Additivity and potentiation of IGF-I and GDNF in the complete rescue of postnatal motor neurons.
BACKGROUND
Both growth and survival of motor neurons may depend on multiple neurotrophic factors. Individually, insulin-like growth factor I (IGF-I) and glial cell line-derived neurotrophic factor (GDNF) are potent neurotrophic/survival factors for postnatal motor neurons.


METHODS
We used an organotypic spinal cord model of glutamatergic degeneration in ALS to investigate whether IGF-I and GDNF interact to enhance motor neuron survival, their trophic effect on choline acetyltransferase (ChAT) activity, and their effect on neurite outgrowth.


RESULTS
We show that the combination of IGF-I and GDNF at active doses (1) is additively neuroprotective, (2) completely rescues rat motor neurons from chronic glutamate-mediated toxicity, and (3) additively upregulates motor neuron ChAT activity. Further, IGF-I, which by itself does not promote neurite outgrowth in this model, potentiates the neurite promoting action of GDNF.


CONCLUSIONS
The results predict that IGF-I combined with GDNF may provide a better therapy for the treatment of motor neuron disorders such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy.
Bilak
M M
MM
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287-7519, USA.
Corse
A M
AM
Kuncl
R W
RW
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000503:physiopathology*; D000818:Animals; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D046508:Culture Techniques; D004195:Disease Models, Animal; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology* / Q000627:therapeutic use; D009046:Motor Neurons / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D016501:Neurites / Q000378:metabolism; D051381:Rats; D013116:Spinal Cord / Q000166:cytology / Q000502:physiology
C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D007334:Insulin-Like Growth Factor I; D002795:Choline O-Acetyltransferase