Abstract
Activation of microglia is a hallmark of neuroinflammation and has been implicated in the development of many psychiatric disorders. Hydrogen sulfide (H2S); a gasotransmitter has recently emerged as a potent antioxidant and anti-inflammatory molecule. However, the protective potential of H2S and its underpin molecular mechanisms in neuroinflammation associated behavioral deficits are still unknown. The present study has been designed to investigate the effect of sodium hydrogen sulfide (NaHS; a source of H2S) on microglial activation and associated behavior phenotype in response to lipopolysaccharide (LPS)-induced neuroinflammation. LPS treatment decreased H2S levels with a concomitant increase in reactive oxygen species (ROS) in the cortex and hippocampus. However, NaHS administration restored the endogenous H2S levels to the normal and decreased ROS levels. NaHS supplementation reduced the number of active microglia in the cortex and hippocampus of LPS treated animals. Morphological analysis of microglia showed significant increase in microglial density, span ratio and soma area in the cortex and hippocampus of LPS treated animals which was decreased by NaHS supplementation. Moreover, NaHS administration reduced the expression of microglial M1 phenotype markers (IL-1β, TNF-α and nitrite) and concomitantly increased the expression of M2 phenotype markers (IL-4 and TGF-β) in the brain regions of LPS treated animals. Furthermore, LPS-induced anxiety-like behavior assessed by open field test and elevated plus maze was reversed by NaHS supplementation. Taken together, these findings suggest that H2S supplementation ameliorates LPS-induced behavioral deficits by suppressing pro-inflammatory and promoting anti-inflammatory microglial response. Therefore, H2S releasing drugs may be potential therapeutics to treat neuroinflammation associated psychiatric disorders.
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Abbreviations
- AzMC:
-
(7-Azido-4-methylcoumarin)
- BBB:
-
(Blood brain barrier)
- CNS:
-
(Central nervous system)
- CSF1:
-
(Colony stimulating factor 1)
- DCFH-DA:
-
(2', 7'-Dichlorofluorescein diacetate)
- GAPDH:
-
(Glyceraldehyde-3-phosphate dehydrogenase)
- H2S:
-
(Hydrogen sulphide)
- Iba1:
-
(Ionized calcium binding adaptor molecule-1)
- IFN-γ:
-
(Interferon γ)
- IL-1β:
-
(Interleukin 1β)
- LPS:
-
(Lipopolysaccharide)
- NaHS:
-
(Sodium hydrogen sulphide)
- ROS:
-
(Reactive oxygen species)
- TNFR:
-
(TNF-α receptor)
- TNF-α:
-
(Tumor necrosis factor α)
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The financial assistance provided by the Department of Biotechnology (DBT), Govt. of India, (grant number BT/361/NE/TBP/2012) is acknowledged. The authors also acknowledge financial assistance provided under the Promotion of University Research and Scientific Excellence (PURSE) by Department of Science and Technology (DST) New Delhi and under University Grants Commission (UGC) under Special Assistance Program (SAP) of UGC (DRS Phase-II).
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Mohit Kumar and Palkin Arora contributed equally. Mohit Kumar and Rajat Sandhir: Conceptualization, Methodology and Software. Mohit Kumar and Palkin Arora: Data curation, Writing- Original draft preparation. Rajat Sandhir: Supervision, Writing- Reviewing and Editing. All authors have read and approved the final version of the manuscript.
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Figure S1
Effect of NaHS supplementation on microglial shape and complexity in LPS treated animals. Representative photomicrograph of FracLac analysis of microglia in the CA1 region of hippocampus of LPS treated animals. (PNG 537 kb)
Figure S2
Effect of NaHS supplementation on microglial shape and complexity in LPS treated animals. Representative photomicrograph of FracLac analysis of microglia in the CA3 region of hippocampus of LPS treated animals. (PNG 521 kb)
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Kumar, M., Arora, P. & Sandhir, R. Hydrogen Sulfide Reverses LPS-Induced Behavioral Deficits by Suppressing Microglial Activation and Promoting M2 Polarization. J Neuroimmune Pharmacol 16, 483–499 (2021). https://doi.org/10.1007/s11481-020-09920-z
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DOI: https://doi.org/10.1007/s11481-020-09920-z