title: Adenovirus vector-mediated in vivo gene transfer of brain-derived neurotrophic factor (BDNF) promotes rubrospinal axonal regeneration and functional recovery after complete transection of the adult rat spinal cord.
abstract: Neurotrophins have been shown to promote axonal regeneration, but the techniques available for delivering neurotrophins have limited effectiveness. The aim of this study was to evaluate the effect of adenovirus vector mediated gene transfer of brain-derived neurotrophic factor (BDNF) on axonal regeneration after spinal cord injury. We prepared adenovirus vectors encoding either beta-galactosidase (AxCALacZ) or BDNF (AxCABDNF). AxCALacZ was used to assess infection levels of the adenovirus BDNF produced by AxCABDNF was detected by Western blotting and its bioactivity was confirmed by bioassay. As a model of spinal cord injury, the rat spinal cord was completely transected at the T8 level. Immediately after transection, the vectors were injected into both stumps of the spinal cord. Axonal regeneration after transection was assessed by retrograde and anterograde tracing. In AxCALacZ-injected rats, adenovirus-infected cells were observed not only at the injected site but also in brainstem nuclei, as shown by LacZ expression. After the injection of the retrograde tracer fluorogold (FG) distal portion to the transection, AxCABDNF-injected rats showed FG-labeled neurons in the red nucleus. The anterograde tracer biotinylated dextran amine (BDA) injected into the red nucleus was also found in regenerating rubrospinal fibers distal to the transection. These tracing experiments demonstrated the regeneration of descending axons. In addition, rats of the AxCABDNF group showed significant locomotor recovery of hindlimb function, which was completely abolished by re-transection. These results indicate that the recovery was caused by regeneration of rubrospinal axons, not by simple enhancement of the central pattern generator.
authors.affiliation: Division of Rehabilitation Medicine, Chiba University Graduate School of Medicine, Chiba, Japan. m-koda@nifty.com
authors.forename: Masao
authors.initials: M
authors.lastname: Koda
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Masazumi
authors.initials: M
authors.lastname: Murakami
authors.forename: Katsunori
authors.initials: K
authors.lastname: Yoshinaga
authors.forename: Osamu
authors.initials: O
authors.lastname: Ikeda
authors.forename: Masashi
authors.initials: M
authors.lastname: Yamazaki
authors.forename: Shuhei
authors.initials: S
authors.lastname: Koshizuka
authors.forename: Takahito
authors.initials: T
authors.lastname: Kamada
authors.forename: Hideshige
authors.initials: H
authors.lastname: Moriya
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shirasawa
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Sakao
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Ino
mesh_terms: D000256:Adenoviridae; D000818:Animals; D001369:Axons / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000627:therapeutic use; D007763:Lac Operon / Q000502:physiology; D008297:Male; D009416:Nerve Regeneration / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000502:physiology; D013119:Spinal Cord Injuries / Q000503:physiopathology / Q000628:therapy*
chemical_list: D019208:Brain-Derived Neurotrophic Factor