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. 2018 May 23;13(5):e0197060.
doi: 10.1371/journal.pone.0197060. eCollection 2018.

Pioglitazone abolishes autistic-like behaviors via the IL-6 pathway

Thiago Berti Kirsten  1   2 , Renato C Casarin  3 , Maria M Bernardi  2   3 , Luciano F Felicio  1
Affiliations

Pioglitazone abolishes autistic-like behaviors via the IL-6 pathway

Thiago Berti Kirsten et al. PLoS One. .

Abstract

Autism is characterized by social deficits, communication abnormalities, and repetitive behaviors. The risk factors appear to include genetic and environmental conditions, such as prenatal infections and maternal dietary factors. Previous investigations by our group have demonstrated that prenatal exposure to lipopolysaccharide (LPS), which mimics infections by gram-negative bacteria, induces autistic-like behaviors. No effective treatment yet exists for autism. Therefore, we used our rat model to test a possible treatment for autism. We selected pioglitazone to block or ease the impairments induced by LPS because although this drug was designed as an anti-diabetic drug (it has an insulin effect), it also exerts anti-inflammatory effects. Juvenile offspring were treated daily with pioglitazone, and the main behaviors related to autism, namely, socialization (play behavior) and communication (50-kHz ultrasonic vocalizations), were studied. Biomarkers linked to autism and/or pioglitazone were also studied to attempt to understand the mechanisms involved, namely, IL-6, TNF-alpha, MCP-1, insulin, and leptin. Prenatal LPS exposure induced social deficits and communicational abnormalities in juvenile rat offspring as well as elevated plasma IL-6 levels. Daily postnatal pioglitazone treatment blocked the impairments found in terms of the time spent on social interaction, the number of vocalizations (i.e., autistic-like behaviors) and the elevated plasma IL-6 levels. Thus, pioglitazone appears to be a relevant candidate for the treatment of autism. The present findings may contribute to a better understanding and treatment of autism and associated diseases.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Play behaviors.
The effects of prenatal LPS (100 μg/kg at gestational day 9.5) and postnatal pioglitazone (0.25 and 1.0 mg/kg/day between postnatal days 21 and 29) exposures on play behaviors in juvenile male rat offspring. SAL+DMSO, prenatal saline injection and postnatal daily DMSO injection; LPS+DMSO, prenatal LPS injection and postnatal daily DMSO injection; LPS+PI0.25, prenatal LPS injection and postnatal pioglitazone 0.25 mg/kg/day; LPS+PI1.0, prenatal LPS injection and postnatal pioglitazone 1.0 mg/kg/day (n = 8 rats/group). *p < 0.05, **p < 0.01, and ***p < 0.0001 (one-way ANOVA followed by the Newman-Keuls test). The data are expressed as the mean ± the SEM.
Fig 2
Fig 2. Ultrasonic vocalizations.
The effects of prenatal LPS (100 μg/kg at gestational day 9.5) and postnatal pioglitazone (0.25 and 1.0 mg/kg/day between postnatal days 21 and 29) exposures on 50-kHz ultrasonic vocalizations in juvenile male rat offspring. SAL+DMSO, prenatal saline injection and postnatal daily DMSO injection; LPS+DMSO, prenatal LPS injection and postnatal daily DMSO injection; LPS+PI0.25, prenatal LPS injection and postnatal pioglitazone 0.25 mg/kg/day; LPS+PI1.0, prenatal LPS injection and postnatal pioglitazone 1.0 mg/kg/day (n = 8 rats/group). *p < 0.05, **p < 0.01, and ***p < 0.0001 (one-way ANOVA followed by the Newman-Keuls test). The data are expressed as the mean ± the SEM.
Fig 3
Fig 3. Plasma evaluations.
The effects of prenatal LPS (100 μg/kg at gestational day 9.5) and postnatal pioglitazone (0.25 and 1.0 mg/kg/day between postnatal days 21 and 29) exposures on IL-6, TNF-alpha, MCP-1, insulin, and leptin plasma levels in juvenile male rat offspring. SAL+DMSO, prenatal saline injection and postnatal daily DMSO injection; LPS+DMSO, prenatal LPS injection and postnatal daily DMSO injection; LPS+PI0.25, prenatal LPS injection and postnatal pioglitazone 0.25 mg/kg/day; LPS+PI1.0, prenatal LPS injection and postnatal pioglitazone 1.0 mg/kg/day (n = 8 rats/group). *p < 0.05 and **p < 0.01 (one-way ANOVA followed by the Newman-Keuls test). The data are expressed as the mean ± the SEM.
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References

    1. DSM-IV. Pervasive Developmental Disorders. 4th ed Washington, DC: American Psychiatric Association; 1994. 65–78 p.
    1. Fernell E, Eriksson MA, Gillberg C. Early diagnosis of autism and impact on prognosis: a narrative review. Clin Epidemiol. 2013;5:33–43. Epub 2013/03/06. doi: 10.2147/CLEP.S41714 clep-5-033 [pii]. ; PubMed Central PMCID: PMC3583438. - DOI - PMC - PubMed
    1. Fombonne E. Epidemiology of pervasive developmental disorders. Pediatr Res. 2009;65(6):591–8. Epub 2009/02/17. doi: 10.1203/PDR.0b013e31819e7203 . - DOI - PubMed
    1. Herbert MR. Contributions of the environment and environmentally vulnerable physiology to autism spectrum disorders. Curr Opin Neurol. 2010;23(2):103–10. Epub 2010/01/21. doi: 10.1097/WCO.0b013e328336a01f . - DOI - PubMed
    1. Johnson NL, Giarelli E, Lewis C, Rice CE. Genomics and autism spectrum disorder. J Nurs Scholarsh. 2013;45(1):69–78. Epub 2013/02/02. doi: 10.1111/j.1547-5069.2012.01483.x . - DOI - PMC - PubMed

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Grants and funding

This research was supported by the São Paulo Research Foundation (FAPESP grant no. 12/07007-8) and the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/Prêmio 1029/2014). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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