Graduation Year

2011

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Molecular Pharmacology and Physiology

Major Professor

Paula C.Bickford, Ph.D.

Co-Major Professor

Dave Morgan, Ph.D.

Committee Member

Carmelina Gemma, Ph.D.

Committee Member

Samuel Saporta, Ph.D.

Committee Member

Robert Hauser, MD

Keywords

Microglia, AAV9, nutraceuticals, CX3CR1, Tyrosine Hydroxylase

Abstract

In my dissertation research we used use human wild type α-synuclein gene expression using an adeno-associated viral vector (AAV9) that induced a slowly progressive loss of dopamine (DA) neurons in the Substantia nigra (SN) as one of our animal model of Parkinson’s disease (PD). It is our hypothesis that neuroinflammation predisposes the brain to susceptibility to neurodegenerative diseases. Thus we examined the progression of a PD lesion and examined the manipulations of the immune system to understand further the inflammatory role when we administered exogenous soluble fractalkine.

The specific etiology of neurodegeneration in PD is unknown, but the inflammatory mechanisms and free radicals have been postulated to play a central role. α-synuclein is believed to be the one of the main characteristic associated with PD. It has been found inside saclike structures, called lewy bodies. α-synuclein is believed to activate resident microglia worsening the degeneration of the nigrostriatal pathway due to its aggregation. Aggregation increases the production of reactive oxygen species (ROS) released from microglia. The constant release of these factors and prolonged activation of microglia could be the cause that leads to neurodegeneration in the SN.

Spirulina, a blue - green algae, has been shown to have anti-oxidant and anti-inflammatory properties. For example, when rats received an intrastriatal injection of 6-OHDA and were fed a spirulina enriched diet for 4 weeks, there was a significant increase in regeneration of DA terminals into the Tyrosine Hydroxylase (TH) -negative zone of the striatum. This regeneration was accompanied by a decrease in microglia activation as determined by immunohistochemistry of major histo compatibility class II (MHC) (OX-6). This suggests that decreases in microglia activation modulate the beneficial effects of spirulina. Another important therapeutic tool we used was fractalkine as an anti-inflammatory treatment. It is known that fractalkine levels are reduced in the brain during aging. For this reason we administered exogenous fractalkine to 6-OHDA model of PD to test the hypothesis that it improved the microenvironment by reducing microglial activation.

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