Targeting The Lingo-1 Spinal Cord Injury In Experimental Therapeutics

Neurons and oligodendrocytes are exquisitely vulnerable and mainly affected cell-types during the wave of secondary cell death after spinal cord injury (SCI). Degeneration of axons and accompanying demyelination caused by the apoptosis and death of myelin-forming oligodendrocytes contribute to the physiological and functional impairment after SCI. Lingo-1 is specially expressed in both neurons and oligodendrocytes in CNS, recently, which has been identified as an important negative regulator in axon regeneration and oligodendrocyte differentiation and myelination. Here, we investigated the expression of Lingo-1 after SCI, by using quantitative real-time RT-PCR (QRT-PCR) and Western Blot. Demyelination induced by lysolecithin injection and dorsal laceration applied by louisville impactor system appratus (LISA) were accepted as two kinds of SCI models. QRT-PCR analysis showed an increased expression of Lingo-1 mRNA at 1 and 3 days post-lysolecithin injection, and at 1, 3, 14, 28 days post dorsal laceration. Western Blot confirmed the higher expression of Lingo-1 protein after SCI in both models. These results show the higher expression of Lingo-1 after SCI and suggest which may involved in the early stages of SCI pathophysiology. One important therapeutic strategy during CNS demyelinating neurological disorders is to develop new methods to promote remyelination. Lingo-1 has been identified as a negative regulator of oligodendrocyte differentiation and myelination. In this study, we demonstrated that loss of lingo-1 function by either Lingo-1 gene knockout or treatment with anti-Lingo-1 antibody can facilitate axons remyelination and tcMMEP recovery following the toxin-induced demyelination by injection of 1% lysolecithin into the VLF of spinal cord. In Lingo-1 KO mice or the mice treated with anti-Lingo-1 antibody, the smaller demyelination area and increased remyelinated axons were determined by toludine blue staining; electron microscope showed the thicker myelion sheathes and which were confirmed by G-ratio measurement; furthermore, better tcMMEP recovery were found in Lingo-1 blocked mice compared to which in control groups, indicating that conduction through the demyelinated VLF axons was preferably restored by remyelination. These results suggest that block Lingo-1 signal can promote remyelination and facilitate the electrophysiological recovery in the CNS demyelination diseases and the anti-Lingo-1 antibody may serve as a potential therapy to enhance myelin repair following CNS injury and diseases. Myelin-derived axonal growth cone inbibitors (MAG, NogoA and OMgp) delivery inhibition role on axon regeneration by binding to Nogo Receptor (NgR1) complex on axon growth cone. NgR complex was composed of NgR1/Lingo- 1/P75 or TROY(TAJ). As a leucine-rich repeat transmembrane Protein, Lingo-1 acts to transduce inhibitory signal across the cell membrane and then active RhoA pathway. It has been demostrated that intrathecal delivery of Lingo-1-Fc can promote rubrospinal tract (RST) and corticospinal tract (CST) axonal regeneration and motor functional recovery. Here we administrate anti-Lingo-1 antibody by intraperitoneal injection to mice after dorsal laceration on spinal cord. The result showed that treatment of anti-Lingo-1 antibody can promote CST axonal regeneration and improve motor functional recovery, also, which can limit the dieback of CTB labeled sensory axons. The experiments indicates that severed CST axons have more robust response to anti-Lingo-1 antibody treatment than CTB labeled sensory axons and suggest that anti-Lingo-1 antibody may serve as a new potential drug for the treatment of SCI.