Pegylated brain-derived neurotrophic factor shows improved distribution into the spinal cord and stimulates locomotor activity and morphological changes after injury

The neurotrophin brain-derived neurotrophic factor (BDNF) shows promise for the treatment of central nervous system (CNS) trauma and disease. Effectiv e delivery methods are required, however, for BDNF to be useful as a therap eutic agent. To this end, we examined the penetration of intrathecally infu sed N-terminal pegylated BDNF (peg-BDNF) compared to similar infusion of na tive BDNF after spinal cord injury (SCI). Pegylation dramatically improved delivery of BDNF to the spinal cord and induced the expression of Fos in sp inal cord neurons. To test whether enhanced delivery would improve the mode st effects on behavioral recovery and axonal outgrowth observed with native BDNF infusion, we assessed the efficacy of 2-week 25-mug/day peg-BDNF trea tment, beginning 12-24 h (early) or 15 days (delayed) after midthoracic spi nal contusion. Similar to native BDNF, early treatment with peg-BDNF accele rated the recovery of stepping in the open-field and acutely stimulated loc omotor central pattern generator activity, as seen by the activation of hin dlimb airstepping during either period of administration. The infusion of p eg-BDNF, regardless of the timing of delivery, was related to enhanced spro uting of putative cholinergic fibers, like that observed after high dose na tive BDNF treatment. Despite improved delivery, however, neither axonal res ponses nor the extent of locomotor recovery were enhanced compared to nativ e BDNF treatment. This suggests that alternative strategies, such as neurot rophin treatment in conjunction with cell transplantation techniques, or tr eatment nearer the cell bodies of target neurons might be employed in an at tempt to effect significant repair after SCI. (C) 2001 Academic Press.