The quantification of brain lesions with an omega 3 site ligand: a critical analysis of animal models of cerebral ischaemia and neurodegeneration.
Previous investigations have indicated that the detection and quantification of omega 3 (peripheral type benzodiazepine) binding site densities that are associated with reactive astroglia and macrophages could be of widespread applicability in the localization and indirect assessment of neural tissue damage in the central nervous system. In the present study, we analyze the usefulness of this approach in a number of experimental models that are characterized by (or putatively involve) neuronal degeneration. One week after the systemic administration of the excitotoxin, kainate, a marked increase in omega 3 site densities (as assessed by [3H]PK 11195 binding) was noted, an increase that was most prominent in known regions of selective vulnerability (hippocampus and septum). However, the kainate-induced omega 3 site proliferation was not a function of the dose administered, a marked interstudy variation was observed, and the binding increase was prevented by the administration of the anticonvulsant, clonazepam. The densities of omega 3 sites were studied, by autoradiography (using [3H]PK 11195 or [3H]PK 14105 as ligands), in 4 groups of Fischer 344 rats aged 3, 12, 22 and 30 months. No age-related changes were noted except in the 30-month-old group in which discrete and focal increases (reflecting tumoral processes) were observed in various brain regions. In spontaneously hypertensive, stroke-prone rats, omega 3 binding increases were observed concomitant with the development of stroke-related neurological signs. With autoradiography, the omega 3 site increase was localized to focal increases in the boundary zones between major cerebral arteries (and corresponding to regions of ischaemic or haemorrhagic infarction). Focal cerebral ischaemia was studied in rats and mice. Subsequent to middle cerebral artery occlusion in normotensive (Wistar/Kyoto) and spontaneously hypertensive rats, the density of omega 3 sites in the ipsilateral hemisphere was markedly elevated, the increase being greater in the spontaneously hypertensive rats. The increases in omega 3 labelling in these two strains matched the absolute volumes of infarctions, determined previously. Middle cerebral artery occlusion in the mouse also increased hemispheric levels of omega 3 sites; the maximum values were obtained between 4 and 8 days following the induction of focal ischaemia. These results demonstrate the feasibility of using omega 3 sites as a marker of excitotoxic, ischaemic and proliferative damage in the rodent brain. Binding measurement in tissue homogenates is an economic and time-efficient approach, whereas the autoradiographic detection of omega 3 sites allows the localization of brain lesions with a macroscopic or microscopic level of anatomical resolution.(ABSTRACT TRUNCATED AT 400 WORDS)
Benavides
J
J
Department of Biology, Synthélabo Recherche (L.E.R.S.), Bagneux, France.
Capdeville
C
C
Dauphin
F
F
Dubois
A
A
Duverger
D
D
Fage
D
D
Gotti
B
B
MacKenzie
E T
ET
Scatton
B
B
D000345:Affinity Labels; D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism*; D002545:Brain Ischemia / Q000473:pathology*; D004195:Disease Models, Animal; D007546:Isoquinolines; D007608:Kainic Acid; D008297:Male; D051379:Mice; D009410:Nerve Degeneration / Q000502:physiology*; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000032:analysis*
D000345:Affinity Labels; D007546:Isoquinolines; D011963:Receptors, GABA-A; D007608:Kainic Acid; C051238:PK 14105; C037850:PK 11195