Anti-inflammatory study of 6-mercaptopurine and Atorvastatin in vasospasm after experimental subarachnoid hemorrhage

• Main Authors: Chih-Zen Chang, 張志任
• Other Authors: Shen-Long Howng
• Format: Others
• Language: zh-TW
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/27649313179459744785

博士 === 高雄醫學大學 === 醫學研究所 === 98 === According to the statistic report of the Department of Health, the Exective Yuan, R.O.C. in 2005, stroke ranks as the second leading cause of death. Among stroke patients, there are seventy percentages with ischemic stroke, and 20% intracerebral hemorrhage. Aneurysmal subarachnoid hemorrhage (SAH) accounts for a critic part of hemorrhagic stroke. The incidence of ruptured cerebral aneurysm is estimated approximately 2-3 among one hundred thousand people per year19,29,42,58. Despite studies in the past fifty years, the pathognesis of aneurysmal vasospasm remained unclear. Those studies accumulated lots of knowledge support that cerebral vasospasm is induced by multifactors, which persist to stimulate more preclinical and clinical studies. However, cerebral vasospasm subject to SAH remains to be a catastrophic mobidity amend to be solved by now. Over the past decades, the neurosurgery team in Kaohsiung Medical University is devoted to the researches dealing with SAH induced vasospasm. Professor Howng and Professor Kwan had been dwelled in the studies of prostaglandin, endothelin-converting enzyme inhibitor, such as CGS26303, CGS26393, CGS35066, in the experimental SAH and endothelin-related cerebral vasospasm. 16,50-51,70-72,81 The study of Professor Lin is set on the preventive and therapeutic effects of female hormone (estrogen) in the pathogenesis of cerebral vasospasm.75-82 The further study of Shi et al is to investigate the effect of 17β-estrodiol on SAH induced cerebral vasospasm through the Nuclear factor-kB (NFκB) path.117 In these studies, the role of inflammatory response cannot be omitted in the whole pathogenesis of SAH induced vasospasm and the relationship has not been well clarified. Therefore, an inflammation-related study is carried out. 2,22,31 The study of 6-mercaptopurine indicates that this compound can be effective in the triscription of deoxyribose nucleotides(DNA) to ribose nucleotides(RNA), direct propriate protein synthesis in the cellular proliferation , as well as white blood cell activation. According to above unsolved pitfalls, it is interested to perform the following studies: 1. 6-mercaptopurine, a nucleotide anti-metabolite, in pro-inflammatory cytokines (IL-1α, IL-1β, IL-6, TNF-α) generation and perivascular common leukocyte antigen, CD45(+) leukocytes infiltration in experimental SAH. Cytokines, derived from marcrophages, play a critic role in the organization and regulation of immune response in many mammalian diseases. Several varieties of cytokines, such as IL-1, IL-6, IL-12, and Tumor necrosis factor-α(TNF-α), deem to empower the bursting immune response. In the contrary, IL-8 is known to be one of the important factors which counteract the immune response. 31,39,46,83 The increased serum TNF-α would promote vascular endothelial cells and polymorphologic neutrophils (PMN) to produce excessive amount of endothelin-1, thereby increasing the tendency of cerebral vasospasm. Therefore, regarding to the immune study of SAH, the utility of purine nucleotide antagonist, 6-mercaptopurine, may be by reducing the bioactivity of Nerve Growth Factor-Induced-B (NGFI-B), while further reduce the levels of IL-1, IL-6 and TNF-α in serum and cerebrospinal fluid. Likewise, 6-mercaptopurine can prohibit the chemoattractant CD45 (+) monocytes migrating to the adventia, and protect vascular endothelial cells as well as decrease the aggregation of white blood cells. Owing to reduce TNF-α levels, the serum level of endothelin and circulating endothelin in the cerebrospinal fluid was decreases. Through this mechanism, 6-mercaptopurine achieves its preventive effect as well as reversal of experimental SAH-induced vasospasm. The interest of current research is that the reduced serum TNF-α level will activate the negative feedback of the Neuron factor-κB (NF-κB) 6,11,44,49,102, hence inhibit the expression of nitric oxide synthase (NOS) in endothelial cells. Thus 6–mercaptopurine is shown to reduce the production of endothelin through the NO-independent mechanism. The conditions of an ideal medication for treatment of cerebral vasospasm subject to SAH should include the lower price, lowest effective dose devoid of side effects. 6-mercaptopurine is a widely used medication for the treatment of leukemia. In our studies, this compound is proved to be able to reduce the white blood production, while reducing the endothelial cells of adhesion molecules inter-cellular adhesion molecule 1(ICAM-1), E-selectin, to achieve the antivasospastic effect within a short duration of therapy. Talking about the side effect of 6-mercaptopurine, long-term administration of 6-mercaptopurine has the potential to destroy the function of bone marrow, also cause damage to the hepatic and renal function. Under the indication of safety, it is not recommended long-term therapy of 6-mercaptopurine, and the patients must undergo regular liver and renal function and hematological examination. Fortunately, in the clinical cases of vascular spasm caused by SAH, the peak of vascular constriction often occur between the fourth day and the 14th day after SAH occurred, and therefore the treatment of such agents will not last for a long period. 6-mercaptopurine is believed to be used as one of the adjuvant treatment in the therapy of aneurysmal vasospasm. 2. The antioxidant and anti-inflammatory effect of Statins in the treatment of SAH-induced vasospasm. Statins have now been used to treat the modern metabolic diseases: three high (high blood lipids, hypertension, high cholesterol). Statins have also been found to treating diseases other than dyslipidemia. Statins are known to have a pleotropic effects such as: anti-oxidation, anti-immune protection of endothelial cells, protecting the apotposis of nerve cells. 3,10,23,33-34,52,65 In our experiment, we found Atorvastain have effectively activated endothelial cell nitric oxide enzymes, while in the pre-conditional status, Atorvastatin will reduce the production of endothelin-1. Atorvastatin can effectively prevent SAH-induced vascular spasm, not only by increasing bioactivation of nitric oxide synthase. It also reduces the infiltration of pSTAT (+) macrophage and 12 lipooxygenase (12LO) white blood cell proliferation. Statins have shown in the diversity of characteristics of treatment of dyslipidemia. In the research of myocardial cell, Statins were found by controlling NO-related Ras homolog gene, member A (RhoA) / Rho kinase (ROCK) path to achieve the vasodilation73-74,101 and therefore it can be regarded that Statins could be included in the treatment of SAH related vasospasm in the future. In conclusion, when considering the mechanism of SAH related vasospasm, it is unclear that inflammation may enhance the vascular spasm caused by SAH immediately or lead to chronic vascular spasm. Lots of experiments show that inhibition of inflammation subsequent to SAH helps to alleviate the nerve damagein the episode of SAH. Presently, we will continue to explore the immunosupressant in bio-medicine, molecular biology and other fields and aim to clarify the mechanism of post-SAH vasospasm. By the way, to grasp the effective treatment of vasospasm subject to SAH.The final target of our studies look forward to find an early solution in clinical practice, in the bitter-free recipe for the treatment of aneurismal vasospasm .