Protective Effects Of Adenovirus NEP1-40 Gene Ttransfer On Spinal Cord Injury In Rats

It is always the focus that the functional recovery after the spinal cord injury (SCI). Following the further studying, some factors were found which inhibit the growth of neuraxon. Nogo gene is one of the most important factors.Now, the structure of Nogo gene is well known since it was found in 1980'. Nogo gene has three kinds of productions, Nogo-A,Nogo-B and Nogo-C,because it has different promoters and the different splicing methods. The Nogo-A is the total length production which contain 1163 amino acids; Nogo-B is 360 amino acid residues and the Nogo-C is consisted of 199 amino acid residues.The Nogo proteins differ in length but share a common188-amino acid-long C-terminus, consisting of two potentially membrane-spanninghydrophobic domains separated by a hydrophilic segmentof 66 amino acids (termed Nogo-66). The C-termini of Nogos share high homology with the reticulon proteinfamily, the prototype of which is reticulon 1, anneuroendorine-specific, endoplasmic reticulum-localizedprotein with unknown function. A dilysine endoplasmic reticulum(ER) retention motif is found at the C-terminus of Nogo. Accordingly, the majority of the Nogo proteins are localized to the ER, with a small amount on the cell surface. The apparent neuronal specific growth inhibitoryeffect of the Nogo-66 region led Strittmatter's group to look for a receptor for Nogo-66, using interaction screening of a mouse brain cDNA expression library transfectedinto non-neuronal COS-7 cells .Two cDNA clones coding for a 473-amino acid proteinwere identified in the screen. The physiological relation of Nogo-66 and this putative Nogo-66 receptor (NgR) was confirmed by an elegant gain of function experiment, where embryonic chick retinal neurons that are insensitive to Nogo-66 became responsive to the viral-mediated expressionof the receptor. NgR transcripts are expressed in a wide variety of CNS neurons but not in oligodendrocytes. The Nogo-66(1-40) antagonist peptide (NEP1–40) blocks Nogo-66 or CNS myelin inhibition of axonal outgrowth in vitro, demonstrating that NgR mediates a significant portion of axonal outgrowth inhibition by myelin. Intrathecal administration of NEP1–40 to rats with midthoracic spinal cord hemisection results in significant axon growth of the corticospinal tract, and improves functional recovery. Thus, Nogo-66 and NgR have central roles in limiting axonal regeneration after CNS injury, and NEP1-40 provides apotential therapeutic agent.