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The Journal of Neuroscience, September 13, 2006, 26(37):9365-9375; doi:10.1523/JNEUROSCI.1504-06.2006

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Neurobiology of Disease
Blocking Soluble Tumor Necrosis Factor Signaling with Dominant-Negative Tumor Necrosis Factor Inhibitor Attenuates Loss of Dopaminergic Neurons in Models of Parkinson's Disease

Melissa K. McCoy,¹ Terina N. Martinez,¹ Kelly A. Ruhn,¹ David E. Szymkowski,⁴ Christine G. Smith,² Barry R. Botterman,³ Keith E. Tansey,² and Malú G. Tansey¹

Departments of ¹Physiology, ²Neurology, and ³Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, and ⁴Xencor, Inc., Monrovia, California 91016

Correspondence should be addressed to Malú G. Tansey, Department of Physiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9040. Email: malu.tansey{at}utsouthwestern.edu

The mechanisms that trigger or contribute to loss of dopaminergic (DA) neurons in Parkinson's disease (PD) remain unclear and controversial. Elevated levels of tumor necrosis factor (TNF) in CSF and postmortem brains of PD patients and animal models of PD implicate this proinflammatory cytokine in the pathophysiology of the disease; but a role for TNF in mediating loss of DA neurons in PD has not been clearly demonstrated. Here, we report that neutralization of soluble TNF (solTNF) in vivo with the engineered dominant-negative TNF compound XENP345 (a PEGylated version of the TNF variant A145R/I97T) reduced by 50% the retrograde nigral degeneration induced by a striatal injection of the oxidative neurotoxin 6-hydroxydopamine (6-OHDA). XENP345 was neuroprotective only when infused into the nigra, not the striatum. XENP345/6-OHDA rats displayed attenuated amphetamine-induced rotational behavior, indicating preservation of striatal dopamine levels. Similar protective effects were observed with chronic in vivo coinfusion of XENP345 with bacterial lipopolysaccharide (LPS) into the substantia nigra, confirming a role for solTNF-dependent neuroinflammation in nigral degeneration. In embryonic rat midbrain neuron/glia cell cultures exposed to LPS, even delayed administration of XENP345 prevented selective degeneration of DA neurons despite sustained microglia activation and secretion of solTNF. XENP345 also attenuated 6-OHDA-induced DA neuron toxicity in vitro. Collectively, our data demonstrate a role for TNF in vitro and in vivo in two models of PD, and raise the possibility that delaying the progressive degeneration of the nigrostriatal pathway in humans is therapeutically feasible with agents capable of blocking solTNF in early stages of PD.

Key words: neuroinflammation; TNF; neuronal apoptosis; degeneration; microglia; Parkinson's disease

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Received Dec. 30, 2005; revised Aug. 3, 2005; accepted Aug. 4, 2006.

Correspondence should be addressed to Malú G. Tansey, Department of Physiology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9040. Email: malu.tansey{at}utsouthwestern.edu

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