Reduced [H-3]IP3 binding but unchanged IP3 receptor levels in the rat hippocampus CA1 region following transient global ischemia and tolerance induction

Changes in inositol (1,4,5)-trisphosphate (IP3) binding properties and the protein level of the IP3 receptor have been reported in different pathologi cal conditions in the brain, e.g. cerebral ischemia, Alzheimer's disease, a nd Huntingtons disease. We used the 4-vessel occlusion model in rat brain t o investigate the effect of transient ischemica insults on the IP3 receptor mRNA level, the IP3 receptor protein level and [H-3]IP3 binding. Recircula tion periods were limited (1-72 h) to avoid the development of delayed neur onal death. We found that the IP3 receptor mRNA levels were decreased after damage-inducing ischemia (9 min) in the hippocampus CA1 and CA3 regions. T he mRNA levels were unaltered after tolerance-inducing ischemia (3 min). Ho wever, [H-3]IP3 binding was significantly reduced after both damage- and to lerance-inducing ischemia in the hippocampus CAI region. Furthermore, all i nvestigated brain areas showed a decreased [H-3]IP3 binding when tolerance- inducing ischemia was followed by a second ischemic insult (3 + 8.5 min isc hemia). The IP3 receptor protein levels remained constant in all investigat ed brain areas. These results indicate that a reduced [H-3]IP3 binding capa bility in the particularly vulnerable areas occurs as an early consequence of cerebral ischemia, before IP3 receptor protein levels are reduced in the se areas. Structural or conformational changes altering IP3 binding may be of necessity on the pathway leading to down-regulation of IP3 receptor prot ein levels, as observed by others. (C) 2000 Elsevier Science Ltd. All right s reserved.