1. Introduction

The walls of normal arteries are made of three distinct layers: intima, media and adventitia. An internal elastic lamina, which provides mechanical strength, separates the intima from the media. Layers of smooth muscle cells are seen in the media ^[1]. There is no external elastic lamina between the media and adventitia in intracranial arteries (Unlike the extracranial arteries) and adventitia is also very thin compared with vessels of similar diameter in other organs ^{[2, 3]}. These peculiar characteristics of cerebral arteries make them suitable vessels for aneurysm formation and growth.

The prevalence of unruptured cerebral aneurysms is estimated to be as high as 5%. ^[4]. Its prevalence in angiographic and autopsy studies, have been reported between 2 and 90 per 1000 ^{[5, 6].}Methodological differences between studies probably lead to this wide range. If all available evidence with inherent overestimation and underestimation is taken together, for adults without risk factors for subarachnoid hemorrhage, aneurysms are found in approximately 2% ^[7].

Intracranial aneurysm, which is the most common cause of spontaneous subarachnoid hemorrhage incidences, has a multifactorial etiology, and the significance of genetic factors is increasingly recognized ^[8]. Theoretically, role of arterial hypertension in aneurysm formation is important. Incidence of multiple aneurysms might also be higher compared to normotensive patients. In an unselected series of 737 aneurysm patients, it has been revealed that the major factor explaining multiplicity is the presence of hypertension, and the influence of age is not significant. Role of gender has been shown, indicating that females are more vulnerable to aneurysm formation ^[9].

Sudden, severe headache is a key symptom of a ruptured aneurysm. Focal neurological deficits may also exist depending on the site of the aneurysm ^[10].

Interventional neuroradiological technique offers minimally invasive procedures for these lesions. Embolization and coiling of aneurysms are the principal endovascular therapies. Although all patients with ruptured or unruptured aneurysms should be evaluated for endovascular therapy, not all patients are best addressed with this therapy. Conventional surgical clipping is still considered the most definite therapy by most professionals ^{[11, 12, 13, 14, 15]}. Damage to vital structures during the operation of aneurysms can be prevented by localization of lesions by neuronavigation system ^[16].

MMPs are important in the processes of degradation and remodeling of the vascular wall matrix which possess major role in development and rupture of aneurysms. Data from different reports on the possible influence of MMP gene polymorphisms on susceptibility to intracranial aneurysms is conflicting and so such possibility is controversial ^[17].

About 40% of MMPs family members have similar basic structure. Approximately 20 different types of MMPs have been known and classified based on their pre-synthetic region on chromosomes and their various substrate specificities. Number designations MMP-1 to MMP- 28 are used for classification ^[18].

Tissue remodeling associated with various physiological and pathological processes are influenced by MMPs. Example of such processes are: morphogenesis, angiogenesis, apoptosis, tissue, cirrhosis, arthritis, metastasis and brain tumors. It is thought that MMP-2 and MMP-9 are important in metastasis. MMP-1 is believed to be important in rheumatoid and osteo-arthritis. Recent data suggests importance of MMPs in the pathogenesis of Aortic Aneurysm. Increased MMPs degrade the structural proteins of the aortic wall ^{[19, 20]}.

Most MMPs are not expressed at high or detectable levels in the adult CNS. Nevertheless there are some exceptions, for example, high constitutive expression of MMP-11 and MMP-14 in the adult mouse brain have been revealed by RNASE protection assays ^[21]. Polymerase chain reaction (PCR) technique has also reveals the expression of MMP-2,-3, -7, -9 and -13 in the normal rat spinal cord ^[22]. As a whole ,MMPs are mainly not detectable in the normal central nervous system (CNS ) and their excess has been observed in some neurological disorders and after tissue injury.

Excess proteolytic activity capable of lysing gelatin and increased expression of plasmin, MT1,MMP (membrane-type matrix metalloproteinase-1), and MMP-2 has been demonstrated in aneurysmal tissues in comparison to normal cerebral arteries. This activity may cause focal degradation of the vascular extracellular matrix and may contribute to aneurysm formation and growth ^[23].

Matrix metalloproteinase-9 (MMP-9; gelatinase B, type 4 collagenase) is a member of the MMP gene family, which encodes a family of zinc-dependent enzymes with proteolytic activity against connective tissue proteins, including collagens, elastin, and proteoglycans. MMP-9 is known to be produced by inflammatory cells, especially macrophages and plays an important role in development and tissue remodeling ^[24]. Increased levels of MMP-9 and tissue inhibitor metalloproteins (TIMP) have been revealed in the aneurysm wall in both extra cerebral and the intracerebral arteries. Perturbations in MMP-9 levels that contribute to the matrix disruption and cerebral aneurysm formation are local rather than systemic and this local up-regulation is not the consequence of TIMP decrement ^[25].

MMP-9 excess has been demonstrated in abdominal aortic and intracranial aneurysms ^{[19, 26, 27, 28]} and its increment results in formation of aneurysms by degradation of type 4 collagen, proteoglycan core protein and elastin, which are not degraded by some other MMPs. MMP-9 is regulated mainly at the level of transcription in response to such regulatory molecules as tumor necrosis factor-a,interleukin-1, platelet-derived growth factor, and epidermal growth factor ^{[29, 30]}. Evidence reveal that imbalance in the local expression of MMP-9 and tissue inhibitors of metalloproteinases is linked to genetic components contributes to the susceptibility to cerebral aneurysms ^[31].

Screening for presymptomatic aneurysms by the use of plasma MMP-9 activity is not possible due to the absence of increased systemic metalloproteinase activity, However, aneurysmal progression and growth may be arrested by local therapeutic modulation of MMP-9 activity ^[25].

Concerning the role of MMPs in pathogenesis of cerebral aneurysms pharmaceutical therapy by MMP inhibitors may reduce the need for invasive treatment and have major advantages for patients as well as socioeconomic benefits ^[32].

Tetracycline has been shown to have MMP inhibitor effects. Doxycycline, a tetracycline analogue, despite its unclear mode of action is considered the main candidate. It has been shown that doxycycline treatment, reduces MMP-8 and MMP-9 levels and concentrations of tissue inhibitor of metalloproteinase-1 and cystatin C. This influence is considered to be through a profound effect on the number aortic wall neutrophils, and a pronounced but selective effect on the proteolytic alance in the abdominal aneurysm. This remarkable and novel observation suggests that doxycycline may also be effective in other vascular conditions involving neutrophils, such Behçet disease and Kawasaki disease, and nonvascular conditions such as chronic obstructive pulmonary disease ^{[33, 34]}.

Findings of a study reveal that MMP-2 expression from cultured human aortic smooth muscle cells (SMCs) and abdominal aortic aneurysm (AAA) tissue explants is inhibited by doxycycline at therapeutic serum concentrations. MMP activity contributes to degradation of extracellular matrix in AAAs and atherosclerotic plaque, so doxycycline may have potential value in treating these diseases ^[35].

There are convincing evidences that doxycycline prevents AAA formation in a variety of animal models ^{[36, 37, 38, 39]}, and the results from two small clinical studies suggest that doxycycline may also reduce AAA expansion and growth in patients ^{[40, 41]}.

There is a report which demonstrates that doxycycline inhibits expression of tissue MMP-2 and MMP-9, arrests degradation of the elastic matrix and delays aneurysm rupture in MFS-like mice (mouse model of Marfan syndrome). the study shows that MMPs causes expansion of thoracic aneurysm in MFS (Marfan syndrome) and that doxycycline may significantly inhibit progression of the disease ^[42].

Doxycycline decreases parenchymal angiogenesis and stimulated cerebral MMP-9 activity. The decrease in MMP-9 activity is associated with decreased micro vessel counts. MMP inhibitors, including tetracycline derivatives may modulate brain abnormalities that are caused by pathologically increased angiogenesis ^[43].

In one study, excess MMP activity was detected in intracerebral aneurysm tissues, and the treatment with doxycycline significantly reduced the incidence of intracranial aneurysms. It is noteworthy that the incidence of aneurysms was dramatically lower in MMP-9 knockout mice but not in MMP-2 knockout mice ^{[26, 44]}.

Incidence of intracranial aneurysms were reduced to 10% in Elastase-Induced Intracranial Aneurysms in Hypertensive Mice treated by doxycycline ^[45].

In spite of the aforementioned studies there is another experiment in rat model which doesn`t confirm that nonspecific MMP inhibition with doxycycline decrease intracranial aneurysm formation (by ligation technique in common carotid artery) ^[46].

Elastase-induced rabbit aneurysm formation in right common carotid artery is accompanied by total elastin destruction. The reason for aneurysm formation in this model may be the initial infusion of elastase, rather than continuous destruction from endogenous proteases released by inflammatory cells. Aneurysmal formation in this experiment, was not inhibited by the administration of doxycycline ^[47].

Statins( hypolipidemic and antiatherosclerotic agents ) are another sort of drugs that are considered MMP inhibitors. In vitro incubation of mouse macrophages and HMs (human monocyte–derived macrophages) with fluvastatin or simvastatin, two hypolipidemic and antiatherosclerotic agents, have been reported to decrease the amount of MMP-9 secreted, suggesting that the effect on MMP-9 activity is affected by statins as a class of drugs ^[48].

Statins also have been shown to decrease MMP-3 and MMP-9 concentrations in AAAs in clinical trials. Recent observational studies in humans suggest that statins may have a role in abdominal aortic aneurysm (AAA) prevention or may even inhibit aneurysm progression and growth ^{[49, 50, 51]}.

It has been reported that simvastatin reduces the risk of rupture of intracranial aneurysms in mice. In addition, simvastatin reduces superoxide production and MMP-related gelatinase activity in aneurysmal walls. anti-inflammatory and anti-oxidative properties of simvastatin may have inhibitory effects on intracerebral aneurismal rupture ^[52].

2. Conclusion

Considering the significant impact of MMPs on tissue remodeling associated with morphogenesis, angiogenesis, apoptosis, tissue repair and so on, and the observations in experimental models, it is probable that MMPs have some role in cerebral aneurysm formation and growth. Their role in abdominal aorta aneurysms have been studied more and there are convincing evidences that prescribing anti MMPs in these patients are helpful. Influence of MMP inhibitors such as doxycycline and statins on cerebral aneurysms have also been studied in some experiments. These have revealed promising results but it seems that designation of more sophisticated studies to demonstrate their exact role are necessary.

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