Triptolide Inhibits the Proliferation of Immortalized HT22 Hippocampal Cells Via Persistent Activation of Extracellular Signal-Regulated Kinase-1/2 by Down-Regulating Mitogen-Activated Protein Kinase Phosphatase-1 Expression

OBJECTIVE: Triptolide (TP) has been reported to suppress the expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1), of which main function is to inactivate the extracellular signal-regulated kinase-1/2 (ERK-1/2), the p38 MAPK and the c-Jun N-terminal kinase-1/2 (JNK-1/2), and to exert antiproliferative and pro-apoptotic activities. However, the mechanisms underlying antiproliferative and pro-apoptotic activities of TP are not fully understood. The purpose of this study was to examine whether the down-regulation of MKP-1 expression by TP would account for antiproliferative activity of TP in immortalized HT22 hippocampal cells. METHODS: MKP-1 expression and MAPK phosphorylation were analyzed by Western blot. Cell proliferation was assessed by 3H-thymidine incorporation. Small interfering RNA (siRNA) against MKP-1, vanadate (a phosphatase inhibitor), U0126 (a specific inhibitor for ERK-1/2), SB203580 (a specific inhibitor for p38 MAPK), and SP600125 (a specific inhibitor for JNK-1/2) were employed to evaluate a possible mechanism of antiproliferative action of TP. RESULTS: At its non-cytotoxic dose, TP suppressed MKP-1 expression, reduced cell growth, and induced persistent ERK-1/2 activation. Similar growth inhibition and ERK-1/2 activation were observed when MKP-1 expression was blocked by MKP-1 siRNA and its activity was inhibited by vanadate. The antiproliferative effects of TP, MKP-1 siRNA, and vanadate were significantly abolished by U0126, but not by SB203580 or SP600125. CONCLUSION: Our findings suggest that TP inhibits the growth of immortalized HT22 hippocampal cells via persistent ERK-1/2 activation by suppressing MKP-1 expression. Additionally, this study provides evidence supporting that MKP-1 may play an important role in regulation of neuronal cell growth.

Ruptured Aneurysm of Distal Posterior Inferior Cerebellar Artery: Report of Two Cases / 대한뇌혈관외과학회지

Aneurysms arising from the distal posterior inferior cerebellar artery (PICA) are rare. We present two cases of ruptured distal PICA aneurysms. A 48-year-old woman was admitted to our hospital because of sudden onset of severe headache and vomiting. A radiological examination revealed intraventricular hemorrhage (IVH) caused by rupture of a right distal PICA aneurysm. The aneurysm was clipped completely through a midline suboccipital approach. A 74-year-old woman was admitted to our hospital because of sudden onset of severe headache and vomiting, which was followed by unconsciousness. A radiological examination showed a hematoma in the cerebellar vermis and IVH from the fourth ventricle to the lateral ventricle with severe hydrocephalus caused by rupture of a left distal PICA aneurysm. After emergency extraventricular drainage was performed, the aneurysm was obliterated by the use of proximal parent artery clipping and coagulation. Aneurysms of the distal PICA are frequently associated with structural vascular anomalies and a high incidence of bleeding when these aneurysms are small. Thus, distal PICA aneurysms should be obliterated in almost all instances whenever they are encountered and these aneurysms should be managed immediately because of the high risk of rebleeding.