Clozapine Regulates Microglia and Is Effective in Chronic Experimental Autoimmune Encephalomyelitis.

Progressive multiple sclerosis is characterized by chronic inflammation with microglial activation, oxidative stress, accumulation of iron and continuous neurodegeneration with inadequate effectiveness of medications used so far. We now investigated effects of iron on microglia and used the previously identified neuroprotective antipsychotic clozapine Microglia were treated with iron and clozapine followed by analysis of cell death and response to oxidative stress, cytokine release and neuronal phagocytosis. Clozapine was investigated in chronic EAE regarding optimal dosing and therapeutic effectiveness in different treatment paradigms. Animals were scored clinically by blinded raters. Spinal cords were analyzed histologically for inflammation, demyelination, microglial activation and iron accumulation and for transcription changes of regulators of iron metabolism and inflammation. Effects on immune cells were analyzed using flow cytometry. Iron impaired microglial function Clozapine regulates microglial function and attenuates chronic EAE, even in a therapeutic treatment paradigm. This well-defined generic medication might therefore be considered as promising add-on therapeutic for further development in progressive MS.

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Copyright © 2021 Ceylan, Haupeltshofer, Kämper, Dann, Ambrosius, Gold and Faissner.

Déclaration de conflit d'intérêts

SF filed a United States Patent Application relating and entitled to “Treatment for Progressive Multiple Sclerosis”, No. 62/412,534, filed October 25, 2016. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.