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Intranigral lentiviral delivery of dominant-negative TNF attenuates neurodegeneration and behavioral deficits in hemiparkinsonian rats.

ABSTRACT: Neuroinflammatory processes have been implicated in the progressive loss of ventral midbrain dopaminergic (DA) neurons that give rise to Parkinson's disease (PD), a late-onset movement disorder that affects 2% of the population over the age of 70 years. We have shown earlier, in two rat models of PD, that inhibition of the proinflammatory cytokine tumor necrosis factor (TNF) through nigral infusion of dominant-negative (DN-TNF) protein (XENP345) attenuates DA neuron loss. The objectives of this study were to develop a constitutive lentiviral vector encoding dominate-negative TNF, and to determine whether a gene therapy approach to deliver DN-TNF directly into the rodent substantia nigra could prevent or attenuate neurotoxin-induced DA neuron loss and associated behavioral deficits. Here we demonstrate that a single injection of lentivirus-expressing DN-TNF into rat substantia nigra, administered concomitant with a striatal 6-hydroxydopamine lesion, results in sufficiently high expression of inhibitor in vivo to attenuate both DA neuron loss and behavioral deficits resulting from striatal dopamine depletion. Our findings demonstrate the feasibility and efficacy of dominant-negative TNF gene transfer as a novel neuroprotective strategy to prevent or delay nigrostriatal pathway degeneration. This strategy holds the potential for therapeutic application in the treatment of PD.

SUBMITTER: McCoy MK

PROVIDER: S-EPMC2670754 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Intranigral lentiviral delivery of dominant-negative TNF attenuates neurodegeneration and behavioral deficits in hemiparkinsonian rats.

McCoy Melissa K MK Ruhn Kelly A KA Martinez Terina N TN McAlpine Fiona E FE Blesch Armin A Tansey Malú G MG

Molecular therapy : the journal of the American Society of Gene Therapy 20080715 9

Neuroinflammatory processes have been implicated in the progressive loss of ventral midbrain dopaminergic (DA) neurons that give rise to Parkinson's disease (PD), a late-onset movement disorder that affects 2% of the population over the age of 70 years. We have shown earlier, in two rat models of PD, that inhibition of the proinflammatory cytokine tumor necrosis factor (TNF) through nigral infusion of dominant-negative (DN-TNF) protein (XENP345) attenuates DA neuron loss. The objectives of this ...[more]

PMID: 18628756

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Project description:UnlabelledParkinson's disease is characterized by a loss of dopaminergic neurons in a specific brain region, the ventral midbrain. Parkinson's disease is diagnosed when approximately 50% of the dopaminergic neurons of the substantia nigra pars compacta (SNpc) have degenerated and the others are already affected by the disease. Thus, it is conceivable that all therapeutic strategies, aimed at neuroprotection, start too late. Therefore, an urgent medical need exists to discover new pharmacological targets and novel drugs with disease-modifying properties. In this regard, modulation of endogenous adult neurogenesis toward a dopaminergic phenotype might provide a new strategy to target Parkinson's disease by partially ameliorating the dopaminergic cell loss that occurs in this disorder. We have previously shown that a phosphodiesterase 7 (PDE7) inhibitor, S14, exerts potent neuroprotective and anti-inflammatory effects in different rodent models of Parkinson's disease, indicating that this compound could represent a novel therapeutic agent to stop the dopaminergic cell loss that occurs during the progression of the disease. In this report we show that, in addition to its neuroprotective effect, the PDE7 inhibitor S14 is also able to induce endogenous neuroregenerative processes toward a dopaminergic phenotype. We describe a population of actively dividing cells that give rise to new neurons in the SNpc of hemiparkinsonian rats after treatment with S14. In conclusion, our data identify S14 as a novel regulator of dopaminergic neuron generation.SignificanceParkinson's disease is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the ventral midbrain. Currently, no cure and no effective disease-modifying therapy are available for Parkinson's disease; therefore, an urgent medical need exists to discover new pharmacological targets and novel drugs for the treatment of this disorder. The present study reports that an inhibitor of the enzyme phosphodiesterase 7 (S14) induces proliferation in vitro and in vivo of neural stem cells, promoting its differentiation toward a dopaminergic phenotype and therefore enhancing dopaminergic neuron generation. Because this drug is also able to confer neuroprotection of these cells in animal models of Parkinson's disease, S14 holds great promise as a therapeutic new strategy for this disorder.

Dataset Information

Intranigral lentiviral delivery of dominant-negative TNF attenuates neurodegeneration and behavioral deficits in hemiparkinsonian rats.

Publications

Intranigral lentiviral delivery of dominant-negative TNF attenuates neurodegeneration and behavioral deficits in hemiparkinsonian rats.

Similar Datasets

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