Asiatic acid, a triterpenoid derivative from Centella asiatica, has shown biological effects such as antioxidant, antiinflammatory, and protection against glutamate-or β-amyloid-induced neurotoxicity. We investigated the neuroprotective effect of asiatic acid in a mouse model of permanent cerebral ischemia. Various doses of asiatic acid (30, 75, or 165 mg/kg) were administered orally at 1 hr pre-and 3, 10, and 20 hr postischemia, and infarct volume and behavioral deficits were evaluated at day 1 or 7 postischemia. IgG (blood-brain barrier integrity) and cytochrome c (apoptosis) immunostaining was carried out at 24 hr postischemia. The effect of asiatic acid on stress-induced cytochrome c release was examined in isolated mitochondrial fractions. Furthermore, its effects on cell viability and mitochondrial membrane potential were studied in HT-22 cells exposed to oxygenglucose deprivation. Asiatic acid significantly reduced the infarct volume by 60% at day 1 and by 26% at day 7 postischemia and improved neurological outcome at 24 hr postischemia. Our studies also showed that the neuroprotective properties of asiatic acid might be mediated in part through decreased blood-brain barrier permeability and reduction in mitochondrial injury. The present study suggests that asiatic acid may be useful in the treatment of cerebral ischemia.Keywords infarct volume; blood-brain barrier; oxygen-glucose deprivation; mitochondria; apoptosis Although the molecular mechanisms involved in ischemic brain injury are not fully understood, much progress has been made in identifying some pathogenic pathways, such as inflammation, excitotoxicity, mitochondrial dysfunction, and oxidative stress, that might be involved in ischemic neuronal death (Durukan and Tatlisumak, 2007 Centella asiatica is a herbaceous plant that might also have medicinal value. It is being used in Ayurvedic preparations to improve learning and memory (Zheng and Qin, 2007). Published data suggest that the plant extract has nootropic effects (Rao et al., 2005), protects the brain from age-related oxidative damage (Subathra et al., 2005), and promotes nerve growth and neuronal dendritic arborization (Mohandas et al., 2006).Asiatic acid (AA), a pentacyclic triterpene derivative from Centella asiatica, has been shown to display neuroprotective properties both in vitro and in vivo (Bonfill et al., 2006). In cellular systems, AA was reported to offer protection against β-amyloid-induced cell death in the neuroblastoma B103 cell line (Mook-Jung et al., 1999;Jew et al., 2000). It also reduced H 2 O 2 -related cell death and decreased intracellular free radical concentration (Mook-Jung et al., 1999). Furthermore, AA derivatives were effective at rescuing primary rat cortical cells from glutamate-induced toxicity through activation of the cellular oxidative defense pathway (Lee et al., 2000).Because AA exhibits numerous pharmacological activities that might be beneficial to the ischemic brain, and given that no significant toxicity was observed following subcutaneous o...

No abstract

No abstract

Carnosine (β-alanyl-L-histidine) has been shown to exhibit neuroprotection in rodent models of cerebral ischemia. In the present study, we further characterized the effects of carnosine treatment in a mouse model of permanent focal cerebral ischemia and compared them with its related peptides anserine and N-acetylated carnosine. We also evaluated the efficacy of bestatin, a carnosinase inhibitor, in ameliorating ischemic brain damage. Permanent focal cerebral ischemia was induced by occlusion of the middle cerebral artery (pMCAO). Mice were subsequently randomly assigned to receive an intraperitoneal injection of vehicle (0.9% saline), carnosine, N-acetyl carnosine, anserine, bestatin alone, or bestatin with carnosine. Infarct size was examined using 2,3,5-triphenyltetrazolium chloride staining 1, 3, and 7 days following pMCAO, and neurological function was evaluated using an 18-point-based scale. Brain levels of carnosine were measured in treated mice using high-performance liquid chromatography 1 day following pMCAO. We demonstrated that treatment with carnosine, but not its analogues, was able to significantly reduce infarct volume and improve neurological function compared with those in vehicle-treated mice. These beneficial effects were maintained for 7 days post-pMCAO. In contrast, compared with the vehicle-treated group, bestatin-treated mice displayed an increase in the severity of ischemic lesion, which was prevented by the addition of carnosine. These new data further characterize the neuroprotective effects of carnosine and suggest that carnosine may be an attractive candidate for testing as a stroke therapy.