Date of Degree


Document Type


Degree Name





Maria E. Figueiredo-Pereira

Committee Members

John Babich

Patricia Rockwell

Peter Serrano

Christopher Cardozo

Subject Categories

Biology | Neuroscience and Neurobiology


rat model, Parkinson's disease, PGJ2, DP2, L-PGDS, PET


Parkinson’s disease (PD) is a neurodegenerative disease with aging as a major risk factor. Its defining symptoms are motor deficits that are primarily associated with dopaminergic neuronal loss in the substantia nigra pars compacta (SNpc) in the midbrain. Post-mortem PD brains exhibit abnormal intraneuronal inclusions of α-synuclein and ubiquitinated protein aggregates known as Lewy bodies, a hallmark of PD pathology.

Currently, there is no validated biomarker for PD. Especially the early stage of PD is difficult to detect as the pathology develops progressively. While symptom-managing treatments are available, there is no neuroprotective treatment as of yet, mainly due to the unknown cause of PD. Animal models of PD have greatly expanded our knowledge on different aspects of PD. However, each has challenges on closely mimicking PD’s major pathological conditions, especially the progressive nature of the pathology. Among the existing PD animal models, a shared feature is neuroinflammation, which has been increasingly implicated in the development of PD by findings from genome-wide association studies, PD-risk genes, environmental risk factors and post-mortem studies. Transition of acute neuroinflammation to the chronic state is critical in the development and worsening of neurodegeneration associated with inflammation.

The cyclooxygenase (COX) pathway is a major contributing factor to the development of PD. Firstly, COX-2 is upregulated in the substantia nigra of PD patients. Secondly, existing genetic and toxin models of PD indicate the involvement of the COX pathway. Thirdly, epidemiological studies report the effect of non-steroid-anti-inflammatory drugs (NSAIDs) in lowering PD risk. However, NSAIDs are not an ideal treatment against PD due to their serious side effects. Prostaglandins are products of the COX pathway but their profile and role in the progression of PD pathology are not fully understood. As endogenous products of neuroinflammation, prostaglandins may be highly relevant to the etiology of PD.

The overall goal of my studies was to gain insights into how prostaglandins contribute to PD neurodegeneration in vivo.

Goal 1: Establish a rat model of neuroinflammation displaying parkinsonian-like pathology induced by the highly neurotoxic prostaglandin J2 (PGJ2), and characterize the impact of PGJ2 on key factors of the PGD2/J2 signaling pathway (Chapter 2).

We found that unilateral nigral PGJ2-microinfusions induced progressive PD-like pathology in the rats. PGJ2-treated rats exhibited dose-dependent and progressive dopaminergic neuronal loss in the SNpc, correlated motor deficits, and gliosis involving microglia and astrocytes. Ibuprofen, an NSAID, prevented most of the PD-like pathology shown in PGJ2-treated rats.

We explored the effect of PGJ2-treatment on COX-2, lipocalin-type PGD2 synthase (L-PGDS), PGD2/J2 receptor 2 (DP2), and 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a PG-deactivating enzyme. We found that COX-2, L-PGDS, and 15-PGDH levels increased significantly in PGJ2-treated rats compared to controls in the SNpc DA neurons. DP2 receptors were found predominantly expressed on dopaminergic neurons. The levels of COX-2 and L-PGDS co-localization in microglia were increased upon PGJ2-treatment. However, 15-PGDH levels were did not differ among all rat groups, while high levels of 15-PGDH were detected in SNpc oligodendrocytes.

Goal 2: Assess chronic neuroinflammation in the PGJ2-induced rat model in vivo with micro-PET imaging (Chapter 3).

We performed µPET imaging with the translocator protein (TSPO) radioligand [11C]PK11195 at two different time points (weeks four and eight), post DMSO and PGJ2-injections. Higher [11C]PK11195 uptake was observed in rats that received two PGJ2-injections compared to controls (DMSO-treated) at both time points, indicating chronic glial activation.

Conclusion: our studies establish that the PGJ2-induced rat model recapitulates the progressive nature of PD pathology albeit in a relatively short term. Chronic neuroinflammation exhibited in the PGJ2 rat model of PD was assessed with PET imaging in vivo. Studies with the PGJ2‑induced rat model of PD have potential to identify and optimize treatments against neurotoxic inflammation, and to evaluate novel PET radiotracers for neuroinflammation. Our studies with the PGJ2-induced rat model of PD, strongly support that therapeutic targets downstream of cyclooxygenases, such as DP2 receptors and L-PGDS, have potential against PD pathology.