EFFECTS OF IMMUNOSUPPRESSANT, FK-506 (TACROLIMUS), ON CHANGES OF BRAIN GENE EXPRESSION AFTER BRAIN INJURY : MOLICULAR BIOLOGICAL ANALYSIS OF INHIBITORY EFFECT OF APOPTOSIS

钙调磷酸酶（calcalineurin）是一种丝氨酸/苏氨酸磷酸酶，它能激活t细胞，对免疫细胞的分化/生长和免疫疾病的病理具有重要作用。FK-506（他克莫司）是一种新的免疫抑制剂，有助于器官移植的成功。已知FK-506的免疫抑制机制是通过与亲免疫蛋白形成钙调神经磷酸酶和FK-506复合物来抑制钙调神经磷酸酶活性。钙调磷酸酶广泛分布于海马体、纹状体和大脑皮层。FK-506对谷氨酸毒性、局灶性和短暂性全脑缺血具有神经保护作用。钙调磷酸酶激活基因转染的细胞在无血清传导下发生明显的凋亡，与Bcl-2直接结合可抑制细胞凋亡。我们推测钙调磷酸酶在各种脑损伤的细胞凋亡中起一定作用。在本研究中，我们明确了在颅内压升高、冲击损伤和低温损伤等条件下，直接早期基因（c-fos、c-jun）和凋亡相关基因的表达变化。然后建立大鼠弥漫性轴索损伤模型，分析钙调磷酸酶给药后大鼠脑电图、凋亡相关基因和淀粉样前体蛋白（APP）表达的变化。然而，我们无法获得这些参数的显著变化。

Calcineurin, serin/threonine phosphatase, has an important role for the differentiation/growth of immune cells and pathology of immune diseases because it acitvates T-cell. FK-506 (tacrolimus), a new immunosuppressant, contributes to success in organ transplantation. The immunosuppressing mechanism of FK-506 is known to be an inhibition of calcineurin activity by complex formation of calcineurin and FK-506 with immunophilin. Calcineurin widely distributes in hippocampus, striatum, and cerebral cortex. FK-506 has neuroprotective effects against glutamate toxicity, focal, and transient global cerebral ischemia. Marked apoptosis occurred in calcineurin activated gene transfected cells under serum-free conduction, which is inhibited by direct combination with Bcl-2. We suspected that calcineurin had some roles on apoptosis in various cerebral damages. In the present study, we clarified changes of expression of immediate early genes (c-fos, c-jun) and apoptosis related gene in some conditions, increased intracranial pressure, impact injury, and cryogenic injury. Then, we produced diffuse axonal injury model using rats, and analyzed changes of IEGs, apoptosis related genes, and amyloid precursor protein (APP) expression after calcineurin administration. However, we could not obtain significant changes of these parameters.