Farnesyl transferase inhibitors induce neuroprotection by inhibiting Ha-Ras signalling pathway.
In previous studies we found that the GTPase p21 Harvey-Ras (Ha-Ras) stimulates the production of reactive oxygen species and induces apoptosis by oxidative stress; this effect was reversed by farnesyl transferase inhibitors (FTIs). In this study we investigated whether FTIs reduce rat brain damage induced by an excitotoxic stimulus, and the signalling pathway(s) underlying the neuroprotection by FTIs. In brain tissue, protein levels of Ha-Ras and farnesylation inhibition were assayed by Western blot, and superoxide production was measured by hydroethidine. The excitotoxic lesion was induced by intrastriatal injection of N-methyl-d-aspartate (NMDA). The survival of mouse neuronal cortical cells was assessed by 3-(4,5 dimethylthialzol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). In brain tissue, NMDA increased the protein levels of Ha-Ras, FTIs caused the accumulation of non-prenylated inactive Ras in the cytosolic fraction, and significantly reduced superoxide production and necrotic volume after excitotoxicity. FTIs increased the viability of mouse neuronal cortical cells following oxidative stress. In conclusion, FTIs inhibited Ha-Ras, decreased oxidative stress and reduced necrotic volume by partly acting on neuronal cells. Thus, Ha-Ras inhibition plays a role in the pathology of neuroprotection, suggesting a potential role of FTIs in the treatment of cerebrovascular diseases.
Ruocco
Antonio
A
Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy.
Santillo
Mariarosaria
M
Cicale
Maria
M
Serù
Rosalba
R
Cuda
Giovanni
G
Anrather
Josef
J
Iadecola
Costantino
C
Postiglione
Alfredo
A
Avvedimento
Enrico V
EV
Paternò
Roberto
R
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D051231:Farnesyltranstransferase / Q000378:metabolism; D008297:Male; D008298:Maleates / Q000494:pharmacology*; D051379:Mice; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013778:Tetrazolium Salts; D013844:Thiazoles
D018690:Excitatory Amino Acid Agonists; D008298:Maleates; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; C080569:chaetomellic acid A; D016202:N-Methylaspartate; D051231:Farnesyltranstransferase; D016283:Proto-Oncogene Proteins p21(ras); C022616:thiazolyl blue