Semisynthetic sphingolipids prevent protein kinase C translocation and neuronal damage in the perifocal area following a photochemically induced thrombotic brain cortical lesion.
A vascular thrombotic lesion localized to the rat sensorimotor cortex was produced following intravenous injection of the photosensitive dye rose bengal, and its activation with a small beam of high-intensity white light focused to the skull overlaying the sensorimotor cortex. In the sensorimotor cortex at various times after the triggering event, two contiguous brain regions with different degree(s) of neuronal damage can be distinguished: (1) a primary thrombotic ischemic core where the majority of cells are dead and (2) a penumbra region surrounding the core lesion in which a slower progressive neuronal degeneration is occurring. Importantly, in both brain regions the neuronal degeneration is associated with the activation and persistent translocation of protein kinase C (PKC) as indicated by an increase in 4-beta-3H-phorbol-12,13-dibutyrate (3H-PDBu) binding. Moreover, the demonstration that in the area penumbra the neuronal degeneration and the persistent translocation of PKC can be inhibited by a pretreatment with dizocilpine (i.e., MK-801) indicates that the dynamics of the progression of the neuronal degeneration are maintained by glutamate accumulating in the extraneuronal fluids. MK-801 additionally prevents the transcriptional activation of several immediate-early genes (IEGs) (e.g., c-fos) and their cognate third nuclear messenger (i.e., c-Fos) expression present in the hemisphere ipsilateral to the lesion. On the other hand, LIGA4 and LIGA20 derivatives of GM1 lysoganglioside reduce the membrane translocation of PKC and the neuronal damage in the penumbra area, but fail to change the increase of IEG expression in the cortex ipsilateral to the lesion.
Fidia-Georgetown Institute for the Neurosciences, Georgetown University, School of Medicine, Washington, D.C. 20007.
A
A
Kharlamov
A
A
Guidotti
E
E
Costa
R
R
Hayes
D
D
Armstrong
D000818:Animals; D001345:Autoradiography; D001692:Biological Transport / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002542:Intracranial Embolism and Thrombosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D008027:Light; D008297:Male; D009474:Neurons / Q000473:pathology*; D015240:Phorbol 12,13-Dibutyrate / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012395:Rose Bengal; D013107:Sphingolipids / Q000138:chemical synthesis / Q000494:pharmacology*
D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D013107:Sphingolipids; D012395:Rose Bengal; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C