Non-angiotensin II [(125)I] CGP42112 binding is a sensitive marker of neuronal injury in brainstem following unilateral nodose ganglionectomy: comparison with markers for activated microglia.
Previously we reported that a non-angiotensin II [(125)I] CGP42112 binding site is up-regulated in rat brainstem nuclei as a result of unilateral nodose ganglionectomy. In the present study, we compared non-angiotensin II [(125)I] CGP42112 binding with microglia/macrophage activation following nodose ganglionectomy, using both in vitro autoradiography and immunohistochemistry. Specific [(125)I] CGP42112 binding was observed in the nucleus of the solitary tract (NTS) and revealed an AT(2) receptor component as well as a non-angiotensin II receptor component. Subsequent to unilateral nodose ganglionectomy, [(125)I] CGP42112 binding in the ipsilateral NTS was increased approximately two-fold and was also induced in the ipsilateral dorsal motor nucleus (DMX) and the nucleus ambiguus (n.amb). This non-angiotensin II [(125)I] CGP42112 binding site was displaced by CGP42112 but not other ligands. Increased [(3)H] PK11195 binding (a known marker of reactive gliosis) was also observed in the same brainstem nuclei as non-angiotensin II [(125)I] CGP42112 binding after nodose ganglionectomy. The similarity in binding patterns between [(125)I] CGP42112 and [(3)H] PK11195 was shown to be primarily due to retrograde degeneration in the ipsilateral NTS, DMX and n.amb, as both radioligands were localized to similar cellular targets within the interstial space and over cellular debris. Immunohistochemical data confirmed reactive gliosis within the ipsilateral NTS, DMX and n.amb, following nodose ganglionectomy, which was predominantly characterized by an increase in OX-42 immunoreactivity (a marker for activated microglia/macrophages), with only a small increase in glial fibrillary acidic protein immunoreactivity (a marker of astrogliosis) detected. These data demonstrate for the first time that non-angiotensin II [(125)I] CGP42112 binding is associated with activated microglia, as well as macrophages, following unilateral nodose ganglionectomy. Furthermore, these studies also demonstrate the potential use of non-angiotensin II [(125)I] CGP42112 binding as a marker for quantitating inflammatory events which occur as a result of damage to the CNS.
Department of Pharmacology, Clayton Monash University, Victoria 3800, Australia.
C L
CL
Roulston
A J
AJ
Lawrence
B
B
Jarrott
R E
RE
Widdop
D000804:Angiotensin II / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001345:Autoradiography; D015415:Biomarkers; D001933:Brain Stem / Q000473:pathology / Q000503:physiopathology*; D015171:Ganglionectomy; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000473:pathology / Q000503:physiopathology; D007457:Iodine Radioisotopes; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D017628:Microglia / Q000502:physiology; D009620:Nodose Ganglion / Q000502:physiology* / Q000601:surgery; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011921:Rats, Inbred WKY; D014316:Tritium; D014662:Vasoconstrictor Agents / Q000378:metabolism / Q000494:pharmacology*
D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D007457:Iodine Radioisotopes; D007546:Isoquinolines; D009842:Oligopeptides; D014662:Vasoconstrictor Agents; D014316:Tritium; D000804:Angiotensin II; C060894:CGP 42112A; C037850:PK 11195