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bioRxiv · 10.1101/2024.10.11.617361

Peripherally administered TNF inhibitor is not protective against α-synuclein-induced dopaminergic neuronal death in rats

Christiansen, J. R.·Ferreira, S. A.·Szymkowski, D. E.·Jakobsson, J.·Tansey, M. G.·Romero-Ramos, M.
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Abstract

The underlying cause of neuronal loss in Parkinsons disease (PD) remains unknown, but evidence implicates neuroinflammation in PD pathobiology. The pro-inflammatory cytokine soluble tumor necrosis factor (TNF) seems to play an important role and thus has been proposed as a therapeutic target for modulation of the neuroinflammatory processes in PD. In this regard, dominant-negative TNF (DN-TNF) agents are promising antagonists that selectively inhibit soluble TNF signaling, while preserving the beneficial effects of transmembrane TNF. Previous studies have tested the protective potential of DN-TNF-based therapy in toxin-based PD models. Here we test for the first time the protective potential of a DN-TNF therapeutic against -synuclein-driven neurodegeneration in the viral vector-based PD rat model. To do so, we administered the DN-TNF agent XPro1595 subcutaneously for a period of 12 weeks. In contrast to previous studies using different PD models, neuroprotection was not achieved by systemic XPro1595 treatment. -synuclein-induced loss of nigrostriatal neurons, accumulation of pathological inclusions and microgliosis was detected in both XPro1595- and saline-treated animals. XPro1595 treatment increased the percentage of the hypertrophic/ameboid Iba1+ cells in SN and reduced the striatal MHCII+ microglia in the striatum of -synuclein-overexpressing animals. However, the treatment did not prevent the MHCII upregulation seen in the SN of the model, nor the increase of CD68+ phagocytic cells. Therefore, despite an apparently positive immune effect, this did not suffice to protect against viral vector-derived -synuclein-induced neurotoxicity. Further studies are warranted to better elucidate the therapeutic potential of soluble TNF inhibitors in PD.

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Christiansen, J. R., Ferreira, S. A., Szymkowski, D. E., Jakobsson, J., Tansey, M. G., Romero-Ramos, M.. 2024-10-12. Peripherally administered TNF inhibitor is not protective against α-synuclein-induced dopaminergic neuronal death in rats. https://doi.org/10.1101/2024.10.11.617361

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