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Brain Behav Immun. 2019 Nov;82:279-297. doi: 10.1016/j.bbi.2019.08.195. Epub 2019 Sep 7.

TNF deficiency causes alterations in the spatial organization of neurogenic zones and alters the number of microglia and neurons in the cerebral cortex.

Author information

1
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
2
Department of Pharmacology, University of Oxford, Oxford, UK.
3
Institute for Neuro Immune Medicine, Dr. Kiran C. Patel College of Osteopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, USA.
4
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; BRIDGE - Brain Research - Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
5
Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
6
Orthopedic Research Unit, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
7
Department of Pharmacology, University of Oxford, Oxford, UK; Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK.
8
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; BRIDGE - Brain Research - Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, Denmark; The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA.
9
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; Department of Pharmacology, University of Oxford, Oxford, UK; BRIDGE - Brain Research - Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
10
Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; BRIDGE - Brain Research - Inter-Disciplinary Guided Excellence, Department of Clinical Research, University of Southern Denmark, Odense, Denmark; Department of Neurology, Odense University Hospital, Odense, Denmark. Electronic address: klambertsen@health.sdu.dk.

Abstract

BACKGROUND:

Although tumor necrosis factor (TNF) inhibitors are used to treat chronic inflammatory diseases, there is little information about how long-term inhibition of TNF affects the homeostatic functions that TNF maintains in the intact CNS.

MATERIALS AND METHODS:

To assess whether developmental TNF deficiency causes alterations in the naïve CNS, we estimated the number of proliferating cells, microglia, and neurons in the developing neocortex of E13.5, P7 and adult TNF knock out (TNF-/-) mice and wildtype (WT) littermates. We also measured changes in gene and protein expression and monoamine levels in adult WT and TNF-/- mice. To evaluate long-term effects of TNF inhibitors, we treated healthy adult C57BL/6 mice with either saline, the selective soluble TNF inhibitor XPro1595, or the nonselective TNF inhibitor etanercept. We estimated changes in cell number and protein expression after two months of treatment. We assessed the effects of TNF deficiency on cognition by testing adult WT and TNF-/- mice and mice treated with saline, XPro1595, or etanercept with specific behavioral tasks.

RESULTS:

TNF deficiency decreased the number of proliferating cells and microglia and increased the number of neurons. At the same time, TNF deficiency decreased the expression of WNT signaling-related proteins, specifically Collagen Triple Helix Repeat Containing 1 (CTHRC1) and Frizzled receptor 6 (FZD6). In contrast to XPro1595, long-term inhibition of TNF with etanercept in adult C57BL/6 mice decreased the number of BrdU+ cells in the granule cell layer of the dentate gyrus. Etanercept, but not XPro1595, also impaired spatial learning and memory in the Barnes maze memory test.

CONCLUSION:

TNF deficiency impacts the organization of neurogenic zones and alters the cell composition in brain. Long-term inhibition of TNF with the nonselective TNF inhibitor etanercept, but not the soluble TNF inhibitor XPro1595, decreases neurogenesis in the adult mouse hippocampus and impairs learning and memory after two months of treatment.

KEYWORDS:

Cytokines; Neurogenesis; TNF inhibitors

PMID:
31505254
DOI:
10.1016/j.bbi.2019.08.195
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