Mesencephalic astrocyte-derived neurotrophic factor prevents neuron loss via inhibiting ischemia-induced apoptosis

Abstract Mesencephalic astrocyte-derived neurotrophic factor (MANF) has been shown to be up-regulated under the focal cerebral ischemia and protected against ischemic injury in rats. However, the underlying mechanisms are unclear. The aim of this study was to verify the protection of MANF on the cerebral ischemic injury and further investigate the possible mechanisms. Rat focal ischemic model was established by middle cerebral artery occlusion (MCAO). The recombinant human MANF was therapeutically administrated to the ipsilateral ventricle at 2 h after MCAO. MANF decreased the number of the propidium iodide (PI)- and TUNEL-positive neural cells. Contrarily, MANF protected the NeuN-positive cells in hippocampus and cortex from death induced by ischemia. The more interesting results in this study were that MANF repressed the cleavage of caspase-3 triggered by focal cerebral ischemia. MANF also reduced the elevated levels of BIP/Grp78, phosphorylated IRE1, and splicing XBP1 induced by focal cerebral ischemia, but not affect CHOP expression. Meanwhile, focal cerebral ischemia elevated the levels of XBP1 mRNA, including unspliced XBP1 (XBP1u) and spliced XBP1 (XBP1s). However, MANF did not affect the expression of XBP1 mRNA, neither XBP1u nor XBP1s. These results suggest that MANF can prevent the neuron loss via inhibiting ischemia-induced apoptosis and regulating unfolded protein response-related genes.