Inhibition of SERPINA3N‐dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

Abstract

Trimethyltin chloride (TMT) is a potent neurotoxin that causes neuroinflammation and neuronal cell death. Melatonin is a well‐known anti‐inflammatory agent with significant neuroprotective activity. Male C57BL/6J mice were intraperitoneally injected with a single dose of melatonin (10 mg/kg) before exposure to TMT (2.8 mg/kg, ip). Thereafter, the mice received melatonin (10 mg/kg, ip) once a day for another three consecutive days. Melatonin dramatically alleviated TMT‐induced neurotoxicity in mice by attenuating hippocampal neuron loss, inhibiting epilepsy‐like seizures, and ameliorating memory deficits. Moreover, melatonin markedly suppressed TMT‐induced neuroinflammatory responses and astrocyte activation, as shown by a decrease in inflammatory cytokine production as well as the downregulation of neurotoxic reactive astrocyte phenotype markers. Mechanistically, serine peptidase inhibitor clade A member 3N (SERPINA3N) was identified as playing a central role in the protective effects of melatonin based on quantitative proteome and bioinformatics analysis. Most importantly, melatonin significantly suppressed TMT‐induced SERPINA3N upregulation at both the mRNA and protein levels. The overexpression of Serpina3n in the mouse hippocampus abolished the protective effects of melatonin on TMT‐induced neuroinflammation and neurotoxicity. Melatonin protected cells against TMT‐induced neurotoxicity by inhibiting SERPINA3N‐mediated neuroinflammation. Melatonin may be a promising and practical agent for reducing TMT‐induced neurotoxicity in clinical practice.

Melatonin Act as an Antidepressant via Attenuation of Neuroinflammation by Targeting Sirt1/Nrf2/HO-1 Signaling

“…Recently it has been demonstrated that melatonin acts through the Nrf2 pathway and prevents the decline of antioxidant enzyme activities during brain pathological conditions (Moezi et al, 2011;Mendez-David et al, 2015;Herrera-Arozamena et al, 2020;Zhi W. et al, 2020), supporting our results that endogenous melatonin counterbalances the oxidative stress by boosting the body antioxidants system via its receptors. Our results are also in agreement with growing evidence that melatonin enhances HO-1 expression via NF-κB, p38 MAPK, and Nrf2 cascade signaling mechanism (Santofimia-Castaño et al, 2015;Yu et al, 2017;Shah et al, 2017;Ma et al, 2018;Zhao et al, 2018;Rehman et al, 2019;Xi et al, 2019;García et al, 2020;Hein et al, 2020;Zhou et al, 2020;Zhi W. et al, 2020).…”

Comprehensive Profiling of Gene Expression in the Cerebral Cortex and Striatum of BTBRTF/ArtRbrc Mice Compared to C57BL/6J Mice

“…BTBR/R mice brains showed increased Serpina3n mRNA expression: intensely in the cerebral cortex, hippocampus, and amygdala; weakly in the striatum. Together with the transcriptomic data showing the enrichment of the immune signaling pathways in BTBR/R mice DEGs, we suggest that these brain regions in BTBR/R mice may have increased neuroinflammatory responses, as reported in other neurological disorders (Switonski et al, 2015;Vanni et al, 2017;Xi et al, 2019). Upregulated DEG Lpl encodes lipoprotein lipase that is the key enzyme in triglyceride metabolism.…”

“…Scg5 (secretogranin V, 7B2) encodes a secreted chaperone protein that prevents the aggregation of other secreted proteins inside of secretory vesicles, and its KO mice show a number of endocrine abnormalities (Bartolomucci et al, 2011). Serpina3n (Serine protease inhibitor A3N) encodes a secretory serine protease inhibitor that mediates neuroinflammation (Xi et al, 2019) and is upregulated in various neurological diseases (Switonski et al, 2015;Vanni et al, 2017). Nudt19 (Nucleoside diphosphate linked moiety X [Nudix]-type motif 19) encodes a peroxysomal nudix hydrolase (Carreras-Puigvert et al, 2017) that exerts a CoA diphosphohydrolase activity in the kidney (Shumar et al, 2018) and its KO mice caused a significant decrease in total CoA levels in the kidney (Shumar et al, 2018).…”

Hydrogen rich water ameliorate Trimethyltin induced spatial learning and memory impairment by regulation of Siah-1

“…Besides, TMT has good lipophilicity and high affinity with hemoglobin in blood, and can be accumulated in human bodies [2]. After TMT treatment, mice can show agitation, aggressive behavior, learning and memory dysfunction [4][5][6][7]. According to reports, TMT can selectively damage the limbic system, especially in the prefrontal cortex, hippocampus and other brain regions and lead to the dysfunction and apoptosis in these regions, which are closely related to learning and memory function, suggesting that TMT-induced learning and memory dysfunction have a special correlation with such selective effect [8][9].…”

“…The mechanisms of nervous system damage induced by TMT include apoptosis, inflammatory response, oxidative damage, glutamate excitability, etc. [6,[10][11]. However, the exact mechanisms of TMT-induced widely nervous system damage are not fully clear.…”