Ras is a universal eukaryotic intracellular protein integrating extracellular signals from multiple receptor types. To investigate its role in the adult central nervous system, constitutively activated V12-Ha-Ras was expressed selectively in neurons of transgenic mice via a synapsin promoter. Ras-transgene protein expression increased postnatally, reaching a four- to fivefold elevation at day 40 and persisting at this level, thereafter. Neuronal Ras was constitutively active and a corresponding activating phosphorylation of mitogen-activated kinase was observed, but there were no changes in the activity of phosphoinositide 3-kinase, the phosphorylation of its target kinase Akt/PKB, or expression of the anti-apoptotic proteins Bcl-2 or Bcl-XL. Neuronal Ras activation did not alter the total number of neurons, but induced cell soma hypertrophy, which resulted in a 14.5% increase of total brain volume. Choline acetyltransferase and tyrosine hydroxylase activities were increased, as well as neuropeptide Y expression. Degeneration of motorneurons was completely prevented after facial nerve lesion in Ras-transgenic mice. Furthermore, neurotoxin-induced degeneration of dopaminergic substantia nigra neurons and their striatal projections was greatly attenuated. Thus, the Ras signaling pathway mimics neurotrophic effects and triggers neuroprotective mechanisms in adult mice. Neuronal Ras activation might become a tool to stabilize donor neurons for neural transplantation and to protect neuronal populations in neurodegenerative diseases.

AIM:The purpose of this study is to detect gene expression patterns following focal cerebral ischemia. MATeRIAL and MeTHods:25 male Wistar rats were divided into control (n = 8) and ischemic (n = 17) groups. In the ischemic group, slowly progressing focal ischemia was simulated by two-vein occlusion with spreading depression (SD) a cortical microinjection of KCl induced. Ischemic tissue was removed at 2, 8, 24, or 72 h postischemia. Using semiquantitative reverse transcription polymerase chain reaction, we investigated mRNA expression levels of 13 representative genes related to cerebral ischemia. Cluster analysis of the gene expression levels was done. ResULTs:In the ischemic group, the expression levels of c-fos, cyclin D1, and COX-2 were significantly higher at 2 h postischemia, and those of bcl-2, bcl-xL, and HO-1 at 72 h. Based on the cluster analysis, we statistically divided examined genes into three groups: group A, early expression (COX-2, c-fos, and bcl-2); group B, s expression (c-jun, SOD-1, bad, p53, SOD-2, bcl-xL, and bax); and group C, late expression (cyclin D1, c-myc, and HO-1). CoNCLUsIoN:We statistically classified the genes into three groups after focal ischemia. The genes of the early-and late-expression groups can be possible therapeutic targets for the treatment of cerebral ischemia.

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