Research Article: Clozapine administration enhanced functional recovery after cuprizone demyelination

Date Published: May 9, 2019

Publisher: Public Library of Science

Author(s): Nikki Templeton, Bronwyn Kivell, Amy McCaughey-Chapman, Bronwen Connor, Anne Camille La Flamme, Fernando de Castro.


The atypical antipsychotic agent, clozapine, is used to treat a variety of neurological disorders including schizophrenia and Parkinson’s disease and readily crosses the blood brain barrier to interact with a wide range of neuroreceptors including those for dopamine and serotonin. Recent work has shown that clozapine can reduce neuroinflammation in experimental autoimmune encephalomyelitis, a neuroinflammatory model of multiple sclerosis (MS) and mediates its effects in the central nervous system. To further characterise the protection provided by clozapine, the cuprizone model of demyelination was used to assess the effect of clozapine treatment on the cellular events surrounding demyelination and remyelination. Using this model of non-immune demyelination, we found that clozapine administration was unable to prevent demyelination, but when administered post demyelination, was able to enhance the rate of functional recovery. The more rapid improvement of clozapine-treated mice correlated with a decreased level of astrocyte and microglial activation but only modestly enhanced remyelination. Together, these studies highlight the potential of clozapine to support enhanced functional recovery after demyelination, such as that occurring during MS.

Partial Text

Multiple Sclerosis (MS) is a disease of the central nervous system (CNS) affecting approximately 2.3 million people worldwide [1]. Disease pathology is characterised by demyelinating lesions forming in the CNS and an infiltration of self-reactive lymphocytes [2]. Current therapies for MS consist primarily of immune-modifying treatments designed to slow disease progression and decrease relapse frequency [3]. The current MS therapeutics available are limited in their ability to treat progressive forms of MS; therefore, alternative MS therapies are still required that can reduce disability in progressive disease [4].

The cuprizone model is a useful model to assess the effect of potential therapeutics, because both remyelination and demyelination occur at the same time, as happens in MS [11, 12]. To our knowledge the effect of in vivo clozapine treatment in the cuprizone model has not previously been investigated. Like previously reported results [17, 18], cuprizone treatment lead to a reduction in the mature OG population, with clozapine unable to protect this population (GST-pi transferase+ cells). Furthermore, a study looking at the role of quetiapine in remyelination after cuprizone-induced demyelination [19] showed that quetiapine treatment during the recovery period (after cuprizone was withdrawn) significantly improved behavioural performance and myelin restoration. Therefore, we hypothesised that like quetiapine, clozapine may have a protective effect in the cuprizone model and may be able to alter myelin levels.




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