{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T13:15:27Z","timestamp":1790169327713,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2003,9,25]],"date-time":"2003-09-25T00:00:00Z","timestamp":1064448000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Neuroscience Research"],"published-print":{"date-parts":[[2003,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Clozapine is a potent atypical neuroleptic or antipsychotic agent used to relieve symptoms of early\u2010diagnosed schizophrenia. Aside from well\u2010described dopamine and serotonin receptor blockade effects, clozapine may also be neuroprotective through its modulation of the p75 neurotrophin receptor (p75<jats:sup>NTR<\/jats:sup>) and superoxide dismutase 1 (SOD1) expression. The death\u2010signalling activities of both p75<jats:sup>NTR<\/jats:sup> 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\u2010dependently inhibited full\u2010length and cleaved p75<jats:sup>NTR<\/jats:sup> but not SOD1 protein expression in the motor neuron\u2010like (NSC\u201034) cell line. Furthermore, low concentrations of clozapine protected NSC\u201034 cells from paraquat\u2010mediated superoxide toxicity, nerve growth factor (NGF)\u2010induced death signalling, and serum deprivation, whereas high concentrations potentiated death. Systemic thrice\u2010weekly administration of low and high\u2010dose clozapine to mutant superoxide dismutase 1 (SOD1<jats:sup>G93A<\/jats:sup>) mice produced differential effects on disease onset and survival. Low\u2010dose treatment was associated with delayed locomotor impairment and death, compared to high\u2010dose clozapine, which accelerated paralysis and mortality (<jats:italic>P<\/jats:italic> &lt; 0.05). Increased death was not attributable to toxicity, as clozapine\u2010induced agranulocytosis was not detected from blood analysis. High\u2010dose clozapine, however, produced extrapyramidal symptoms in mice manifest by hindlimb rigidity, despite reducing spinal cord p75<jats:sup>NTR<\/jats:sup> levels overall. These results suggest that although clozapine may exert p75<jats:sup>NTR<\/jats:sup>\u2010mediated 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. \u00a9 2003 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jnr.10796","type":"journal-article","created":{"date-parts":[[2003,10,30]],"date-time":"2003-10-30T11:29:54Z","timestamp":1067513394000},"page":"605-613","source":"Crossref","is-referenced-by-count":31,"title":["Opposing effects of low and high\u2010dose clozapine on survival of transgenic amyotrophic lateral sclerosis 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