Premium
Opposing effects of low and high‐dose clozapine on survival of transgenic amyotrophic lateral sclerosis mice
Author(s) -
Turner B.J.,
Rembach A.,
Spark R.,
Lopes E.C.,
Cheema S.S.
Publication year - 2003
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.10796
Subject(s) - clozapine , neuroprotection , amyotrophic lateral sclerosis , pharmacology , sod1 , medicine , glial cell line derived neurotrophic factor , neurotrophic factors , schizophrenia (object oriented programming) , receptor , psychiatry , disease
Clozapine is a potent atypical neuroleptic or antipsychotic agent used to relieve symptoms of early‐diagnosed schizophrenia. Aside from well‐described dopamine and serotonin receptor blockade effects, clozapine may also be neuroprotective through its modulation of the p75 neurotrophin receptor (p75 NTR ) and superoxide dismutase 1 (SOD1) expression. The death‐signalling activities of both p75 NTR and mutant SOD1 are implicated in motor neuron degeneration in humans and transgenic mice with amyotrophic lateral sclerosis (ALS). We therefore investigated the effects of clozapine in cell culture and mouse models of ALS. Clozapine dose‐dependently inhibited full‐length and cleaved p75 NTR but not SOD1 protein expression in the motor neuron‐like (NSC‐34) cell line. Furthermore, low concentrations of clozapine protected NSC‐34 cells from paraquat‐mediated superoxide toxicity, nerve growth factor (NGF)‐induced death signalling, and serum deprivation, whereas high concentrations potentiated death. Systemic thrice‐weekly administration of low and high‐dose clozapine to mutant superoxide dismutase 1 (SOD1 G93A ) mice produced differential effects on disease onset and survival. Low‐dose treatment was associated with delayed locomotor impairment and death, compared to high‐dose clozapine, which accelerated paralysis and mortality ( P < 0.05). Increased death was not attributable to toxicity, as clozapine‐induced agranulocytosis was not detected from blood analysis. High‐dose clozapine, however, produced extrapyramidal symptoms in mice manifest by hindlimb rigidity, despite reducing spinal cord p75 NTR levels overall. These results suggest that although clozapine may exert p75 NTR ‐mediated neuroprotective activity in vitro, its profound antagonistic effects on dopaminergic and serotonergic systems in vivo at high doses may exacerbate the phenotype of transgenic ALS mice. © 2003 Wiley‐Liss, Inc.