Tumor Necrosis Factor Dependent Mechanisms and Neuroprotective Strategies in Models of Parkinson's Disease




McCoy, Melissa Kay

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Parkinson's disease is a chronic, progressive, neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra that innervate the striatum. Although the nigral cell loss that causes motor dysfunction in Parkinson's disease has been identified for some time, the mechanisms that lead to this dopaminergic neuron loss are unclear. Elevated levels of the cytokine tumor necrosis factor in cerebrospinal fluid and postmortem brains of Parkinson's patients and in animal models of the disease implicate tumor necrosis factor in contributing to disease pathology; but a specific role for this cytokine in mediating loss of dopaminergic neurons in Parkinson's disease has not been clearly established. Here I demonstrate that neutralization of soluble tumor necrosis factor in vivo with a recombinant dominant-negative tumor necrosis factor inhibitor reduced 6-hydroxydopamine-induced nigral degeneration by 50% and attenuated amphetamine-induced rotational behavior, indicative of striatal dopamine preservation in a rodent model of Parkinson's disease. Similar protective effects were observed with in vivo chronic co-infusion of dominant-negative tumor necrosis factor inhibitor with a proinflammatory initiator, low-dose lipopolysaccharide, into the substantia nigra of rodents, confirming a role for soluble tumor necrosis factor inhibitor-dependent neuroinflammation in contributing to nigral degeneration. In rat embryonic midbrain neuron/glia mixed cell cultures exposed to lipopolysaccharide, delayed administration of dominant-negative tumor necrosis factor inhibitor prevented degeneration of dopaminergic neurons despite sustained microglia activation. Addition of a dominant-negative tumor necrosis factor inhibitor also attenuated 6-hydroxydopamine-induced dopaminergic neuron toxicity in vitro. In this dissertation the ability of lentiviral-encoded dominant-negative tumor necrosis factor inhibitor to provide neuroprotection was also investigated. Intranigral delivery of lentiviral dominant-negative tumor necrosis factor inhibitor in a hemiparkinsonian rat 6-hydroxydopamine model attenuated nigral dopaminergic neuron loss and reduced behavior deficits when compared to control lentiviral-infected animals. Collectively, these data identify tumor necrosis factor signaling in contributing to dopaminergic neuron loss in vitro and in vivo in two chronic rat models of Parkinson's disease, and provide evidence that delaying the progressive degeneration of the nigrostriatal pathway in the early stages of Parkinson's disease in humans may be therapeutically feasible with agents that block soluble tumor necrosis factor signaling.

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