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Resveratrol Ameliorates Dysregulation of Th1, Th2, Th17, and T Regulatory Cell-Related Transcription Factor Signaling in a BTBR T + tf/J Mouse Model of Autism

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Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder. It is characterized by impaired social communication, abnormal social interactions, and repetitive behaviors and/or restricted interests. BTBR T + tf/J (BTBR) inbred mice are commonly used as a model for ASD. Resveratrol is used widely as a beneficial therapeutic in the treatment of an extensive array of pathologies, including neurodegenerative diseases. In the present study, the effect of resveratrol administration (20 and 40 mg/kg) was evaluated in both BTBR and C57BL/6 (B6) mice. Behavioral (self-grooming), Foxp3, T-bet, GATA-3, RORγt, and IL-17A in CD4+ T cells were assessed. Our study showed that BTBR control mice exhibited a distinct immune profile from that of the B6 control mice. BTBR mice were characterized by lower levels of Foxp3+ and higher levels of RORγt+, T-bet+, and GATA-3+ production in CD4+ T cells when compared with B6 control. Resveratrol (20 and 40 mg/kg) treatment to B6 and BTBR mice showed substantial induction of Foxp3+ and reduction of T-bet+, GATA-3+, and IL-17A+ expression in CD4+ cells when compared with the respective control groups. Moreover, resveratrol treatment resulted in upregulated expression of Foxp3 mRNA and decreased expression levels of T-bet, GATA-3, RORγt, and IL-17A in the spleen and brain tissues. Western blot analysis confirmed that resveratrol treatment decreased the protein expression of T-bet, GATA-3, RORγ, and IL-17 and that it increased Foxp3 in B6 and BTBR mice. Our results suggest that autism is associated with dysregulation of transcription factor signaling that can be corrected by resveratrol treatment.

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Abbreviations

ASD:

Autism spectrum disorder

CD4:

Cluster of differentiation 4

Th cells:

T helper cells

IL:

Interleukin

Foxp3:

Forkhead box P3

STAT3:

Signal transducer and activator of transcription 3

RORγt:

retinoid-acid receptor-related orphan receptor gamma t

T-bet:

T-box transcription factor

GATA3:

GATA binding protein 3

mRNA:

Messenger RNA

RT-PCR:

Reverse transcription polymerase chain reaction

FITC:

Fluoroisothiocyanate

PE:

Phycoerythrin

i.p:

Intraperitoneally

DMSO:

Dimethyl sulfoxide

CNS:

Central nervous system

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Acknowledgments

The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding the work through the research group project No. RGP-VPP-120.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia

    Saleh A. Bakheet, Mohammad Zeed Alzahrani, Mushtaq Ahmad Ansari, Ahmed Nadeem, Khairy M. A. Zoheir, Sabry M. Attia & Sheikh Fayaz Ahmad

  2. Department of Cell Biology, National Research Centre, Cairo, Egypt

    Khairy M. A. Zoheir

  3. Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo, Egypt

    Sabry M. Attia

  4. Autism Research and Treatment Center, AL-Amodi Autism Research Chair, Department of Physiology, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia

    Laila Yousef AL-Ayadhi

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  1. Saleh A. Bakheet
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  2. Mohammad Zeed Alzahrani
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  3. Mushtaq Ahmad Ansari
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  4. Ahmed Nadeem
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  5. Khairy M. A. Zoheir
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  7. Laila Yousef AL-Ayadhi
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  8. Sheikh Fayaz Ahmad
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Correspondence to Sheikh Fayaz Ahmad.

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Bakheet, S.A., Alzahrani, M.Z., Ansari, M.A. et al. Resveratrol Ameliorates Dysregulation of Th1, Th2, Th17, and T Regulatory Cell-Related Transcription Factor Signaling in a BTBR T + tf/J Mouse Model of Autism. Mol Neurobiol 54, 5201–5212 (2017). https://doi.org/10.1007/s12035-016-0066-1

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