Detection and quantification of remote microglial activation in rodent models of focal ischaemia using the TSPO radioligand CLINDE.
OBJECTIVE
Neuroinflammation is involved in stroke pathophysiology and might be imaged using radioligands targeting the 18 kDa translocator protein (TSPO).


METHODS
We studied microglial reaction in brain areas remote from the primary lesion site in two rodent models of focal cerebral ischaemia (permanent or transient) using [125I]-CLINDE, a promising TSPO single photon emission computed tomography radioligand.


RESULTS
In a mouse model of permanent middle cerebral artery occlusion (MCAO), ex vivo autoradiographic studies demonstrated, besides in the ischaemic territory, accumulation of [125I]-CLINDE in the ipsilateral thalamus with a binding that progressed up to 3 weeks after MCAO. [125I]-CLINDE binding markedly decreased in animals pre-injected with either unlabelled CLINDE or PK11195, while no change was observed with flumazenil pre-treatment, demonstrating TSPO specificity. In rats subjected to transient MCAO, [125I]-CLINDE binding in the ipsilateral thalamus and substantia nigra pars reticulata (SNr) was significantly higher than that in contralateral tissue. Moreover, [125I]-CLINDE binding in the thalamus and SNr was quantitatively correlated to the ischaemic volume assessed by MRI in the cortex and striatum, respectively.


CONCLUSIONS
Clinical consequences of secondary neuronal degeneration in stroke might be better treated thanks to the discrimination of neuronal processes using in vivo molecular imaging and potent TSPO radioligands like CLINDE to guide therapeutic interventions.
Arlicot
Nicolas
N
UMR Inserm U 930, CNRS ERL 3106, Université François Rabelais de Tours, CHRU de Tours, Tours, France. nicolas.arlicot-2@etu.univ-tours.fr
Petit
Edwige
E
Katsifis
Andrew
A
Toutain
Jérôme
J
Divoux
Didier
D
Bodard
Sylvie
S
Roussel
Simon
S
Guilloteau
Denis
D
Bernaudin
Myriam
M
Chalon
Sylvie
S
D000818:Animals; D002545:Brain Ischemia / Q000000981:diagnostic imaging* / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics*; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D017628:Microglia / Q000000981:diagnostic imaging* / Q000378:metabolism*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
C504993:6-chloro-2-(4'-iodophenyl)-3-(N,N-diethyl)imidazo(1,2-a)pyridine-3-acetamide; D019086:Bridged Bicyclo Compounds, Heterocyclic; C463819:Bzrp protein, mouse; D019275:Radiopharmaceuticals; D018079:Receptors, GABA
Stroke. 2007 Feb;38(2):303-7
17170357
Mol Endocrinol. 2005 Mar;19(3):588-94
15528269
Nucl Med Biol. 1994 May;21(4):573-81
9234314
Stroke. 2008 May;39(5):1541-7
18323485
J Cereb Blood Flow Metab. 2009 Jun;29(6):1216-25
19352400
J Nucl Med. 2008 May;49(5):814-22
18413395
Ann Neurol. 1996 Apr;39(4):460-70
8619524
Neuroscience. 2003;122(2):373-80
14614903
J Cereb Blood Flow Metab. 2007 Dec;27(12):1975-86
17457364
Acta Neuropathol. 2009 May;117(5):497-509
19225790
Neuroimage. 2005 Jan 15;24(2):591-5
15627603
Prog Neurobiol. 2006 Dec;80(6):308-22
17156911
Brain Res. 2001 Jan 19;889(1-2):165-73
11166700
J Nucl Med. 2007 Apr;48(4):573-81
17401094
Trends Pharmacol Sci. 2006 Aug;27(8):402-9
16822554
Brain Res. 1993 Aug 6;618(2):251-60
8374756
Pharmacol Ther. 2008 Apr;118(1):1-17
18374421
Lancet Neurol. 2009 Apr;8(4):355-69
19233729
Behav Neurosci. 2009 Feb;123(1):224-30
19170448
Acta Neuropathol. 1998 Aug;96(2):172-8
9705133
Stroke. 1989 Jan;20(1):84-91
2643202
Curr Pharm Des. 2008;14(31):3297-315
19075709
Eur J Nucl Med. 2000 Mar;27(3):308-13
10774883
Stroke. 2003 Jan;34(1):214-23
12511777
J Neuropathol Exp Neurol. 2008 Oct;67(10):1001-10
18800007
Stroke. 2006 Jul;37(7):1749-53
16763188
Eur J Nucl Med Mol Imaging. 2008 Apr;35(4):779-89
18057934
Curr Med Chem. 2009;16(22):2899-923
19689272
Curr Pharm Des. 2008;14(33):3549-64
19075732
Stroke. 1999 Sep;30(9):1844-50
10471434
Prog Neurobiol. 2005 Jun;76(2):77-98
16081203
Steroids. 2003 Sep;68(7-8):569-85
12957662
Eur J Nucl Med Mol Imaging. 2008 Dec;35(12):2203-11
18536913
Glia. 2000 Jul;31(1):39-50
10816605
J Cereb Blood Flow Metab. 2010 Jan;30(1):230-41
19794397
Neurosci Lett. 2007 Jan 16;411(3):200-5
17127001
Neurosci Lett. 1991 Nov 25;133(1):20-4
1791992
Neurochem Int. 2009 Jan;54(1):28-36
18984021
Eur J Pharmacol. 1991 Aug 6;200(2-3):347-51
1782994
J Nucl Med. 2009 Aug;50(8):1276-82
19617321
Ann Neurol. 2009 Dec;66(6):825-32
20035510
J Neurosci. 1995 Jul;15(7 Pt 2):5263-74
7623150
Eur J Nucl Med Mol Imaging. 2005 May;32(5):557-63
15875181
J Neurochem. 1983 Dec;41(6):1744-50
6315880
Int J Neuropsychopharmacol. 2010 Aug;13(7):943-50
20350336
Neuropharmacology. 2009 Feb;56(2):329-41
19007799
Neurology. 2000 Oct 10;55(7):1052-4
11061271
Neuroimage. 2008 Apr 1;40(2):451-457
18221893
Int J Cancer. 2002 Dec 1;102(4):318-27
12402299
Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3170-4
1373486
J Cereb Blood Flow Metab. 1999 Jun;19(6):643-51
10366194