Cilostazol Protects Against Brain White Matter Damage and Cognitive Impairment in a Rat Model of Chronic Cerebral Hypoperfusion

Cho

Korean J Physiol Pharmacol

2008

In order to reproduce chronic cerebral hypoperfusion as it occurs in human aging and Alzheimer's disease, we introduced permanent, bilateral occlusion of the common carotid arteries (BCCAO) in rats (Farkas et al, 2007). Here, we induced BCCAO in two different rat strains in order to determine whether there was a strain difference in the pathogenic response to BCCAO. Male W istar and Sprague-Dawley (SD) rats (250-270 g) were subjected to BCCAO for three weeks. Klüver-Barrera and cresyl violet staining were used to evaluate white matter and gray matter damage, respectively. W istar rats had a considerably higher mortality rate (four of 14 rats) as compared to SD rats (one of 15 rats) following BCCAO. Complete loss of pupillary light reflex occurred in all Wistar rats that survived, but loss of pupillary light reflex did not occur at all in SD rats. Moreover, BCCAO induced marked vacuolation in the optic tract of Wistar rats as compared to SD rats. In contrast, SD rats showed fewer CA1 hippocampal neurons than W istar rats following BCCAO. These results suggest that the neuropathological process induced by BCCAO takes place in a region-specific pattern that varies according to the strain of rat involved.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

White Matter Damage and Hippocampal Neurodegeneration Induced by Permanent Bilateral Occlusion of Common Carotid Artery in the Rat: Comparison between Wistar and Sprague-Dawley Strain

Cho

Korean J Physiol Pharmacol

2008

“…This may represent a beneficial effect of clopidogrel on cerebrovascular endothelium as reported in the second Trial of Cilostazol in Symptomatic Intracranial Arterial Stenosis (TOSS 2) study for preventing intracranial atherosclerotic progression. 17 Previous studies have shown that cilostazol increases rCBF in a rat model of chronic cerebral hypoperfusion, 18,19 and that cilostazol improves rCBF in the penumbral region in a rat model of middle cerebral artery occlusion. 20 In clinical studies, cilostazol also increases rCBF compared with ticlopidine at the chronic stage of cerebral infarction with a vasodilating effect.…”

Section: Omote Et Al Pleiotropic Effect Of Cilostazol In Shr-spmentioning

confidence: 99%

Clinical and Pathological Improvement in Stroke-Prone Spontaneous Hypertensive Rats Related to the Pleiotropic Effect of Cilostazol

Omote

Deguchi

Tian

et al. 2012

Stroke

Background and Purpose-Cerebral infarction is a major cause of death or decreasing activities of daily living. This study aimed to investigate the efficacy of commonly used antiplatelet drugs on stroke and motor and cognitive functions in relation to oxidative stress markers and insulin-like growth factor 1 receptor (IGF-1R). Methods-Stroke-prone spontaneously hypertensive rats were treated with vehicle, aspirin, clopidogrel, and cilostazol from 8 to 10 weeks of age. Physiological parameters, regional cerebral blood flow, and serum lipids were examined. Motor and cognitive functions were evaluated weekly by the Rotorod and water maze task. Spontaneous infarct volume, oxidative stress markers for lipid, protein, and DNA at the ischemic boundary zone of spontaneous infarction, and the IGF-1R-positive cell ratio in the hippocampus were immunohistochemically examined in brain sections. IGF-1R␤ expression in the hippocampus was assessed by Western blotting. Results-The antiplatelet drugs, cilostazol and clopidogrel, reduced the spontaneous infarct volume more than aspirin.Only cilostazol improved motor and cognitive functions with a significant increase (PϽ0.05) in the memory-related IGF-1R-positive ratio and IGF-1R␤ expression in the hippocampus. Cilostazol reduced the 4 oxidative stress markers in affected neurons in stroke-prone spontaneously hypertensive rats regardless of blood pressure, regional cerebral blood flow, or serum lipid levels. Conclusions-The

“…The rat model of BCCAO shows marked white matter rarefaction and glial cell activation (Wakita et al, 1994(Wakita et al, , 1998. WM lesions are thought to contribute to cognitive impairment, and they have a strong relationship with oxidative stress, apoptosis and inflammatory damage (Wakita et al, 1994;Tanaka et al, 2001;Watanabe et al, 2006).…”

mentioning

confidence: 99%

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

Peng¹,

Xu²,

Chen³

et al. 2007

J Pharmacol Exp Ther

3-n-Butylphthalide (NBP) may be beneficial for the treatment of ischemic stroke with multiple actions on different pathophysiological processes. In the present study, we investigated the effect of NBP isomers on learning and memory impairment induced by chronic cerebral hypoperfusion in rats. Male Wistar rats were orally administered 10 and 30 mg/kg l-, d-, or dl-NBP daily for 23 days after bilateral permanent occlusion of the common carotid arteries. Rats receiving 10 mg/kg l-NBP performed significantly better in tests for spatial learning and memory, and they had attenuated cerebral pathology, including neuronal damage, white matter rarefaction, and glial activation compared with controls. Furthermore, 10 mg/kg l-NBP-treated rats had significantly higher choline acetyltransferase activity, decreased cortical lipid peroxide, and reduced hippocampal superoxide dismutase activity, compared with vehicle controls. However, d-and dl-NBP did not show significant beneficial effects. The present findings demonstrate that the beneficial effects of l-NBP on hypoperfusion-induced cognitive deficits may be due to preventing neuropathological alterations, inhibiting oxidative damage and increasing acetylcholine synthesis. Our results strongly suggest that l-NBP has therapeutic potential for the treatment of dementia caused by decreased cerebral blood flow.Senile dementia, a progressive aging-related disease, has become an important medical and social problem due to the increase in the number of elderly. Vascular dementia (VaD), as the second most common form of dementia in the elderly, accounts for approximately 20 to 30% of dementia cases (Giacobini, 2004). VaD is a syndrome presenting with both cognitive and noncognitive symptoms. Cognitive deficits of VaD include memory deficits, executive function damage, slow processing of information, and behavioral and mood abnormalities (Micieli, 2006). The underlying basis of VaD is complicated, because cerebral multi-infarct, cerebrovascular diseases, arterial hypotension, cardiac arrest, and hemorrhagic diseases may all result in VaD (Micieli, 2006). At present, no specific drug exists to prevent, delay, or cure VaD.It is well known that a decrease in cerebral blood flow precedes the onset of VaD (Roman et al., 1993), and chronic cerebral hypoperfusion may be a trigger for VaD and the accompanying cognitive deficits (Kasparova et al., 2005). As well, the decrease in cerebral blood flow relates to the cognitive impairment seen in AD (Kasparova et al., 2005). 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 en...