Ivermectin inhibits AMPA receptor-mediated excitotoxicity in cultured motor neurons and extends the life span of a transgenic mouse model of amyotrophic lateral sclerosis.
alpha-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-mediated excitotoxicity contributes to the selective motor neuron death in amyotrophic lateral sclerosis (ALS). In this study, we investigated the effect of P2 receptor-influencing substances on kainate-induced motor neuron death in an in vitro model for AMPA receptor-mediated excitotoxicity. Complete protection was found after preincubation of the motor neurons with ivermectin or Cibacron Blue 3G-A. Preincubation with both P2X4 modulators did not influence the number or Ca2+ permeability of the AMPA receptors and addition during kainate stimulation alone had no effect. Preincubation with a low concentration of ATP, the natural agonist of the P2X4 receptor, also protected the motor neurons against a subsequent excitotoxic stimulation, while high concentrations of ATP were toxic. Moreover, ivermectin increased the toxicity of low ATP concentrations, indicating that ivermectin can potentiate the effect of ATP on its receptor. Ivermectin and ATP also protected against hypoxia/hypoglycemia. To further investigate the relevance of these findings for ALS, we treated SOD1(G93A)-mice, a transgenic animal model for familial ALS, with ivermectin. This resulted in an extension of the life span of these mice with almost 10%. We conclude that ivermectin induces a mechanism in motor neurons, in vivo and in vitro, that protects against subsequent excitotoxic insults. Our in vitro data indicate that this protective mechanism is due to the potentiation by ivermectin of an effect of ATP mediated by the P2X4 receptor.
Andries
Maria
M
Department of Molecular Cell Biology, Faculty of Medicine, KU Leuven, Campus Gasthuisberg, Leuven, Belgium. maria.andries@med.kuleuven.be
Van Damme
Philip
P
Robberecht
Wim
W
Van Den Bosch
Ludo
L
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004594:Electrophysiology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists; D007003:Hypoglycemia / Q000188:drug therapy / Q000473:pathology; D002534:Hypoxia, Brain / Q000188:drug therapy / Q000473:pathology; D007559:Ivermectin / Q000494:pharmacology*; D007608:Kainic Acid / Q000633:toxicity; D008136:Longevity / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects* / Q000473:pathology; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D018048:Receptors, Purinergic P2 / Q000187:drug effects; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D014227:Triazines / Q000494:pharmacology
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D018048:Receptors, Purinergic P2; D014227:Triazines; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; C012842:Cibacron Blue F 3GA; D011732:Pyridoxal Phosphate; D007559:Ivermectin; D000255:Adenosine Triphosphate; C000606291:Sod1 protein, mouse; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D007608:Kainic Acid