Mueller M, Schoeberlein A, Zhou J, Joerger-Messerli M, Oppliger B, Reinhart U, Bordey A, Surbek D, Barnea E R, Huang Y, Paidas M
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
Department of Obstetrics and Gynecology, University Hospital Bern, Bern, Switzerland.
Cell Death Differ. 2015 Dec;22(12):2078-86. doi: 10.1038/cdd.2015.55. Epub 2015 May 15.
A synthetic peptide (sPIF) analogous to the mammalian embryo-derived PreImplantation Factor (PIF) enables neuroprotection in rodent models of experimental autoimmune encephalomyelitis and perinatal brain injury. The protective effects have been attributed, in part, to sPIF's ability to inhibit the biogenesis of microRNA let-7, which is released from injured cells during central nervous system (CNS) damage and induces neuronal death. Here, we uncover another novel mechanism of sPIF-mediated neuroprotection. Using a clinically relevant rat newborn brain injury model, we demonstrate that sPIF, when subcutaneously administrated, is able to reduce cell death, reverse neuronal loss and restore proper cortical architecture. We show, both in vivo and in vitro, that sPIF activates cyclic AMP dependent protein kinase (PKA) and calcium-dependent protein kinase (PKC) signaling, leading to increased phosphorylation of major neuroprotective substrates GAP-43, BAD and CREB. Phosphorylated CREB in turn facilitates expression of Gap43, Bdnf and Bcl2 known to have important roles in regulating neuronal growth, survival and remodeling. As is the case in sPIF-mediated let-7 repression, we provide evidence that sPIF-mediated PKA/PKC activation is dependent on TLR4 expression. Thus, we propose that sPIF imparts neuroprotection via multiple mechanisms at multiple levels downstream of TLR4. Given the recent FDA fast-track approval of sPIF for clinical trials, its potential clinical application for treating other CNS diseases can be envisioned.
一种与哺乳动物胚胎来源的着床前因子（PIF）类似的合成肽（sPIF）可在实验性自身免疫性脑脊髓炎和围产期脑损伤的啮齿动物模型中发挥神经保护作用。这种保护作用部分归因于sPIF抑制微小RNA let-7生物合成的能力，let-7在中枢神经系统（CNS）损伤时从受损细胞中释放出来并诱导神经元死亡。在此，我们发现了sPIF介导神经保护的另一种新机制。使用临床相关的新生大鼠脑损伤模型，我们证明皮下注射sPIF能够减少细胞死亡、逆转神经元丢失并恢复正常的皮质结构。我们在体内和体外均表明，sPIF激活环磷酸腺苷依赖性蛋白激酶（PKA）和钙依赖性蛋白激酶（PKC）信号传导，导致主要神经保护底物GAP-43、BAD和CREB的磷酸化增加。磷酸化的CREB反过来促进已知在调节神经元生长、存活和重塑中起重要作用的Gap43、Bdnf和Bcl2的表达。与sPIF介导的let-7抑制情况一样，我们提供证据表明sPIF介导的PKA/PKC激活依赖于TLR4表达。因此，我们提出sPIF通过TLR4下游多个水平的多种机制赋予神经保护作用。鉴于sPIF最近已获得FDA的快速通道批准用于临床试验，可以设想其在治疗其他中枢神经系统疾病方面的潜在临床应用。
