Gut neurotoxin p-cresol induces brain-derived neurotrophic factor secretion and increases the expression of neurofilament subunits in PC-12 cells

Gigi Tevzadze; Tamar Barbakadze; Elisabed Kvergelidze; Elene Zhuravliova; Lali Shanshiashvili; David Mikeladze; Gigi Tevzadze; Tamar Barbakadze; Elisabed Kvergelidze; Elene Zhuravliova; Lali Shanshiashvili; David Mikeladze

doi:10.3934/Neuroscience.2022002

AIMS Neuroscience

2022, Volume 9, Issue 1: 12-23. doi: 10.3934/Neuroscience.2022002

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Research article

Gut neurotoxin p-cresol induces brain-derived neurotrophic factor secretion and increases the expression of neurofilament subunits in PC-12 cells

1.
4-D Research Institute, Ilia State University, 3/5 Cholokashvili av, Tbilisi, 0162, Georgia
2.
School of Natural Sciences and Medicine, Institute of Chemical Biology, Ilia State University, 3/5 Cholokashvili ave, Tbilisi, 0162, Georgia
3.
I. Beritashvili Center of Experimental Biomedicine 14, Gotua Str., Tbilisi 0160, Georgia

Received: 01 October 2021 Revised: 30 November 2021 Accepted: 19 December 2021 Published: 23 December 2021

Increased p-cresol levels reportedly alter brain dopamine metabolism and exacerbate neurological disorders in experimental animals. In contrast to toxic concentrations, low doses of p-cresol may have distinct effects on neuronal metabolism. However, the role of p-cresol in synapse remodeling, neurite outgrowth, and other anabolic processes in neurons remains elusive. We propose that low doses of p-cresol affect neuronal cell structural remodeling compared with the high concentration-mediated harmful effects. Thus, the effects of p-cresol on the secretion of brain-derived neurotrophic factor (BDNF) and neurofilament subunit expression were examined using rat pheochromocytoma cells (PC-12 cells). We observed that low doses of p-cresol potentiated nerve growth factor-induced differentiation via secretion of BDNF in cultured PC-12 cells. Opioidergic compounds modulated these p-cresol effects, which were reversed by oxytocin. We propose that this effect of p-cresol has an adaptive and compensatory character and can be attributed to the induction of oxidative stress. Accordingly, we hypothesize that low doses of p-cresol induce mild oxidative stress, stimulating BDNF release by activating redox-sensitive genes. Given that the intestinal microbiome is the primary source of endogenous p-cresol, the balance between gut microbiome strains (especially Clostridium species) and opioidergic compounds may directly influence neuroplasticity.
- p-cresol,
- microbiome,
- BDNF,
- oxytocin,
- neurofilament
Citation: Gigi Tevzadze, Tamar Barbakadze, Elisabed Kvergelidze, Elene Zhuravliova, Lali Shanshiashvili, David Mikeladze. Gut neurotoxin p-cresol induces brain-derived neurotrophic factor secretion and increases the expression of neurofilament subunits in PC-12 cells[J]. AIMS Neuroscience, 2022, 9(1): 12-23. doi: 10.3934/Neuroscience.2022002

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Abstract

Increased p-cresol levels reportedly alter brain dopamine metabolism and exacerbate neurological disorders in experimental animals. In contrast to toxic concentrations, low doses of p-cresol may have distinct effects on neuronal metabolism. However, the role of p-cresol in synapse remodeling, neurite outgrowth, and other anabolic processes in neurons remains elusive. We propose that low doses of p-cresol affect neuronal cell structural remodeling compared with the high concentration-mediated harmful effects. Thus, the effects of p-cresol on the secretion of brain-derived neurotrophic factor (BDNF) and neurofilament subunit expression were examined using rat pheochromocytoma cells (PC-12 cells). We observed that low doses of p-cresol potentiated nerve growth factor-induced differentiation via secretion of BDNF in cultured PC-12 cells. Opioidergic compounds modulated these p-cresol effects, which were reversed by oxytocin. We propose that this effect of p-cresol has an adaptive and compensatory character and can be attributed to the induction of oxidative stress. Accordingly, we hypothesize that low doses of p-cresol induce mild oxidative stress, stimulating BDNF release by activating redox-sensitive genes. Given that the intestinal microbiome is the primary source of endogenous p-cresol, the balance between gut microbiome strains (especially Clostridium species) and opioidergic compounds may directly influence neuroplasticity.

Acknowledgments

This research was supported by the Shota Rustaveli National Science Foundation of Georgia (grant # FR -19-3114).

Conflict of interests

The authors declare that there are no conflicts of interest.

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