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Microglial-induced apoptosis is potentially responsible for hyperalgesia variations during CFA-induced inflammation

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Abstract

Aims

Activated microglia is known as a main mediator of inflammatory pain, but the possible mechanisms of its operation are poorly understood. Microglial cells have considered as one of the main sources of pro-inflammatory cytokines in the CNS. PTEN is one of the important targets of pro-inflammatory cytokines and the main mediator of apoptotic cell death. In this study, we investigated the possible effect of microglial activation on PTEN/PI3K/Akt signaling pathway and apoptosis in an inflammatory rat model of Complete Freund’s adjuvant (CFA).

Methods

Persistent peripheral inflammation was induced by a subcutaneous injection of CFA into the rats’ right hind paw on day 0. Minocycline (a potent selective inhibitor of microglial) was administered intraperitoneally during days 1–21 after CFA injection. Hyperalgesia was assessed on days 0, 7, and 21 using plantar test, then lumbar spinal cord segments were isolated, and the amount of spinal Iba1 (microglial marker), PTEN, P.Akt, and cleaved caspase-3 (a marker of apoptosis activation) were analyzed using Western blot. The spinal TNF-α levels were assayed by ELISA and the microglia numbers were determined using immunohistochemical technique.

Results

Results revealed that increased hyperalgesia was concurrent with an increment of Iba1 (P < 0.001), TNF-α (P < 0.001), PTEN (P < 0.01), cleaved caspase-3 (P < 0.001), and a decrement of P.Akt (P < 0.01) during the acute phase of CFA-induced inflammation, while, at the same time as decreasing hyperalgesia during the chronic phase of study, Iba1 and TNF-α expression significantly decreased and PTEN, cleaved caspase-3, and P.Akt restored to baseline on day 0. Minocycline administration reduced the elevation of spinal Iba1 (P < 0.001), TNF-α (0.001), PTEN (P < 0.01), and cleaved caspase-3 (P < 0.001) expression induced by CFA injection, and also restored Akt activity to the baseline on day 0 (P < 0.001).

Conclusions

These results suggest that microglial-mediated pain following CFA injection might be related in part to increased spinal cell apoptosis which probably is mediated by PTEN/PI3K/Akt deregulation.

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Acknowledgements

This article has been extracted from the PhD thesis written by Mrs "Mansoureh Baniasadi" in School of Medicine, Shahid Beheshti University of Medical Sciences (Registration No: 304), and supported by Iran National Science Foundation (INSF) (No. 95840128) and Neurophysiology Research Center of Shahid Beheshti University of Medical Sciences (No. 742).

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Authors and Affiliations

  1. Physiology Department, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Mansoureh Baniasadi, Homa Manaheji, Samira Danyali & Jalal Zaringhalam

  2. Neurophysiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Mansoureh Baniasadi & Jalal Zaringhalam

  3. Department of Biology, Queens College and Graduate Center,, City University of New York, Flushing, NY, USA

    Nader Maghsoudi & Zahra Zakeri

  4. Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Nader Maghsoudi

  5. Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Nader Maghsoudi

  6. Queens Borough Community College, New York, USA

    Amirabbas Maghsoudi

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  1. Mansoureh Baniasadi
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  2. Homa Manaheji
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  7. Jalal Zaringhalam
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Correspondence to Jalal Zaringhalam.

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Baniasadi, M., Manaheji, H., Maghsoudi, N. et al. Microglial-induced apoptosis is potentially responsible for hyperalgesia variations during CFA-induced inflammation. Inflammopharmacol 28, 475–485 (2020). https://doi.org/10.1007/s10787-019-00623-3

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