Mast cell tumors are among the most commonly seen tumors of the skin in dogs and are more highly aggressive than mast cell tumors of other species. Some breeds display a markedly higher incidence of mast cell tumor development than others and appear to have some genetic predisposition. Recently, mutations have been found in canine mast cell tumor tissues and cell lines within the juxtamembrane domain of the protooncogene c-KIT In previous studies utilizing a small number of cases, no association between the presence of a mutation and the breed of dog or grade of the tumor could be identified. An expanded study with a larger sample set was performed to explore this possibility. The juxtamembrane domain of c-KIT was amplified using the polymerase chain reaction from genomic DNA preparations of 88 paraffin-embedded mast cell tumors from selected breeds. Mutations, consisting of duplications and deletions, were found in 12 of the tumors. A significant association was found between the presence of a mutation and a higher grade of tumor but not between breed and grade or between breed and the presence of a mutation.

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...

Background and Purpose-Carnosine is a naturally occurring dipeptide with multiple neuroprotective properties. In addition, it is well tolerated in high doses with minimal side effects. The purposes of this study were to determine whether carnosine is neuroprotective in permanent focal cerebral ischemia and to determine potential mechanisms of neuroprotection. Methods-We investigated the efficacy of carnosine in a mouse model of permanent focal cerebral ischemia. The effects of carnosine were investigated with respect to neuronal damage and infarct formation, endogenous antioxidant status, and matrix metalloproteinase activity. Results-Carnosine significantly decreased infarct size and neuronal damage when administered at time points both before and after the induction of ischemia. Carnosine also decreased reactive oxygen species levels in the ischemic brain, preserved normal glutathione levels, and decreased matrix metalloproteinase protein levels and activity. Conclusions-Carnosine is neuroprotective in focal cerebral ischemia and appears to influence deleterious pathological processes that are activated after the onset of ischemia.

Minocycline is a member of the tetracycline class of molecules with broad-spectrum antibiotic activity. The unique properties of minocycline result in increased tissue distribution when compared with the other tetracyclines. Of particular interest is the ability of minocycline to diffuse into the central nervous system at clinically effective levels. Aside from its antimicrobial properties, minocycline has been found to have beneficial effects on inflammation, microglial activation, matrix metalloproteinases, nitric oxide production, and apoptotic cell death. Concordantly, minocycline has been found to have neuroprotective effects in animal models of a number of diseases including stroke, multiple sclerosis, and Parkinson disease. The proven safety of minocycline over decades of use as an antibiotic suggests that it may have potential for development into an effective treatment of multiple neurologic conditions in humans.

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.