ABSTRACT
TTC-909 is a newly developed isocarbacyclin methyl ester (TEI-9090) incorporated in lipid microspheres. The neuroprotective effect of TTC-909 was histologically examined in the pyramidal cell layer of the hippocampus CA1 subfield 7 days after transient forebrain ischemia using stroke-prone spontaneously hypertensive rats. TTC-909, given intravenously 10 min after the transient forebrain ischemia, dose-dependently protected against ischemia-related delayed neuronal death. The blood pressure remained unchanged following TTC-909 administration. This finding suggests that TTC-909 has a neuroprotective action on ischemic delayed neuronal death in the hippocampus.
Subject(s)
Epoprostenol/analogs & derivatives , Hippocampus/drug effects , Animals , Blood Pressure/drug effects , Brain Ischemia , Cell Count/drug effects , Dose-Response Relationship, Drug , Epoprostenol/pharmacology , Male , Microspheres , Neurons/pathology , Neuroprotective Agents , Pyramidal Cells/cytology , Pyramidal Cells/drug effects , Rats , Rats, Inbred SHRABSTRACT
1. The time course of nitric oxide synthase (NOS) activity in neuronal, endothelial, and glial cells in the rat striatum after middle cerebral artery (MCA) occlusion and reperfusion was examined using a histochemical NADPH-diaphorase staining method. 2. In sham-operated rats, neuronal cells of the striatum exhibited strong NADPH-diaphorase activities. When rats were subjected to MCA occlusion for 1 hr, neuronal damage, including neurons with positive NADPH-diaphorase activities, appeared in the striatum at 3 hr after and extended to all areas of the striatum 3-4 days after reperfusion. 3. NADPH-diaphorase activities in the endothelial cells increased in the damaged part of striatum from 3 hr after, peaked at 1-2 days after MCA occlusion/reperfusion, then gradually decreased. 4. In parallel with the development of neuronal damage, some astrocytes and a high proportion of microglia/macrophages located in the perisite and in the center of the damaged striatum, respectively, exhibited a moderate to high level of NADPH-diaphorase activities. Most of these activities disappeared at 4 days after MCA occlusion. 5. These findings provided evidence that an inappropriate activation of NOS in endothelial cells and microglia/macrophages, in response to MCA occlusion/reperfusion, is closely associated with initiation and progression of ischemic neuronal injury in the striatum.
Subject(s)
Corpus Striatum/blood supply , Corpus Striatum/enzymology , Endothelium, Vascular/enzymology , Ischemic Attack, Transient/enzymology , Neuroglia/enzymology , Neurons/enzymology , Nitric Oxide Synthase/metabolism , Animals , Astrocytes/pathology , Cerebral Arteries , Corpus Striatum/pathology , Endothelium, Vascular/pathology , Glial Fibrillary Acidic Protein/analysis , Immunohistochemistry , Ischemic Attack, Transient/pathology , Kinetics , Male , NADPH Dehydrogenase/metabolism , Neuroglia/pathology , Neurons/pathology , Rats , Rats, Wistar , Reperfusion , Time FactorsABSTRACT
1. When delayed neuronal death occurred in the hippocampus CA1 pyramidal cell layer of stroke-prone spontaneously hypertensive rats (SHRSP) at 4 and 7 days after a 10 min bilateral carotid occlusion and reperfusion, intense endothelin-1 (ET-1)- and ET-3-like immunoreactivities became evident in astrocytes in the damaged hippocampus CA1 subfields. 2. We also observed that microglia equipped with an ETB receptor aggregated within the CA1 pyramidal cell layer with neuronal death. 3. There was a dramatic increase in nitric oxide synthase (NOS) activity in astrocytes and microglia in the damaged hippocampus CA1 subfields. 4. Thus, the possibility that microglia with the ETB receptor are activated to produce NO, a neurotoxic factor, by astrocytic ET-1 and ET-3 produced in response to transient forebrain ischaemia would have to be considered.
