Inhibition of Vascular Nitric Oxide after Rat Chronic Brain Hypoperfusion: Spatial Memory and Immunocytochemical Changes

Abstract

An aging rat model of chronic brain hypoperfusion (CBH) that mimics human mild cognitive impairment (MCI) was used to examine the role of nitric oxide synthase (NOS) isoforms on spatial memory function. Rats with CBH underwent bilateral common carotid artery occlusion (2-vessel occlusion (2-VO)) for either 26 or 8 weeks and were compared with nonoccluded sham controls (S-VO). The neuronal and endothelial (nNOS/eNOS) constitutive inhibitor nitro-L-arginine methyl ester (L-NAME) 20 mg/kg was administered after 26 weeks for 3 days to 2-VO and S-VO groups and spatial memory was assessed with a modified Morris watermaze test. Only 2-VO rats worsened their spatial memory ability after L-NAME. Electron microscopic immunocytochemical examination using an antibody against eNOS showed 2-VO rats had significant loss or absence of eNOS-containing positive gold particles in hippocampal endothelium and these changes were associated with endothelial cell compression, mitochondrial damage and heavy amyloid deposition in hippocampal capillaries and perivascular region. In the 8-week study, three groups of 2-VO rats were administered an acute dose of 7-NI, aminoguanidine or L-NIO, the relatively selective inhibitors of nNOS, inducible NOS and eNOS. Only rats administered the eNOS inhibitor L-NIO worsened markedly their watermaze performance (P ¼ 0.009) when compared with S-VO nonoccluded controls. We conclude from these findings that vascular nitric oxide derived from eNOS may play a critical role in spatial memory function during CBH possibly by keeping cerebral perfusion optimal through its regulation of microvessel tone and cerebral blood flow and that disruption of this mechanism can result in spatial memory impairment. These findings may identify therapeutic targets for preventing MCI and treating Alzheimer's disease.

Vascular dysfunction in the pathogenesis of Alzheimer's disease — A review of endothelium-mediated mechanisms and ensuing vicious circles

“…These findings suggest that vascular NO derived from eNOS may play an important role in regulating microvascular tone in the attempt to contrast the chronic reduction of CBF [100].…”

“…Constitutive endothelial NO is reduced in chronic hypoperfusion, as evidenced by reduced eNOS immunostaining in rat hippocampal capillaries following chronic bilateral carotid occlusion [100], with concomitant evidence of mitochondrial damage in endothelial and perivascular cells. These abnormalities were associated with amyloid deposition surrounding the capillary wall, suggesting a possible interaction of the vascular damage with A deposits.…”

Ceftriaxone improves spatial learning and memory in chronic cerebral hypoperfused rats

“…There are several mechanisms leading to neuronal injury and death after insufficient CBF. Previous studies showed that oxidative stress plays a key role in chronic cerebral hypoperfusion 11,12 . Nevertheless, other mechanisms including glutamatemediated excitotoxicity, acidotoxicity, and inflammation are thought to participate in the process of neuronal injury 13 .…”

l-3-n-Butylphthalide Improves Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats

“…It has been widely accepted that chronic cerebral hypoperfusion induces oxidative stress damage and brain energy failure in neuronal tissues and cells, at least partially due to the generation of reactive oxygen species and reactive nitrogen species (Aliev et al, 2003;de la Torre and Aliev, 2005). Reactive oxygen species are directly toxic to neurons, and They initiate a free-radical-mediated chain reactions resulting in neuronal system damage.…”

“…Bilateral permanent occlusion of the common carotid arteries (BCCAO) in rats results in a significant reduction in cerebral blood flow; therefore, it is a useful model of chronic cerebral hypoperfusion (Tsuchiya et al, 1993). This animal model exhibits learning and memory impairments resembling those found in AD and VaD, accompanied by neuronal degeneration and microvascular abnormalities (Farkas et al, 2004).It has been widely accepted that chronic cerebral hypoperfusion induces oxidative stress damage and brain energy failure in neuronal tissues and cells, at least partially due to the generation of reactive oxygen species and reactive nitrogen species (Aliev et al, 2003;de la Torre and Aliev, 2005). Reactive oxygen species are directly toxic to neurons, and They initiate a free-radical-mediated chain reactions resulting in neuronal system damage.…”