Enhancement of BDNF and activated-ERK immunoreactivity in spinal motor neurons after peripheral administration of BDNF.
Brain-derived neurotrophic factor (BDNF) shows neurotrophic effects on adult motor neurons when given systemically, But it is unknown whether systemically administered BDNF is transported to central cell bodies to affect them directly. Here we used immunohistochemistry to investigate the transport of peripherally injected BDNF to spinal motor neurons and the subsequent activation of a signaling pathway. We first injected BDNF into the flexor digitorum brevis (FDB) and analyzed the motor nucleus that projects to the FDB for BDNF immunoreactivity (BDNF-ir) and phosphorylated extracellular signal-regulated kinase (ERK) 1/2 immunoreactivity (pERK1/2-ir). Both immunoreactivities were observed in the motor neuron cell bodies. Next, BDNF was injected subcutaneously (s.c.) into rats with a unilaterally axotomized sciatic nerve. pERK1/2-ir was detected in motor neurons of the lesioned side. BDNF-ir and pERK1/2-ir were also observed on the unlesioned side when a high dose of BDNF was injected. Therefore, we examined BDNF-ir and pERK1/2-ir after injecting BDNF s.c. into normal rats. Both immunoreactivities were observed in motor nuclei on both sides. Finally, we examined pERK1/2-ir after a lower dose of BDNF was injected, which prevents the decrease in choline acetyl transferase that occurs in the motor neuron upon axotomy. Spinal motor nuclei contained a few cell bodies with pERK1/2-ir. These findings represent the first direct evidence that subcutaneously injected BDNF is transported to motor neurons and that it activates a signaling pathway in the spinal cord and exhibits neurotrophic effects in vivo.
Kishino
Akiyoshi
A
Sumitomo Pharmaceuticals Research Division, 3-1-98 Kasugadenaka, Konohana-ku, Osaka 554-0022, Japan. kishino@sumitomopharm.co.jp
Nakayama
Chikao
C
D000818:Animals; D000870:Anterior Horn Cells / Q000187:drug effects* / Q000378:metabolism; D001370:Axonal Transport / Q000187:drug effects* / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007839:Functional Laterality / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry; D007273:Injections, Intramuscular; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D016472:Motor Neuron Disease / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000294:innervation*; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D017729:Presynaptic Terminals / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D020928:Mitogen-Activated Protein Kinases