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

Abstract

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...

L-3-n-Butylphthalide Improves Cognitive Impairment and Reduces Amyloid- in a Transgenic Model of Alzheimer's Disease

“…The inhibitory effect of L-NBP on gliosis may be secondary to the lowering of the A␤ plaque burden. However, L-NBP has been shown to have a direct antiinflammatory effect independent of A␤ (Peng et al, 2007b). Additional studies of L-NBP on neuroinflammation are ongoing, but the anti-inflammatory effect of L-NBP demonstrated here provide additional evidence of the therapeutic potential of L-NBP for AD.…”

“…Previous studies showed that L-NBP significantly improved microcirculation in pial arterioles (Xu and Feng, 1999), reduced the area of cerebral infarct and inhibited platelet aggregation (Peng et al, 2004(Peng et al, , 2005, improved mitochondrial function and decreased oxidative damage (Dong and Feng, 2002), reduced neuronal apoptosis (Chang and Wang, 2003), and inhibited increases in intracellular calcium levels and the inflammatory re-sponse (Xu and Feng, 2000) in experimental ischemic animal models. Recently, we found that L-NBP alleviated the learning and memory deficits induced by chronic cerebral hypoperfusion in rats (Peng et al, 2007b). In A␤ intracerebroventricularly infused rats, oral gavage with L-NBP significantly improved cognitive impairment and inhibited oxidative injury, neuronal apoptosis, and glial activation (Peng et al, 2009).…”

l-3-n-butylphthalide alleviates hydrogen peroxide-induced apoptosis by PKC pathway in human neuroblastoma SK-N-SH cells

“…Recently, L-NBP has been separated from DL-NBP, and our study showed that L-NBP might be potent for AD treatment. In the AD animal models, we found that L-NBP significantly improved learning and memory deficits by reducing oxidative stress, neuronal apoptosis, and reduced Aβ plaques deposits (Peng et al 2007b(Peng et al , 2009(Peng et al , 2010Ma et al 2009). Furthermore, we found that L-NBP protected neurons against Aβ-induced apoptosis in vitro study (Peng et al 2008).…”

Retrospect and prospect of active principles from Chinese herbs in the treatment of dementia

“…L-NBP treatment could significantly reverse Aβ-induced cytotoxicity, probably through an inhibition of tau protein hyperphosphorylation [97] . L-NBP significantly attenuates cerebral hypoperfusion-induced learning dysfunction and brain damage in rats [98] . Moreover, recent results indicate that long-term treatment with L-NBP may prevent age-associated cognitive dysfunction in rats [99] .…”