title: Delayed transplantation of fibroblasts genetically modified to secrete BDNF and NT-3 into a spinal cord injury site is associated with limited recovery of function.
abstract: Delivery of neurotrophic factors in acute models of spinal cord injury in adult rats can rescue axotomized neurons, promote axonal growth, and partially restore function. The extent to which repair and recovery of function can be achieved after chronic injury has received less attention. In the companion paper we show that transplanting fibroblasts genetically modified to produce neurotrophic factors into chronic (6-week) hemisection injuries results in sprouting, partial neuroprotection, but only limited regeneration. Here we describe functional consequences of this treatment using a series of behavioral tests. Adult rats received a complete unilateral C3/C4 hemisection and recovery from the injury was assessed over 5 weeks. At 6 weeks postoperative, the experimental group received grafts of a combination of fibroblasts modified to secrete BDNF or NT-3. The operated control groups received grafts of either gelfoam or gelfoam with fibroblasts expressing GFP into the lesion site. Behavioral recovery in the three groups was assessed over the next 10 weeks. Severe deficits with no recovery in any of the groups were observed in several tests (BBB, limb preference, narrow beam, horizontal rope test) that measure primarily motor function. Recovery was observed in the grid test, a measure of sensorimotor function, and the von Frey test, a measure of response to mechanical stimulation, but there were no differences between the operated control or experimental groups. Both groups also showed recovery from heat-induced hyperalgesia, with the experimental group exhibiting greater recovery than the operated control groups. In this test, delivery of neurotrophic factors from transplanted fibroblasts does not worsen responses to nociceptive stimuli and in fact appears to reduce hypersensitivity. Our data also demonstrate that additional damage to the spinal cord upon placement of a graft further compromises behavioral recovery for locomotor and postural function. Additional therapeutic interventions will be necessary to provide greater levels of recovery after chronic injuries.
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA. shumsky@drexel.edu
authors.forename: J S
authors.initials: JS
authors.lastname: Shumsky
authors.forename: C A
authors.initials: CA
authors.lastname: Tobias
authors.forename: M
authors.initials: M
authors.lastname: Tumolo
authors.forename: W D
authors.initials: WD
authors.lastname: Long
authors.forename: S F
authors.initials: SF
authors.lastname: Giszter
authors.forename: M
authors.initials: M
authors.lastname: Murray
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000637:transplantation*; D005552:Forelimb / Q000502:physiology; D007839:Functional Laterality / Q000502:physiology; D018737:Hand Strength / Q000502:physiology; D006614:Hindlimb / Q000502:physiology; D006358:Hot Temperature; D008124:Locomotion / Q000502:physiology; D009043:Motor Activity / Q000502:physiology; D009068:Movement / Q000502:physiology; D020933:Neurotrophin 3 / Q000096:biosynthesis* / Q000235:genetics; D010147:Pain Measurement; D010812:Physical Stimulation; D011187:Posture / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D020933:Neurotrophin 3