Hasarmeh Malik, Itzik Anna, Weidenfeld Joseph, Ovadia Haim
Department of Neurology, the Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Neuroimmunomodulation. 2016;23(1):1-7. doi: 10.1159/000441948. Epub 2015 Dec 16.
The role of nitric oxide (NO) in modulating the blood-brain barrier (BBB) is not entirely clear. We examined the effect of different NO synthase (NOS) inhibitors and NO donors on the permeability of the BBB in animals with normally functioning brain blood vessels, following disruption by hyperosmotic mannitol and during immune inflammation.
We administered L-NAME, aminoguanidine, S-methyl-thiocitrulline (SMT) and 7-indazole (NOS inhibitors) and NOR-4 (an NO donor) into the cerebral ventricle of rats. Disruption of the BBB was induced by intracarotid injection of mannitol (25%). Experimental autoimmune encephalomyelitis (EAE) was induced by brain homogenate. The extent of disruption was evaluated by Evans blue (2%) dye extravasation.
L-NAME (a nonspecific NOS inhibitor) and SMT (a neuronal and endothelial NOS inhibitor) increased mannitol-induced disruption of BBB. This effect was inhibited by NO donors. In animals with a normally functioning BBB, none of these inhibitors or NO donors caused a change in the permeability. 7-indazole (a specific neuronal NOS inhibitor) and aminoguanidine (an inducible NOS inhibitor) had no facilitatory effect on BBB permeability, either alone or in combination with hyperosmotic mannitol. Administration of L-NAME and SMT to rats with EAE significantly aggravated the clinical outcome. In contrast, the administration of NOR-4 diminished clinical signs of EAE.
The NOS system does not play a role in BBB permeability in naïve animals. Only endothelial NOS takes part in the facilitation of BBB compromised by mannitol and EAE. Extrinsic NO decreases this facilitatory effect.
一氧化氮（NO）在调节血脑屏障（BBB）中的作用尚不完全清楚。我们研究了不同的一氧化氮合酶（NOS）抑制剂和NO供体对脑血管功能正常的动物、经高渗甘露醇破坏后以及免疫炎症期间血脑屏障通透性的影响。
我们将L-硝基精氨酸甲酯（L-NAME）、氨基胍、S-甲基硫代瓜氨酸（SMT）和7-吲唑（NOS抑制剂）以及NOR-4（一种NO供体）注入大鼠脑室。通过颈内注射甘露醇（25%）诱导血脑屏障破坏。用脑匀浆诱导实验性自身免疫性脑脊髓炎（EAE）。通过伊文思蓝（2%）染料外渗评估破坏程度。
L-NAME（一种非特异性NOS抑制剂）和SMT（一种神经元和内皮NOS抑制剂）增加了甘露醇诱导的血脑屏障破坏。这种作用被NO供体抑制。在血脑屏障功能正常的动物中，这些抑制剂或NO供体均未引起通透性改变。7-吲唑（一种特异性神经元NOS抑制剂）和氨基胍（一种诱导型NOS抑制剂）单独或与高渗甘露醇联合使用时，对血脑屏障通透性均无促进作用。给患有EAE的大鼠注射L-NAME和SMT会显著加重临床症状。相比之下，注射NOR-4可减轻EAE的临床症状。
在未接触过抗原的动物中，NOS系统在血脑屏障通透性方面不起作用。只有内皮NOS参与促进甘露醇和EAE破坏的血脑屏障。外源性NO可降低这种促进作用。
