TY - JOUR
T1 - Preclinical testing of neuroprotective neurotrophic factors in a model of chronic motor neuron degeneration
AU - Corse, Andrea M.
AU - Bilak, Masako M.
AU - Bilak, Stephan R.
AU - Lehar, Mohamed
AU - Rothstein, Jeffrey D.
AU - Kuncl, Ralph W.
N1 - Funding Information:
We thank Carol Coccia and Margaret Dykes-Hoberg for their technical assistance. This work was supported by a grant (RO1 NS33985-01) from the National Institutes of Health (A.M.C. and R.W.K.), a Clinician Scientist Investigator Award (K08 NS01722-02) from the National Institutes of Health (A.M.C.), Regeneron Pharmaceuticals, Inc., Cephalon, Inc., and The Cal Ripken Fund for Neuromuscular Research and The Jay Slotkin Fund for Neuromuscular Research, both at the Johns Hopkins University School of Medicine, Department of Neurology.
PY - 1999/10
Y1 - 1999/10
N2 - Many neurotrophic factors have been shown to enhance survival of embryonic motor neurons or affect their response to injury. Few studies have investigated the potential effects of neurotrophic factors on more mature motor neurons that might be relevant for neurodegenerative diseases. Using organotypic spinal cord cultures from postnatal rats, we have demonstrated that insulin-like growth factor-I (IGF-I) and glial-derived neurotrophic factor (GDNF) significantly increase choline acetyltransferase (ChAT) activity, but brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT- 4/5), and neurotrophin-3 (NT-3) do not. Surprisingly, ciliary neurotrophic factors (CNTF) actually reduces ChAT activity compared to age-matched control cultures. Neurotrophic factors have also been shown to alter the sensitivity of some neurons to glutamate neurotoxicity, a postulated mechanism of injury in the neurodegenerative disease, amyotrophic lateral sclerosis (ALS). Incubation of organotypic spinal cord cultures in the presence of the glutamate transport inhibitor threo-hydroxyaspartate (THA) reproducibly causes death of motor neurons which is glutamate-mediated. In this model of motor neuron degeneration, IGF-I, GDNF, and NT-4/5 are potently neuroprotective, but BDNF, CNTF, and NT-3 are not. The organotypic glutamate toxicity model appears to be the best preclinical predictor to date of success in human clinical trials in ALS.
AB - Many neurotrophic factors have been shown to enhance survival of embryonic motor neurons or affect their response to injury. Few studies have investigated the potential effects of neurotrophic factors on more mature motor neurons that might be relevant for neurodegenerative diseases. Using organotypic spinal cord cultures from postnatal rats, we have demonstrated that insulin-like growth factor-I (IGF-I) and glial-derived neurotrophic factor (GDNF) significantly increase choline acetyltransferase (ChAT) activity, but brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT- 4/5), and neurotrophin-3 (NT-3) do not. Surprisingly, ciliary neurotrophic factors (CNTF) actually reduces ChAT activity compared to age-matched control cultures. Neurotrophic factors have also been shown to alter the sensitivity of some neurons to glutamate neurotoxicity, a postulated mechanism of injury in the neurodegenerative disease, amyotrophic lateral sclerosis (ALS). Incubation of organotypic spinal cord cultures in the presence of the glutamate transport inhibitor threo-hydroxyaspartate (THA) reproducibly causes death of motor neurons which is glutamate-mediated. In this model of motor neuron degeneration, IGF-I, GDNF, and NT-4/5 are potently neuroprotective, but BDNF, CNTF, and NT-3 are not. The organotypic glutamate toxicity model appears to be the best preclinical predictor to date of success in human clinical trials in ALS.
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U2 - 10.1006/nbdi.1999.0253
DO - 10.1006/nbdi.1999.0253
M3 - Article
C2 - 10527802
AN - SCOPUS:0032702435
VL - 6
SP - 335
EP - 346
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
IS - 5
ER -