Malonate-induced cortico-motoneuron death is attenuated by NT-4, but not by BDNF or NT-3.
Neurotrophins are promising candidates to slow the progression of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease in which spinal and cortical motoneurons selectively degenerate. In a long-term in vitro model, malonate-induced toxicity and cell death of motoneurons have been demonstrated. Here we studied the neuroprotective effect of BDNF, NT-3, and NT-4 on the cell death of cortical motoneurons in an organotypic culture model after chronic mitochondrial inhibition with malonate. Our data show that NT-4 completely prevents malonate-induced toxicity, whereas BDNF or NT-3 had no neuroprotective effect. In clinical trials for ALS, predominantly focussed on the survival of spinal motoneurons, BDNF has already been tested with disappointing results; our results suggest that NT-4 may be a better neurotrophin to prevent motoneuron loss.
Van Westerlaak
M G
MG
Department of Experimental Neurology, RMI for Neurosciences, Utrecht, The Netherlands.
Bär
P R
PR
Cools
A R
AR
Joosten
E A
EA
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008314:Malonates / Q000494:pharmacology; D009044:Motor Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016900:Neurofilament Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020933:Neurotrophin 3 / Q000494:pharmacology; D009924:Organ Culture Techniques; D017966:Pyramidal Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D020813:Receptor, trkB / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D008314:Malonates; D009414:Nerve Growth Factors; D016900:Neurofilament Proteins; D018696:Neuroprotective Agents; D020933:Neurotrophin 3; D020813:Receptor, trkB; C073922:neurotrophin 4