:133–141CrossRef Vingill S, Connor-Robson N, Wade-Martins R (2017) Are rodent models of Parkinson’s disease behaving as they should? Behav Brain Res 352:133–141CrossRef
23.
Zurück zum Zitat Hemshekhar M, Anaparti V, Hitchon C, Mookherjee N (2017) Buprenorphine alters inflammatory and oxidative stress molecular markers in arthritis. Mediat Inflamm 2017:2515408CrossRef Hemshekhar M, Anaparti V, Hitchon C, Mookherjee N (2017) Buprenorphine alters inflammatory and oxidative stress molecular markers in arthritis. Mediat Inflamm 2017:2515408CrossRef
24.
Zurück zum Zitat Chakfe Y, Seguin R, Antel JP, Morissette C, Malo D, Henderson D, Séguéla P (2002) ADP and AMP induce interleukin-1beta release from microglial cells through activation of ATP-primed P2X7 receptor channels. J Neurosci 22:3061–3069CrossRef Chakfe Y, Seguin R, Antel JP, Morissette C, Malo D, Henderson D, Séguéla P (2002) ADP and AMP induce interleukin-1beta release from microglial cells through activation of ATP-primed P2X7 receptor channels. J Neurosci 22:3061–3069CrossRef
25.
Zurück zum Zitat Apolloni S, Amadio S, Parisi C, Matteucci A, Potenza RL, Armida M, Popoli P, D’Ambrosi N, Volonte C (2014) Spinal cord pathology is ameliorated by P2X7 antagonism in a SOD1-mutant mouse model of amyotrophic lateral sclerosis. Dis Model Mech 7:1101–1109CrossRef Apolloni S, Amadio S, Parisi C, Matteucci A, Potenza RL, Armida M, Popoli P, D’Ambrosi N, Volonte C (2014) Spinal cord pathology is ameliorated by P2X7 antagonism in a SOD1-mutant mouse model of amyotrophic lateral sclerosis. Dis Model Mech 7:1101–1109CrossRef
26.
Zurück zum Zitat Higashi Y, Aratake T, Shimizu S, Shimizu T, Nakamura K, Tsuda M, Yawata T, Ueba T, Saito M (2017) Influence of extracellular zinc on M1 microglial activation. Sci Rep 7:43778CrossRef Higashi Y, Aratake T, Shimizu S, Shimizu T, Nakamura K, Tsuda M, Yawata T, Ueba T, Saito M (2017) Influence of extracellular zinc on M1 microglial activation. Sci Rep 7:43778CrossRef
27.
Zurück zum Zitat 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 47:1858–1866PubMed 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 47:1858–1866PubMed
28.
Zurück zum Zitat Sérrière S, Tauber C, Vercouillie J, Guilloteau D, Deloye JB, Garreau L, Galineau L, Chalon S (2014) In vivo PET quantification of the dopamine transporter in rat brain with [18F]LBT-999. Nucl Med Biol 41:106–113CrossRef Sérrière S, Tauber C, Vercouillie J, Guilloteau D, Deloye JB, Garreau L, Galineau L, Chalon S (2014) In vivo PET quantification of the dopamine transporter in rat brain with [18F]LBT-999. Nucl Med Biol 41:106–113CrossRef
29.
Zurück zum Zitat Sauer H, Oertel WH (1994) Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 59:401–415CrossRef Sauer H, Oertel WH (1994) Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 59:401–415CrossRef
30.
Zurück zum Zitat Shytle RD, Mori T, Townsend K, Vendrame M, Sun N, Zeng J, Ehrhart J, Silver AA, Sanberg PR, Tan J (2004) Cholinergic modulation of microglial activation by alpha 7 nicotinic receptors. J Neurochem 89:337–343CrossRef Shytle RD, Mori T, Townsend K, Vendrame M, Sun N, Zeng J, Ehrhart J, Silver AA, Sanberg PR, Tan J (2004) Cholinergic modulation of microglial activation by alpha 7 nicotinic receptors. J Neurochem 89:337–343CrossRef
31.
Zurück zum Zitat Teaktong T, Graham A, Court J, Perry R, Jaros E, Johnson M, Hall R, Perry E (2003) Alzheimer’s disease is associated with a selective increase in alpha7 nicotinic acetylcholine receptor immunoreactivity in astrocytes. Glia 41:207–211CrossRef Teaktong T, Graham A, Court J, Perry R, Jaros E, Johnson M, Hall R, Perry E (2003) Alzheimer’s disease is associated with a selective increase in alpha7 nicotinic acetylcholine receptor immunoreactivity in astrocytes. Glia 41:207–211CrossRef
32.
Zurück zum Zitat 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 9:971–985PubMedPubMedCentral 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 9:971–985PubMedPubMedCentral
33.
Zurück zum Zitat 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 32:71–81CrossRef 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 32:71–81CrossRef
34.
Zurück zum Zitat Perego C, Fumagalli S, De Simoni MG (2011) Temporal pattern of expression and colocalization of microglia/macrophage phenotype markers following brain ischemic injury in mice. J Neuroinflammation 8:174CrossRef Perego C, Fumagalli S, De Simoni MG (2011) Temporal pattern of expression and colocalization of microglia/macrophage phenotype markers following brain ischemic injury in mice. J Neuroinflammation 8:174CrossRef
35.
Zurück zum Zitat Hu X, Li P, Guo Y, Wang H, Leak RK, Chen S, Gao Y, Chen J (2012) Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43:3063–3070CrossRef Hu X, Li P, Guo Y, Wang H, Leak RK, Chen S, Gao Y, Chen J (2012) Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43:3063–3070CrossRef
Metadaten
Titel
Longitudinal PET Imaging of α7 Nicotinic Acetylcholine Receptors with [18F]ASEM in a Rat Model of Parkinson’s Disease
Publikationsdatum
08.07.2019
Erschienen in
Molecular Imaging and Biology / Ausgabe 2/2020
Print ISSN: 1536-1632
Elektronische ISSN: 1860-2002
DOI
https://doi.org/10.1007/s11307-019-01400-y

Weitere Artikel der Ausgabe 2/2020

Molecular Imaging and Biology 2/2020 Zur Ausgabe

Akuter Schwindel: Wann lohnt sich eine MRT?

28.04.2024 Schwindel Nachrichten

Akuter Schwindel stellt oft eine diagnostische Herausforderung dar. Wie nützlich dabei eine MRT ist, hat eine Studie aus Finnland untersucht. Immerhin einer von sechs Patienten wurde mit akutem ischämischem Schlaganfall diagnostiziert.

Screening-Mammografie offenbart erhöhtes Herz-Kreislauf-Risiko

26.04.2024 Mammografie Nachrichten

Routinemäßige Mammografien helfen, Brustkrebs frühzeitig zu erkennen. Anhand der Röntgenuntersuchung lassen sich aber auch kardiovaskuläre Risikopatientinnen identifizieren. Als zuverlässiger Anhaltspunkt gilt die Verkalkung der Brustarterien.

S3-Leitlinie zu Pankreaskrebs aktualisiert

23.04.2024 Pankreaskarzinom Nachrichten

Die Empfehlungen zur Therapie des Pankreaskarzinoms wurden um zwei Off-Label-Anwendungen erweitert. Und auch im Bereich der Früherkennung gibt es Aktualisierungen.

Fünf Dinge, die im Kindernotfall besser zu unterlassen sind

18.04.2024 Pädiatrische Notfallmedizin Nachrichten

Im Choosing-Wisely-Programm, das für die deutsche Initiative „Klug entscheiden“ Pate gestanden hat, sind erstmals Empfehlungen zum Umgang mit Notfällen von Kindern erschienen. Fünf Dinge gilt es demnach zu vermeiden.

Update Radiologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.