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. 2016 Mar;241(5):509-18.
doi: 10.1177/1535370215619707. Epub 2015 Dec 6.

Possible involvement of the JAK/STAT signaling pathway in N-acetylcysteine-mediated antidepressant-like effects

Marwa M Al-Samhari  1 , Nouf M Al-Rasheed  1 , Salim Al-Rejaie  1 , Nawal M Al-Rasheed  2 , Iman H Hasan  1 , Ayman M Mahmoud  3 , Nduna Dzimiri  4
Affiliations

Possible involvement of the JAK/STAT signaling pathway in N-acetylcysteine-mediated antidepressant-like effects

Marwa M Al-Samhari et al. Exp Biol Med (Maywood). 2016 Mar.

Abstract

Advances in depression research have targeted inflammation and oxidative stress to develop novel types of treatment. The JAK/STAT signaling pathway plays pivotal roles in immune and inflammatory responses. The present study was designed to investigate the effects of N-acetylcysteine, a putative precursor of the antioxidant glutathione, in an animal model of depression, with an emphasis on the JAK/STAT signaling pathway. Fluoxetine, a classical antidepressant drug was also under investigation. Male Wistar rats were subjected to forced swimming test and given N-acetylcysteine and fluoxetine immediately after the pre-test session, 5 h later and 1 h before the test session of the forced swimming test. N-acetylcysteine decreased immobility time (P < 0.05), serum corticosterone (P < 0.001), and hydrogen peroxide (P < 0.001), while restored glutathione concentration. Treatment of the rats with N-acetylcysteine produced significant (P < 0.001) down-regulation of STAT3 mRNA expression and protein phosphorylation. On the other hand, N-acetylcysteine significantly (P < 0.001) increased SOCS3 gene expression; however, SOCS3 protein was not changed. In conclusion, our study suggests that modulation of the JAK/STAT pathway might mediate the antidepressant-like effects of N-acetylcysteine. Therefore, depression research may target the JAK/STAT signaling pathway to provide a novel effective therapy.

Keywords: Depression; SOC3; forced swimming test; glutathione; inflammation; oxidative stress.

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Figures

Figure 1
Figure 1
Effect of NAC and fluoxetine on (a) the immobility time in FST and (b) the number of crossings in OFT. Data are mean ± SEM (N = 12).*P < 0.05 and **P < 0.01
Figure 2
Figure 2
Effect of NAC and fluoxetine on (a) hydrogen peroxide and (b) reduced glutathione in rats subjected to the FST. Data are mean ± SEM (N = 12).*P < 0.05, **P < 0.01 and ***P < 0.001. NAC: N-acetylcysteine; H2O2: hydrogen peroxide; GSH: reduced glutathione
Figure 3
Figure 3
Effect of NAC and fluoxetine on serum corticosterone levels in rats subjected to the FST. Data are mean ± SEM (N = 12). **P < 0.01
Figure 4
Figure 4
Effect of NAC and fluoxetine on mRNA expression of (a) SOCS3 and (b) STAT3 in rats subjected to the FST. Data are mean ± SEM (N = 12). **P < 0.01 and ***P < 0.001. SOCS: suppressor of cytokine signaling; STAT: signal transducer and activator of transcription.
Figure 5
Figure 5
Effect of NAC and fluoxetine on protein expression of (a) SOCS3 and (b) pSTAT3 in rats subjected to the FST. Data are mean ± SEM (N = 12). **P < 0.01 and ***P < 0.001. SOCS: suppressor of cytokine signaling; STAT: signal transducer and activator of transcription.
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