Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases Expression in Human Ruptured and Unruptured Cerebral Aneurysm and the Inhibition with Doxycycline in Rat Intracranial Aneurysm

Cerebral aneurysms is a common vascular disease, is the first cause of subarachnoid hemorrhage . in general cerebral aneurysms hasnot any symptom before rupture , although there are many advanced therapy , the morality of ruptured aneurysms is up to 50%.By now, the molecule pathology mechanics is not very clear . cerebral aneurysms has many affected factors: age, smoke, hypertension etc. in the past people think aneurysms formation is influenced by genetics , blood flow dynamic and degeneration. During deep research , a lot of evidence show matrix metalloproteinase(MMPs) take part in the aneurysms formation and rupture . MMP can degrade elastin and collagen, regulate the remodeling of vascular, play a important role in aneurysms foemation andevolution. Part 1Object matrix metalloproteinases (MMPs)and tissue inhibitors of metalloproteinases (TIMPs) are potent elastases and collagenases, which regulate the remodeling of vascular, play a important role in the development of cerebral aneurysm. Methods The patients were divided to 2 groups: ruptured and unruptured. Tissue samples of the cerebral aneurysm were obtained from 30 patients who underwent cerebral aneurysm clipping operation .We use real-time RT-PCR method to quantitatively measure mRNA levels in small tissue samples and determined gene expression levels of MMPs and TIMPs relative to that of glutaraldehyde 3-phosphate dehydrogenase (GAPDH) in each sample. ELISA method measure the serum level of MMP-2,MMP-9 in cerebral ruptured aneurysm patients and unruptured aneurysm patients. Result MMP-2 and MMP-9 were overexpressed in cerebral ruptured aneurysmcompared with unruptured aneurysm. The expression levels of MMP-2 to TIMP-l,MMP-2 to TIMP-2,MMP-2 to TIMP-3 and MMP-9 to TIMP-2 were higher in cerebral ruptured aneurysms than in unruptured aneurysms. Patients with cerebral ruptured aneurysm (n = 15) had higher serum MMP-2, MMP-9 levels than those unruptured aneurysm detectable by angiography. Conclusion The disproportional expression of both MMP-2, MMP-9 and TIMP contribute to the evolution of cerebral aneurysm..part 2Object to study nonspecific matrix metalloproteinase (MMP) inhibition with doxycycline decrease the incidence of intracranial aneurysm formation in a rat aneurysm model. Methods We performed common carotid artery ligation on 96 Long-Evans rats. A treatment group of 48 animals was chosen at random to receive oral doxycycline (3 mg/kg) in addition to standard rat chow, and the control group of 48 animals received standard rat chow only. The major circle of Willis arteries was dissected at 1 year following carotid ligation, and the proportions of animals with aneurysms were compared between groups. Result Four animals given oral doxycycline and five control animals expired before 1 year. Of the examined animals, 4 saccular intracranial aneurysms were found in 4 of 44 animals which had received doxycycline (9%) , and 10 saccular intracranial aneurysms were found in 10 of 43 control animals (23.2%) . There was significant difference in aneurysm formation between the doxycycline-treated and control groups (P=0.01). Conclusion nonspecific MMP inhibition with doxycycline is effective in preventing intracranial aneurysm formation in a rat model.