Abstract
Background: Non-selective inhibition of TNF can cause suppression of the immune system and due to this inhibitors are used for long-term treatment of peripheral autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. Inhibition of TNF is known to cause demyelination but otherwise little is known about the effects of long-term treatment in central nervous system (CNS) when CNS itself is not affected by an autoimmune disease or an insult. Since TNF signaling is associated with synaptic function and plasticity and there is evidence that it is involved in learning and memory, it is possible that long-term treatment with TNF inhibitors could alter hippocampal functions in otherwise healthy brain.
Aim of the study: To test the effect of a long-term inhibition of TNF in learning and memory and cell proliferation in hippocampus.
Methods: Adult male mice (C57BL6/J) were divided in three groups; treated with non-selective TNF inhibitor etanercept, selective soluble TNF (solTNF) inhibitor XPro1595 or saline. Drugs were administered 10 mg/kg subcutaneously every third day for two months. Spatial learning and memory were tested on Barnes maze after the treatment period. Proliferation marker BrdU was administered i.p. in the beginning of the treatment period and EdU before the Barnes maze test. The number of BrdU+ and EdU+ cells were counted in hippocampal dentate gyrus.
Results: We found that non-selective inhibition of TNF with etanercept impairs learning and memory while animals treated with solTNF inhibitor XPro1595 express normal behaviour. Also number of BrdU+ cells was decreased after treatment with etanercept suggesting non-selective inhibition of TNF to alter neurogenesis in hippocampus. No differences in the number of EdU+ positive cells were seen between the treatment groups.
Conclusion: Non-selective inhibition of TNF can impair learning and memory and decrease neurogenesis, while inhibiting only solTNF does not cause a decline in cognitive functions.
Aim of the study: To test the effect of a long-term inhibition of TNF in learning and memory and cell proliferation in hippocampus.
Methods: Adult male mice (C57BL6/J) were divided in three groups; treated with non-selective TNF inhibitor etanercept, selective soluble TNF (solTNF) inhibitor XPro1595 or saline. Drugs were administered 10 mg/kg subcutaneously every third day for two months. Spatial learning and memory were tested on Barnes maze after the treatment period. Proliferation marker BrdU was administered i.p. in the beginning of the treatment period and EdU before the Barnes maze test. The number of BrdU+ and EdU+ cells were counted in hippocampal dentate gyrus.
Results: We found that non-selective inhibition of TNF with etanercept impairs learning and memory while animals treated with solTNF inhibitor XPro1595 express normal behaviour. Also number of BrdU+ cells was decreased after treatment with etanercept suggesting non-selective inhibition of TNF to alter neurogenesis in hippocampus. No differences in the number of EdU+ positive cells were seen between the treatment groups.
Conclusion: Non-selective inhibition of TNF can impair learning and memory and decrease neurogenesis, while inhibiting only solTNF does not cause a decline in cognitive functions.
| Original language | English |
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| Publication date | 2018 |
| Publication status | Published - 2018 |
| Event | The Brain Conferences: Computational Neuroscience of Prediction - Rungstedgaard, Rungsted, Denmark Duration: 16. Apr 2018 → 19. Apr 2018 |
Conference
| Conference | The Brain Conferences: Computational Neuroscience of Prediction |
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| Location | Rungstedgaard |
| Country/Territory | Denmark |
| City | Rungsted |
| Period | 16/04/2018 → 19/04/2018 |