Pitavastatin suppresses formation and progression of cerebral aneurysms through inhibition of the nuclear factor kappaB pathway.
OBJECTIVE
Recent investigations strongly suggest that the pathophysiology of cerebral aneurysms (CA) is closely associated with chronic inflammation in vascular walls. Nuclear factor kappaB (NF-kappaB) has a key role in the formation and progression of CAs. Because statins exert anti-inflammatory effects in various vascular diseases, we investigated the effect of pitavastatin on NF-kappaB activation and CA formation in experimentally induced CAs in rats.


METHODS
CAs were induced in Sprague-Dawley rats with or without administration of pitavastatin (4 mg/kg/d orally). Size, change of internal elastic lamina, and media thickness of induced CAs were measured in both groups after aneurysm induction. The effects of pitavastatin on NF-kappaB activation in aneurysmal walls were examined by immunohistochemistry and gel shift assay. Expression of downstream genes was analyzed by quantitative polymerase chain reaction and immunohistochemistry. To examine whether pitavastatin has a suppressive effect on preexisting CAs, pitavastatin administration started 1 month after aneurysm induction.


RESULTS
Pitavastatin treatment significantly prevented CA progression (P < 0.01) and NF-kappaB activation in aneurysmal walls. Expression of monocyte chemotactic protein-1, vascular cell adhesion molecule-1, interleukin-1beta, inducible nitric oxide synthase, and matrix metalloproteinase-9 in aneurysmal walls was also inhibited by pitavastatin. Pitavastatin treatment led to media thickening in preexisting CAs.


CONCLUSIONS
Pitavastatin has a suppressive effect on CA progression through the inhibition of NF-kappaB activation in aneurysmal walls. Moreover, pitavastatin treatment can cause the regression of degenerative changes in preexisting CA walls. Pitavastatin is a promising candidate for a novel preventive agent against subarachnoid hemorrhage.
Aoki
Tomohiro
T
Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Kataoka
Hiroharu
H
Ishibashi
Ryota
R
Nakagami
Hironori
H
Nozaki
Kazuhiko
K
Morishita
Ryuuichi
R
Hashimoto
Nobuo
N
D000818:Animals; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D002532:Intracranial Aneurysm / Q000188:drug therapy* / Q000378:metabolism* / Q000517:prevention & control; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D011804:Quinolines / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D016896:Treatment Outcome
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; D011804:Quinolines; C108475:pitavastatin