Strokin Mikhail, Sergeeva Marina, Reiser Georg
Medizinische Fakultät, Institut für Neurobiochemie, Otto-von-Guericke-Universitaet Magdeburg, Leipziger Strasse 44, D-39120 Magdeburg, Germany.
Int J Dev Neurosci. 2004 Nov;22(7):551-7. doi: 10.1016/j.ijdevneu.2004.07.002.
Various diseases of the central nervous system are characterized by induction of inflammatory events, which involve formation of prostaglandins. Production of prostaglandins is regulated by activity of phospholipases A(2) and cyclooxygenases. These enzymes release the prostaglandin precursor, the n-6 polyunsaturated fatty acid, arachidonic acid and oxidize it into prostaglandin H(2). Docosahexaenoic acid, which belongs to the n-3 class of polyunsaturated fatty acids, was shown to reduce production of prostaglandins after in vivo and in vitro administration. Nevertheless, the fact that in brain tissue cellular phospholipids naturally have a uniquely high content of docosahexaenoic acid was ignored so far in studies of prostaglandin formation in brain tissue. We consider the following possibilities: docosahexaenoic acid might attenuate production of prostaglandins by direct inhibition of cyclooxygenases. Such inhibition was found with the isolated enzyme. Another possibility, which has been already shown is reduction of expression of inducible cyclooxygenase-2. Additionally, we propose that docosahexaenoic acid could influence intracellular Ca(2+) signaling, which results in changes of activity of Ca(2+)-dependent phospholipase A(2), hence reducing the amount of arachidonic acid available for prostaglandin production. Astrocytes, the main type of glial cells in the brain control the release of arachidonic acid, docosahexaenoic acid and the formation of prostaglandins. Our recently obtained data revealed that the release of arachidonic and docosahexaenoic acids in astrocytes is controlled by different isoforms of phospholipase A(2), i.e. Ca(2+)-dependent phospholipase A(2) and Ca(2+)-independent phospholipase A(2), respectively. Moreover, the release of arachidonic and docosahexaenoic acids is differently regulated through Ca(2+)- and cAMP-dependent signal transduction pathways. Based on analysis of the current literature and our own data we put forward the hypothesis that Ca(2+)-independent phospholipase A(2) and docosahexaenoic acid are promising targets for treatment of inflammatory related disorders in brain. We suggest that Ca(2+)-independent phospholipase A(2) and docosahexaenoic acid might be crucially involved in brain-specific regulation of prostaglandins.
各种中枢神经系统疾病的特征是炎症反应的诱导，这涉及前列腺素的形成。前列腺素的产生受磷脂酶A(2)和环氧化酶活性的调节。这些酶释放前列腺素前体，即n-6多不饱和脂肪酸花生四烯酸，并将其氧化为前列腺素H(2)。属于n-3类多不饱和脂肪酸的二十二碳六烯酸在体内和体外给药后均显示可减少前列腺素的产生。然而，在脑组织中细胞磷脂天然具有独特的高含量二十二碳六烯酸这一事实，在迄今为止关于脑组织中前列腺素形成的研究中被忽视了。我们考虑以下可能性：二十二碳六烯酸可能通过直接抑制环氧化酶来减弱前列腺素的产生。在分离的酶中发现了这种抑制作用。另一种已经被证实的可能性是诱导型环氧化酶-2表达的降低。此外，我们提出二十二碳六烯酸可能影响细胞内Ca(2+)信号传导，这导致Ca(2+)依赖性磷脂酶A(2)活性的变化，从而减少可用于前列腺素产生的花生四烯酸的量。星形胶质细胞是脑中主要的胶质细胞类型，控制着花生四烯酸、二十二碳六烯酸的释放以及前列腺素的形成。我们最近获得的数据表明，星形胶质细胞中花生四烯酸和二十二碳六烯酸的释放分别受磷脂酶A(2)的不同同工型，即Ca(2+)依赖性磷脂酶A(2)和Ca(2+)非依赖性磷脂酶A(2)的控制。此外，花生四烯酸和二十二碳六烯酸的释放通过Ca(2+)和cAMP依赖性信号转导途径受到不同的调节。基于对当前文献和我们自己数据的分析，我们提出假设，Ca(2+)非依赖性磷脂酶A(2)和二十二碳六烯酸是治疗脑部炎症相关疾病的有希望的靶点。我们认为Ca(2+)非依赖性磷脂酶A(2)和二十二碳六烯酸可能在前列腺素的脑特异性调节中起关键作用。
