clozapine and Amyotrophic-Lateral-Sclerosis

Inspiratory accessory respiratory muscles (ARMs) enhance ventilation when demands are high, such as during exercise and/or pathological conditions. Despite progressive degeneration of phrenic motor neurons innervating the diaphragm, amyotrophic lateral sclerosis (ALS) patients and rodent models are able to maintain ventilation at early stages of disease. In order to assess the contribution of ARMs to respiratory compensation in ALS, we examined the activity of ARMs and ventilation throughout disease progression in SOD1

Topics: Amyotrophic Lateral Sclerosis; Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Brain Stem; Clozapine; Disease Models, Animal; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Homeodomain Proteins; Humans; Interneurons; Male; Membrane Potentials; Mice; Mice, Transgenic; Plasma Membrane Neurotransmitter Transport Proteins; Receptor, Muscarinic M3; Receptors, Muscarinic; Respiration; Respiratory Muscles; Spinal Cord; Superoxide Dismutase; Transcription Factors

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.

Topics: Amyotrophic Lateral Sclerosis; Animals; Cell Death; Cells, Cultured; Clozapine; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Gene Expression; Mice; Mice, Transgenic; Motor Neurons; Neuroprotective Agents; Receptor, Nerve Growth Factor; Receptors, Nerve Growth Factor; Signal Transduction; Superoxide Dismutase