Simultaneous GDNF and BDNF Application Leads to Increased Motoneuron Survival and Improved Functional Outcome in an Experimental Model for Obstetric Brachial Plexus Lesions

Abstract

Motoneurons of the neonate rat respond to proximal axonal injury with morphologic and functional changes and ultimately with neuronal death. Recent studies showed that both glial cell-line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) reduce induced degeneration of motoneurons after axotomy and avulsion. Whether rescued motoneurons are functionally intact has been argued. In the present investigation, the authors have used a proximal crush lesion of the brachial plexus in neonatal rats as the experimental model of neuronal injury. This allowed the authors to study the effects of trophic factor administration on injured motoneurons and the relationship between motoneuron survival and extremity function. Trophic factors were locally released by small polymer implants in a low-dose slow-release mode. Six groups of 10 animals were prepared: BDNF, GDNF, GDNF/BDNF, control, sham, and normals. The number of surviving motoneurons was determined by retrograde tracer techniques using Fluorogold and Fastblue. Extremity function was quantitatively evaluated with functional muscle testing at day 56. The results of this study demonstrate that trophic factors applied separately had no effect, whereas combined trophic factor application (GDNF/BDNF group) had a dramatic rescue effect on motoneuron survival as compared with the control groups, which also effected significantly greater strength. The authors conclude that a combination of trophic factors leads to enhanced motoneuron survival, with improved voluntary function as the animal enters adulthood so that exogenous trophic support of motoneurons might have a role in the treatment of all types of severe neonatal plexopathies, maintaining the viability of motoneurons until reconstructive surgery provides them with a pathway for regeneration and endogenous trophic support.

Tissue engineering of the peripheral nervous system

“…This study demonstrated that the use of two combined physical fillers promotes an efficient nerve regeneration and sensory recovery [157]. Growth factors can also be used in combination providing a synergetic effect to the nerve regeneration [158][159][160]. The use of a codelivery system for the slow release of both GDNF and NGF showed a significant improvement of the nerve regeneration [147].…”

“…These growth factors have some limitations that could be solved by the use of controlled delivery systems, where they are efficiently immobilized or cross-linked into NC and/or intraluminal fillers [139,145,147,[152][153][154][155]. These studies also demonstrate that the combined use of physical fillers and growth factors or the combination of two growth factors provide a synergetic effect to the regenerative microenvironment, promoting a comparable nerve regeneration to the use of autograft [140,141,146,148,153,158,160].…”

The behavioral and biochemical effects of BDNF containing polymers implanted in the hippocampus of rats

“…The development of controlled release biomaterials for application in the brain could allow for the delivery of psychotropic agents that would not otherwise be tested. Polymeric drug delivery devices have been applied in both the central and peripheral nervous systems (Menei et al, 1994, Aebischer et al, 1996, Valtonen et al, 1997, Xudong and Shoichet, 1999, Terenghi, 1999, Bloch et al, 2001, Stokols et al, 2006), and for the controlled delivery of BDNF (Mittal et al, 1994, Sakane and Pardridge, 1997, Vejsada et al, 1998, Penschuck et al, 1999, Loh et al, 2001, Aszmann et al, 2002, Patist et al, 2004, Winter et al, 2008, Shi et al, 2008). However, to our knowledge, this is the first study to utilize controlled release biomaterials in a model of rodent behavior.…”

Diagnostisches und therapeutisches Prozedere bei geburtstraumatischer Plexus-brachialis-Läsion: Review und Empfehlungen einer interdisziplinären Arbeitsgruppe

“…Diese permanenten Ver ä nderungen der Architektur der peripheren Innervation und der Repr ä sentation im R ü ckenmark bei Kindern mit OBPP konnte auch die Arbeitsgruppe um Korak [20] best ä tigen. Aszmann [21]…”