Abstract
At present, therapeutic options available for treating schizophrenia are limited to monoamine-based antipsychotic drugs. Recent genome wide association study (GWAS) indicated a close relationship between immune system and schizophrenia. To leverage the GWAS finding for therapeutic strategy, we conducted a mechanism and effect study on application of human umbilical cord-derived mesenchymal stem cells (hUC-MSC) with potent immune-modulatory effect in an animal model useful for the study of schizophrenia. Schizophrenia-relevant behaviors were induced by amphetamine administration (amphetamine-sensitized mice) and the effect of a single intravenous administration of hUC-MSC was examined in the amphetamine-sensitized mice. Schizophrenia-relevant behaviors were assessed by open field test, light/dark box, social interaction test, latent inhibition, prepulse inhibition, tail suspension test, and forced swimming test. Our results indicated that neuroinflammation along with peripheral TNF-α elevation is associated with schizophrenia-relevant behaviors in amphetamine-sensitized mice. In addition, hUC-MSC inhibited schizophrenia-relevant and the neuroinflammatory changes. The main mechanism of hUC-MSC was associated with the induction of Treg and production of the anti-inflammatory cytokine, IL-10 in periphery. In vitro study revealed that amphetamine did not directly induce a neuroinflammatory reaction, while recombinant TNF-α (rTNF-α) increased mRNA expression of TNF-α, KMO, and IL-1β in several microglial cell lines. Moreover, recombinant IL-10 (rIL-10) and MSC conditioned media inhibited the inflammatory response in rTNF-α-treated microglial cells. Assuming that hUC-MSCs rarely reach the CNS and do not remain in the body for an extended time, these findings suggest that a single hUC-MSC infusion have long-term beneficial effect via regulatory T cell induction and secretion of IL-10 in amphetamine-sensitized mice.
Highlights
Schizophrenia is a serious, debilitating mental disorder associated with a substantial global health burden[1]
The time spent in the dark zone by amphetaminesensitized mice in the light/dark test (LD) test was lower than that in the control group (Fig. 1c), and immobility time was decreased in TST (Fig. 1d) and forced swim test (FST) (Fig. 1e)
No difference was observed in the prepulse inhibition (PPI) test (Fig. 1h), and the mania-like behavior observed in the first week disappeared in the resumed LD (Fig. 1i), TST (Fig. 1j) and FST (Fig. 1k) at 3 weeks
Summary
Schizophrenia is a serious, debilitating mental disorder associated with a substantial global health burden[1]. The currently available antipsychotic drugs (APDs) exert modest positive effects on symptomatic. APDs can cause considerable side effects, wherein the use of typical APDs may cause extrapyramidal symptoms, including rigidity, tremor, and tardive dyskinesia[4], while the use of atypical ones have raised concerns regarding weight gain and metabolic dysregulation[5,6]. The need to identify novel therapeutic targets for the treatment of schizophrenia is felt to be constantly increasing. More recent studies have focused on the role of neuroinflammation in the pathogenesis and disease progression of schizophrenia. Epidemiological studies have suggested that maternal immune activation (MIA) caused by prenatal infections, may increase liability to schizophrenia by disrupting neurodevelopmental process[7,8].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
