RESUMO
In an attempt to elucidate the pathophysiology and clinical significance of global cerebral edema (GCE) following aneurysmal subarachnoid hemorrhage (SAH), the authors explored potential mechanisms and reviewed findings associated with this phenomenon. Admission computed tomography (CT) scans show GCE in up to 20% of patients experiencing aneurysmal SAH. This edema is likely to have been initiated by transient global ischemia, as indicated by an association between ictal loss of consciousness and the development of edema. A further cascade of events, including a rise in intracranial pressure and compromise of the blood-brain barrier, are also likely contributors. Clinically, GCE on CT after aneurysmal SAH is predictive of a poor outcome. Further investigation is needed to gain a full understanding of edema development following SAH, with the hope that the knowledge can be used to influence treatment positively and improve outcome.
Assuntos
Edema Encefálico/etiologia , Aneurisma Intracraniano/complicações , Hemorragia Subaracnóidea/complicações , Barreira Hematoencefálica/fisiopatologia , Progressão da Doença , Humanos , Pressão Intracraniana/fisiologia , Modelos Biológicos , Fatores de TempoRESUMO
Overexpression of glucosylceramide synthase (GCS), a pivotal enzyme in glycolipid biosynthesis, contributes to cancer cell resistance to chemotherapy. We previously showed that transfection of doxorubicin-resistant MCF-7-AdrR cells with GCS antisense restored cell sensitivity to doxorubicin and greatly enhanced sensitivity to vinblastine and paclitaxel. In that study, doxorubicin promoted generation of ceramide in MCF-7-AdrR/GCS antisense cells; the present study implicates factors in addition to ceramide that augment sensitivity to chemotherapy. Although GCS antisense cells showed enhanced ceramide formation compared with MCF-7-AdrR when challenged with paclitaxel, GCS antisense cells also showed a 10-fold increase in levels of intracellular drug (paclitaxel and vinblastine). In addition, transfected cells had dramatically decreased expression (80%) of P-glycoprotein and a 4-fold decrease in the level of cellular gangliosides. Chemical inhibition of GCS produced the same effects as antisense transfection: exposure of MCF-7-AdrR cells to the GCS inhibitor 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP, 5.0 micromol/L, 4 days) decreased ganglioside levels, restored sensitivity to vinblastine, enhanced vinblastine uptake 3-fold, and diminished expression of MDR1 by 58%, compared with untreated controls. A similar effect was shown in vinblastin-resistant KB-V0.01 cells; after 7 days with PPMP (10 micromol/L), MDR1 expression fell by 84% and P-glycoprotein protein levels decreased by 50%. MCF-7-AdrR cells treated with small interfering RNAs to specifically block GCS also showed a dramatic decrease in MDR1 expression. This work shows that limiting GCS activity down-regulates the expression of MDR1, a phenomenon that may drive the chemosensitization associated with blocking ceramide metabolism. The data suggest that lipids play a role in the expression of multidrug resistance.