Wen Yuetao, Fu Pengfei, Wu Kunlun, Si Kaichuang, Xie Yanfeng, Dan Wei, Zhan Yan, Shi Quanhong
Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, No.1, Youyi Road, Chongqing, 400010, China.
Neurochem Res. 2017 Aug;42(8):2154-2166. doi: 10.1007/s11064-017-2221-0. Epub 2017 Mar 15.
FK506, a calcineurin inhibitor, shows neuroprotective effects and has been associated with neurodegenerative diseases. Calcineurin A (CaNA), a catalytic subunit of calcineurin, mediates the dephosphorylation of various proteins. N-methyl-D-aspartate receptor (GluN) is closely related to epileptogenesis, and various phosphorylation sites of GluN2B, a regulatory subunit of the GluN complex, have different functions. Thus, we hypothesized that one of the potential anti-epileptic mechanisms of FK506 is mediated by its ability to promote the phosphorylation of GluN2B and reduce the expression of GluN2B in membrane fraction by down-regulating CaNA. CaNA expression was increased in the cortex of patients with temporal lobe epilepsy and pentylenetetrazol (PTZ)-induced epileptic models. CaNA was shown to be expressed in neurons using immunofluorescence staining. According to our behavioral observations, epileptic rats exhibited less severe seizures and were less sensitive to PTZ after a systemic injection of FK506. The levels of phosphorylated GluN2B were decreased in epileptic rats but increased after the FK506 treatment. Moreover, there was no difference in the total GluN2B levels before and after FK506 treatment. However, the expression of GluN2B in membrane fraction was suppressed after FK506 treatment. Based on these results, FK506 may reduce the severity and frequency of seizures by reducing the expression of GluN2B in membrane fraction.
FK506是一种钙调神经磷酸酶抑制剂，具有神经保护作用，并与神经退行性疾病有关。钙调神经磷酸酶A（CaNA）是钙调神经磷酸酶的催化亚基，介导多种蛋白质的去磷酸化。N-甲基-D-天冬氨酸受体（GluN）与癫痫发生密切相关，GluN复合物的调节亚基GluN2B的各种磷酸化位点具有不同功能。因此，我们推测FK506潜在的抗癫痫机制之一是通过下调CaNA促进GluN2B的磷酸化并降低膜组分中GluN2B的表达来介导的。在颞叶癫痫患者和戊四氮（PTZ）诱导的癫痫模型的皮质中，CaNA表达增加。使用免疫荧光染色显示CaNA在神经元中表达。根据我们的行为观察，癫痫大鼠在全身注射FK506后癫痫发作较轻，对PTZ的敏感性较低。癫痫大鼠中磷酸化GluN2B的水平降低，但在FK506治疗后升高。此外，FK506治疗前后GluN2B的总水平没有差异。然而，FK506治疗后膜组分中GluN2B的表达受到抑制。基于这些结果，FK506可能通过降低膜组分中GluN2B的表达来降低癫痫发作的严重程度和频率。
