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Role for the Peripheral Benzodiazepine Receptor in Neuroinflammation of Neurodegenerative disorders

Venneti, Sriram (2006) Role for the Peripheral Benzodiazepine Receptor in Neuroinflammation of Neurodegenerative disorders. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Neuroinflammation is a major component of several neurodegenerative disorders such as Alzheimer's disease, HIV-associated dementia, Multiple sclerosis and Parkinson's disease. Although the primary pathology underlying each of these diseases is vastly different, neuroinflammation, consisting of chronic activation of brain macrophages, is a significant factor that contributes to neuronal damage in all these conditions. Were it possible to image chronic activation of brain macrophages, it would be possible to monitor developing neuroinflammation and assess the efficacy of therapies that are targeted at modulating CNS inflammation. The goal of this thesis is to determine if activated brain macrophages can be imaged in vivo using positron emission tomography. We propose to take advantage of increased expression of the peripheral benzodiazepine receptor in activated brain macrophages and hypothesize that ligands that bind specifically to this receptor will label activated brain macrophages in vivo using positron emission tomography. The peripheral benzodiazepine receptor is normally expressed at low levels in the central nervous system in astrocytes and brain macrophages and is hypothesized to increase specifically on brain macrophages in neuroinflammation. We show that PK11195, a specific ligand to the peripheral benzodiazepine receptor, shows increased binding to brain macrophages in HIV encephalitis and that PK11195 can be used to image brain macrophages in vivo using positron emission tomography in a macaque model of HIV encephalitis. PK11195 binding is also increased in activated brain macrophages in Alzheimer's disease and shows age dependent increases in transgenic mice models of Alzheimer's disease. Finally we compare binding characteristics of DAA1106, a novel peripheral benzodiazepine receptor ligand, with PK11195 to show that DAA1106 binds with greater affinity in rat models of neuroinflammation both in brain tissues as well as in vivo. These data suggest that ligands of the peripheral benzodiazepine receptor specifically label activated brain macrophages and may be used to image neuroinflammation in vivo using positron emission tomography.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Venneti, Sriramvenneti@pitt.eduVENNETI
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairDeFranco, Donalddod1@pitt.eduDOD1
Committee CoChairWiley, Clayton
Committee MemberZigmond, Michael Jzigmondm@upmc.eduZIGMOND
Committee MemberChu, Charleen Tctc4@pitt.eduCTC4
Committee MemberMasliah,
Committee MemberCard, Patrick Jcard@bns.pitt.eduCARD
Date: 28 June 2006
Date Type: Completion
Defense Date: 14 April 2006
Approval Date: 28 June 2006
Submission Date: 28 April 2006
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Alzheimer's disease; HIV; Macropahges; peripheral Benzodiazepine Receptor; PET
Other ID:, etd-04282006-185724
Date Deposited: 10 Nov 2011 19:42
Last Modified: 19 Dec 2016 14:35


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