Clozapine administration enhanced functional recovery after cuprizone demyelination

Abstract

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.

Tyrosine Kinase Receptors Axl and MerTK Mediate the Beneficial Effect of Electroacupuncture in a Cuprizone‐Induced Demyelinating Model

“…Here, we used 0.3% cuprizone supplement in our animal facility since our previous pilot experiments reported insufficient demyelination or weight loss/behavioral deficits using 0.2%. Of note, compared to previous studies [47,50], we found a faster recovery after the withdrawal of cuprizone for 1 week, indicating a potential batch discrepancy when inducing the cuprizone model.…”

“…However, by performing behavioral test such as beam-walking test, pole test, and rotarod test, it was demonstrated by others and our group that cuprizone-treated mice show affected locomotor-coordinative function [ 15 , 25 , 27 , 45 , 46 ]. In general, most studies [ 24 , 47 , 48 ] used 6- to 9-week-old mice maintaining a diet containing 0.2–0.3% cuprizone for 5-6 weeks to induce CNS demyelination. The outcome effect of cuprizone-induced intoxication could vary depending on many factors, such as mouse strain, age, gender, and even the local environment in the animal facility [ 49 , 50 ].…”

Safety and acceptability of clozapine and risperidone in progressive multiple sclerosis: a phase 1, randomized, blinded, placebo-controlled trial

“…[5,6,[8][9][10] Previous work evaluating the effect of clozapine and risperidone treatment in two mouse models of multiple sclerosis (MS) has demonstrated a dose-dependent reduction in the severity of disease and improvement in disease resolution. [11][12][13] This protection correlates with reduced CNS inflammation, enhanced functional recovery, and can be achieved at doses that do not promote weight gain, a dosedependent side effect of both clozapine and risperidone. [12,13] Together this preclinical work suggests that clozapine and risperidone, which readily pass through an intact blood brain barrier and reduce neuroinflammation in mice and humans, [1] may be useful to treat the chronic neuroinflammation associated with progressive MS (pMS).…”

“…[11][12][13] This protection correlates with reduced CNS inflammation, enhanced functional recovery, and can be achieved at doses that do not promote weight gain, a dosedependent side effect of both clozapine and risperidone. [12,13] Together this preclinical work suggests that clozapine and risperidone, which readily pass through an intact blood brain barrier and reduce neuroinflammation in mice and humans, [1] may be useful to treat the chronic neuroinflammation associated with progressive MS (pMS). [14][15][16] To this end, the Clozapine and RISperidone in Progressive MS (CRISP) trial was designed to investigate to suitability of clozapine and risperidone treatment during pMS.…”

Overexpression of Astroglial Major Histocompatibility Complex Class I in the Medial Prefrontal Cortex Impairs Visual Discrimination Learning in Mice

“…Clozapine, an atypical antipsychotic drug, exerts antagonistic effects on multiple neurotransmitter receptors, such as serotonin 5-HT2, muscarinic M1, and dopamine D1, D2, and D4 receptors, and attenuates behavioral impairments in animal models of schizophrenia, including the neonatal polyI:C treatment model [60]. This antipsychotic drug has been reported to exhibit anti-in ammatory activities, and decrease astrocyte and microglial activation [61,62]. Thus, clozapine protects neurons from the in ammatory changes induced by poly I:C and prevents increases in interleukin-6 levels in the rodent brain [63,64].…”