Neue Therapieansätze bei hypoxisch-ischemischem Hirnschaden
Dysfunction and loss of neurons are the major characteristics of CNS disorders that include stroke, multiple sclerosis, Alzheimer's disease, and perinatal brain injury. Perinatal brain injury is a major cause of neonatal death and long-term disability and successful therapeutic approaches are lacking.
PreImplantation Factor (PIF) can be detected in the maternal circulation during pregnancy and its presence has been correlated with live birth. PIF has been implicated in promoting embryo implantation through modulating maternal immune tolerance. Consistent with the immune function, a synthetic PIF analog (sPIF) enables neuroprotection in rodent models of experimental autoimmune encephalomyelitis.
Here we show that in both neuronal and immune cells sPIF inhibits the biogenesis of micro-RNA let-7, which released from injured cells exacerbates CNS damage. sPIF destabilizes KH-type splicing regulatory protein (KSRP), a key microRNA-processing protein, in a Toll-like receptor 4 (TLR4)-dependent manner, leading to decreased production of let-7. Furthermore, in neonatal rats following hypoxic-ischemic brain injury sPIF robustly rescued cortical volume and number of neurons and decreased the detrimental glial response, as is consistent with diminished levels of KSRP and let-7 in sPIF-treated brains. Interestingly sPIF is able to reduce cell death and restore proper cortical architecture as well. Given that cyclic AMP-dependent protein kinase (PKA) and calcium dependent protein kinase (PKC) are important signaling molecules in neuronal plasticity and cellular response to hypoxia-ischemia we tested PKA/PKC activation as well. sPIF activates PKA/PKC signaling, leading to increased phosphorylation of major neuroprotective substrates GAP-43, BAD and CREB in vitro and in vivo. 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.