Neuroprotection Exerted by Netrin-1 and Kinesin Motor KIF1A in Secondary Brain Injury following Experimental Intracerebral Hemorrhage in Rats

Jun Wang, Weiwei Zhai, Zhengquan Yu, Liang Sun, Haiying Li, Haitao Shen, Xiang Li, Chunfeng Liu, Gang Chen

Binding of extracellular netrin-1 to its receptors, deleted in colorectal cancer (DCC) and uncoordinated gene 5H2 (UNC5H2), inhibits apoptosis mediated by these receptors. A neuron-specific kinesin motor protein, KIF1A, has been shown to participate in netrin-1 secretion. This study aimed to identify the roles of netrin-1 and KIF1A in secondary brain injury after intracerebral hemorrhage (ICH) and the potential mechanisms. An autologous blood ICH model was established in adult male Sprague-Dawley rats, and cultured neurons were exposed to OxyHb to mimic ICH conditions in vitro. Mouse recombinant netrin-1, expression vectors encoding KIF1A, and KIF1A-specific siRNAs were administered intracerebroventricularly. After ICH, protein levels of netrin-1, DCC, and UNC5H2 increased, while protein levels of KIF1A decreased. Levels of UNC5H2 and DCC bound to netrin-1 increased after ICH but were significantly lower than the increase in total amount of protein. Administration of recombinant netrin-1 attenuated neuronal apoptosis and degeneration in ICH rats. Moreover, KIF1A overexpression increased concentrations of netrin-1 in cerebrospinal fluid and cell culture supernatant and exerted neuroprotective effects via netrin-1 and its receptor pathways. KIF1A plays a critical role in netrin-1 secretion by neurons. An increase in protein levels of netrin-1 may be a neuroprotective strategy after ICH. However, this process is almost completely abolished by ICH-induced loss of KIF1A. An exogenous increase of KIF1A may be a potential strategy for neuroprotection via the netrin-1 pathway.