Time course of nitric oxide synthase activity in neuronal, glial, and endothelial cells of rat striatum following focal cerebral ischemia

Abstract

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.

Widespread Peroxynitrite-Mediated Damage in Alzheimer’s Disease

“…NOS-containing neurons are relatively spared in Alzheimer's disease (Hyman et al, 1992), perhaps suggesting that NOS-containing neurons are better able to deal with oxidative stress than other neurons or, alternatively, that nitric oxide, from NOS-positive neurons, diffuses to other cells and reacts with superoxide to form peroxynitrite distal to the NOS-positive neurons. Activated microglia, present in most senile plaques in Alzheimer's disease (Cras et al, 1991), can also produce nitric oxide (Goodwin et al, 1995;Nakashima et al, 1995;Paakkari and Lindsberg, 1995), and it is of note that the involvement of nitric oxide produced by microglia may provide an additional link to the lower incidence of Alzheimer's disease with use of anti-inflammatory agents (Marx, 1996).…”

Inhibition of mitochondrial function in astrocytes: implications for neuroprotection

“…Exposure to elevated ROS levels results in oxidation of mitochondrial lipids, sulfhydryl groups and iron sulfur complexes of mitochondrial respiratory enzymes (Wagner et al 1990;Gilboe et al 1991;Nakahara et al 1992;Liu et al 1993) leading to impairment of mitochondrial oxidative phosphorylation. Different isoforms of nitric oxide synthase are activated during cerebral ischemia (Endoh et al 1994;Nakashima et al 1995;Bolanos et al 1997;Wiencken and Casagrande 1999) leading to excessive production of nitric oxide (NO). NO is a potent competitive inhibitor of mitochondrial cytochrome oxidase (complex IV) (Brown 1995;Giuffre et al 1996).…”

Microglia/Macrophages Proliferate in Striatum and Neocortex but Not in Hippocampus after Brief Global Ischemia That Produces Ischemic Tolerance in Gerbil Brain

“…This idea originates from the phagocytic (Banati and Graeber, 1994) and immune functions of microglia, and the expression of potentially injurious molecules like inducible nitric oxide synthase (Murphy et al, 1993;Nakashima et al, 1995). However, some data suggest that microglia might be beneficial in some circumstances.…”