Abstract
Experimental model based on the C5 ventral root avulsion was used to evaluate the efficacy of brain-derived neurotrophic factor (BDNF) and Cerebrolysin treatment on motor neuron maintenance and survival resulted in the functional reinnervation of the nerve stump. In contrast to vehicle, BDNF treatment reduced the loss and atrophy of motor neurons and enhanced the regrowth axon sprouts into the distal stump of musculocutaneous nerve. However, the axon diameter of the myelinated fibers was smaller than those of control rats. The morphometric results were related to a low score in behavioral test similar to vehicle-treated rats. Cerebrolysin treatment greatly protected the motor neurons against cell death. Moreover, morphometric features of myelinated axons were better than those of rats treated with vehicle or BDNF. The mean score of grooming test suggested better results of the functional motor reinnervation than after BDNF administration. The majority of rescued motor neurons regenerating their axons through nerve graft in both BDNF- and Cerebrolysin-treated rats expressed choline acetyltransferase immunostaining. The results demonstrate that BDNF has more modest effects in preventing the death of motor neurons and functional recovery of injured motor nerve after root avulsion than Cerebrolysin.
Similar content being viewed by others
References
Akai F, Hiruma S, Sato T, Iwamoto N, Fujimoto M, Ioku M, Hashimoto S (1992) Neurotrophic factor like effect of FPF1070 on septal cholinergic neurons after transection of fimbria-fornix in the rat brain. Histol Histopathol 7:213–221
Bertelli JA, Mira JC (1993) Behavioral evaluating methods in the objective clinical assessment of motor function after experimental brachial plexus reconstruction in the rat. J Neurosci Methods 46:203–208
Bertelli JA, Mira JC (1995) The grasping test: a simple behavioral method for objective quantitative assessment of peripheral nerve regeneration in the rat. J Neurosci Methods 58:1–2
Bowe CM, Evans NH, Vlacha V (1992) Progressive morphological abnormalities observed in rat spinal motor neurons at extended intervals after axonal regeneration. J Comp Neurol 321:576–590
Cao X, Shoichet MS (2003) Investigating the synergistic effect of combined neurotrophic factor concentracion gradients to guide axonal growth. Neuroscience 122:381–389
Carlstedt T, Linda H, Cullheim S, Risling M (1986) Reinnervation of hind limb muscles after ventral root avulsion and implantation in the lumbar spinal cord. Acta Physiol Scand 128:645–646
Carlstedt T, Grane P, Hallin RG, Norén G (1995) Return of function after spinal cord implantation of avulsed spinal nerve roots. Lancet 346:1323–1325
Chiu AY, Chen EW, Loera S (1994) Distinct neurotrophic responses of axotomized motor neurons to BDNF and CNTF in adult rats. Neuroreport 5:693–696
Clatterbuck RE, Price DL, Koliatsos VE (1994) Further characterization of the effects of brain-derived neurotrophic factor and ciliary neurotrophic factor on axotomized neonatal and adult mammalian motor neurons. J Comp Neurol 342:45–56
Cruz R, Francis L, Diaz-Suarez CM, Gonzalez-Fraguela ME (1998) Short-term effects of septo-hippocampal pathway transection and Cerebrolysin effects on glutathione-related enzymes in the rat brain. Rev Neurol (Paris) 26:551–554
De Medinaceli L (1995) Interpreting nerve morphometry data after experimental traumatic lesions. J Neurosci Methods 58:29–37
Friedman B, Kleinfeld D, Ip NY, Verge VM, Moulton R, Boland P, Zlotchenko E, Lindsay RM, Liu L (1995) BDNF and NT-4/5 exert neurotrophic influences on injured adult spinal motor neurons. J Neurosci 15:1044–1056
Gillespie MJ, Stein RB (1983) The relationship between axon diameter, myelin thickness and conduction velocity during atrophy of mammalian peripheral nerves. Brain Res 259:41–56
Haninec P, Dubový P, Houšt’ava L, Stejskal L (1996) Alternative methods of the brachial plexus reconstruction-An experimental study. Scripta Med 69:221–226
Haninec P, Dubový P, Houšt’ava L, Stejskal L (1997) Reconstructive operations of brachial plexus injury and the experimental model of their management. Intern Proc Div, Centennial perspective. Monduzzi, Amsterdam, pp 2103–2107
Haninec P, Dubový P, Houšt’ava L, Stejskal L (2000) Acellular nerve graft re-seeded by Schwann cells migrating from the nerve stump can stimulate spinal motor neurons for functional reinnervation of the rat muscle. Ann Anat 182:123–131
Haninec P, Houšt’ava L, Stejskal L, Dubový P (2003) Rescue of rat spinal motor neurons from avulsion-induced cell death by intrathecal administration of IGF-I and Cerebrolysin. Ann Anat 185:233–238
Heumann R (1994) Neurotrophin signaling. Curr Opin Neurobiol 4:668–679
Horvat JC, Pecot-Deachavassine M, Mira JC (1988) Functional reinnervation of a denervated skeletal muscle of the adult rat by axons regenerating from the spinal cord through a peripheral nervous system graft. Progr Brain Res 78:219–224
Hutter-Paier B, Steiner E, Windisch M (1998) Cerebrolysin protects isolated cortical neurons from neurodegeneration after brief histotoxic hypoxia. J Neural Transm 53:351–361
Kishino A, Ishige Y, Tatsuno T, Nakayama C, Noguchi H (1997) BDNF prevents and reverses adult rat motor neuron degeneration and induces axonal outgrowth. Exp Neurol 144:273–286
Klocker N, Kermer P, Weishaupt JH, Labes M, Ankerhold R, Bahr M (2000) Brain-derived neurotrophic factor-mediated neuroprotection of adult rat retinal ganglion cells in vivo does not exclusively depend on phosphatidyl-inositol-3′-kinase/protein kinase B signaling. J Neurosci 20:6962–6967
Koliatsos VE, Applegate MD, Kitt CA, Walker LC, DeLong MR, Price DL (1989) Aberrant phosphorylation of neurofilaments accompanies transmitter-related changes in rat septal neurons following transection of the fimbria-fornix. Brain Res 482:205–218
Koliatsos VE, Price WL, Pardo CA, Price DL (1994) Ventral root avulsion-an experimental model of death of adult motor neurons. J Comp Neurol 342:35–44
Li L, Oppenheim RW, Lei M, Houenou J (1994) Neurotrophic agents prevent motor neuron death following sciatic nerve section in the neonatal mouse. J Neurobiol 25:759–766
Li LX, Wu WT, Lin LFH, Lei M, Oppenheim RW, Houenou LJ (1995) Rescue of adult mouse motor neurons from injury-induced cell death by glial cell line-derived neurotrophic factor. Proc Natl Acad Sci USA 92:9771–9775
Mitsumoto H, Ikeda K, Klinkosz B, Cedarbaum JM, Wong V, Lindsay RM (1994) Arrest of motor neuron disease in wobbler mice cotreated with CNTF and BDNF. Science 265:1107–1110
Murray M, Kim D, Liu Y, Tobias C, Tessler A, Fischer I (2002) Transplantation of genetically modified cells contributes to repair and recovery from spinal injury. Brain Res Brain Res Rev 40:292–300
Novikov L, Novikova L, Kellerth JO (1995) Brain-derived neurotrophic factor promotes survival and blocks nitric oxide synthase expression in adult rat spinal motor neurons after ventral root avulsion. Neurosci Lett 200:45–48
Oppenheim RW (1996) Neurotrophic survival molecules for motor neurons: an embarrassment of riches. Neuron 17:195–197
Oppenheim RW, Prevette D, Haverkamp LJ, Houenou L, Yin QW, McManaman J (1993) Biological studies of a putative avian muscle-derived neurotrophic factor that prevents naturally occurring motor neuron death in vivo. J Neurobiol 24:1065–1079
Ruther E, Ritter R, Apecechea M, Freytag S, Windish M (1994) Efficacy of peptidergic nootropic drug Cerebrolysin in patients with senile dementia of Alzheimer type. Pharmacopsychiatry 27:32–40
Satou T, Imano M, Akai F, Hashimoto S, Itoh T, Fujimoto M (1993) Morphological observation of effects of Cerebrolysin on cultured neuronal cells. In: Nicolini, Zatta, Coraine (eds) Alzheimer’s disease and related disorders. Pergamon, Oxford, pp 195–196
Segal RA, Greenberg ME (1996) Intracellular signaling pathways activated by neurotrophic factors. Annu Rev Neurosci 19:463–489
Shibata M, Murray M, Tessler A, Ljubetic C, Connors T, Saavedra RA (2000) Single injections of a DNA plasmid that contains the human Bcl-2 gene prevent loss and atrophy of distinct neuronal populations after spinal cord injury. Neurorehabil Neural Repair 14:319–330
Sugita Y, Kondo T, Kanazawa A, Itou T, Mizuno Y (1993) Protective effect of FPF 1070 (Cerebrolysin) on delayed neuronal death in the gerbil-detection of hydroxyl radicals with salicylic acid. No To Shinkei 45:325–331
Windisch M, Gschanes A, Hutter-Paier B (1998) Neurotrophic activities and therapeutic experience with a brain derived peptide preparation. J Neural Transm 53:289–298
Wu W (1993) Expression of nitric-oxide synthase (NOS) in injured CNS neurons as shown by NADPH diaphorase histochemistry. Exp Neurol 120:153–159
Wu W (1996) Potential roles of gene expression change in adult rat spinal motor neurons following axonal injury: a comparison among c-jun, low-affinity nerve growth factor receptor (LNGFR), and nitric oxide synthase (NOS). Exp Neurol 141:190–200
Yan Q, Elliott J, Snider WD (1992) Brain-derived neurotrophic factor rescues spinal motor neurons from axotomy-induced cell death. Nature 360:755–777
Zamboni L, De Martino C (1967) Buffered picric acid-formaldehyde: a new, rapid fixative for electron microscopy. J Cell Biol 35:14
Acknowledgements
We thank Ms. Dana Kutějová for her skillful technical assistance. This work was supported by grants NF/6658-3 (the Ministry of Health of the Czech Republic), and CEZ: J07/98:141100001 (the Ministry of Education of the Czech Republic).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Haninec, P., Dubový, P., Šámal, F. et al. Reinnervation of the rat musculocutaneous nerve stump after its direct reconnection with the C5 spinal cord segment by the nerve graft following avulsion of the ventral spinal roots: a comparison of intrathecal administration of brain-derived neurotrophic factor and Cerebrolysin. Exp Brain Res 159, 425–432 (2004). https://doi.org/10.1007/s00221-004-1969-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00221-004-1969-z