prostaglandin-d2 and Parkinson-Disease

Prostaglandins (PGs) are produced via cyclooxygenases, which are enzymes that play a major role in neuroinflammation. Epidemiological studies show that chronic treatment with low levels of cyclooxygenase inhibitors (nonsteroidal anti-inflammatory drugs (NSAIDs)) lowers the risk for Alzheimer's disease (AD) and Parkinson's disease (PD) by as much as 50%. Unfortunately, inhibiting cyclooxygenases with NSAIDs blocks the synthesis of downstream neuroprotective and neurotoxic PGs, thus producing adverse side effects. We focus on prostaglandin J2 (PGJ2) because it is highly neurotoxic compared to PGA1, D2, and E2. Unlike other PGs, PGJ2 and its metabolites have a cyclopentenone ring with reactive α,β-unsaturated carbonyl groups that form covalent Michael adducts with key cysteines in proteins and GSH. Cysteine-binding electrophiles such as PGJ2 are considered to play an important role in determining whether neurons will live or die. We discuss in vitro and in vivo studies showing that PGJ2 induces pathological processes relevant to neurodegenerative disorders such as AD and PD. Further, we discuss our work showing that increasing intracellular cAMP with the lipophilic peptide PACAP27 counteracts some of the PGJ2-induced detrimental effects. New therapeutic strategies that neutralize the effects of specific neurotoxic PGs downstream from cyclooxygenases could have a significant impact on the treatment of chronic neurodegenerative disorders with fewer adverse side effects.

Topics: Alzheimer Disease; Animals; Disease Models, Animal; Humans; Inflammation; Lipopolysaccharides; Neurodegenerative Diseases; Neurons; Parkinson Disease; Prostaglandin D2; Prostaglandins; Protein Binding; Protein Processing, Post-Translational; Receptors, Prostaglandin; Signal Transduction

Neuroinflammation is a major risk factor in Parkinson's disease (PD). Alternative approaches are needed to treat inflammation, as anti-inflammatory drugs such as NSAIDs that inhibit cyclooxygenase-2 (COX-2) can produce devastating side effects, including heart attack and stroke. New therapeutic strategies that target factors downstream of COX-2, such as prostaglandin J2 (PGJ2), hold tremendous promise because they will not alter the homeostatic balance offered by COX-2 derived prostanoids. In the current studies, we report that repeated microinfusion of PGJ2 into the substantia nigra of non-transgenic mice, induces three stages of pathology that mimic the slow-onset cellular and behavioral pathology of PD: mild (one injection) when only motor deficits are detectable, intermediate (two injections) when neuronal and motor deficits as well as microglia activation are detectable, and severe (four injections) when dopaminergic neuronal loss is massive accompanied by microglia activation and motor deficits. Microglia activation was evaluated in vivo by positron emission tomography (PET) with [(11)C](R)PK11195 to provide a regional estimation of brain inflammation. PACAP27 reduced dopaminergic neuronal loss and motor deficits induced by PGJ2, without preventing microglia activation. The latter could be problematic in that persistent microglia activation can exert long-term deleterious effects on neurons and behavior. In conclusion, this PGJ2-induced mouse model that mimics in part chronic inflammation, exhibits slow-onset PD-like pathology and is optimal for testing diagnostic tools such as PET, as well as therapies designed to target the integrated signaling across neurons and microglia, to fully benefit patients with PD.

Topics: Animals; Antineoplastic Agents; Behavior, Animal; Disease Models, Animal; Encephalitis; Immunoenzyme Techniques; Male; Mice; Microglia; Motor Skills Disorders; Neurons; Parkinson Disease; Pituitary Adenylate Cyclase-Activating Polypeptide; Positron-Emission Tomography; Prostaglandin D2

Excessive exposure to manganese (Mn) increases levels of oxidative stressors and proinflammatory mediators, such as cyclooxygenase-2 and prostaglandin E(2). Mn also activates nuclear factor-κB (NF-κB), an important mediator of inflammation. The signaling molecule 15-deoxy-Δ12,14-prostaglandin J(2) (15 d-PGJ(2)) is an anti-inflammatory prostaglandin. Here, we tested the hypothesis that 15 d-PGJ(2) modulates Mn-induced activation of astrocytic intracellular signaling, including NF-κB and nuclear factor erythroid 2-related factor (Nrf2), a master regulator of antioxidant transcriptional responses. The results establish that 15 d-PGJ(2) suppresses Mn-induced NF-κB activation by interacting with several signaling pathways. The PI3K/Akt pathway, which is upstream of NF-κB, plays a role in this activation, because (i) pretreatment with 15 d-PGJ(2) (10 μM for 1h) significantly (p<0.01) inhibited Mn (500 μM)-induced PI3K/Akt activation and (ii) inhibition of the PI3K/Akt pathway with LY29004 significantly (p<0.05) decreased NF-κB activation. 15 d-PGJ(2) also significantly (p<0.05) attenuated Mn-induced astrocytic NF-κB activation by inhibiting the Mn-induced phosphorylation of IκB kinase and subsequent IκB-α degradation. Because Mn-induced oxidative stress is also associated with Nrf2 activation, additional studies addressed the ability of 15 d-PGJ(2) to modulate the Nrf2 pathway. 15 d-PGJ(2) significantly (p<0.01) increased Nrf2 expression in whole-cell lysates. Consistent with its pro-oxidant properties, Mn also increased Nrf2 expression. Nevertheless, cotreatment of whole-cell lysates with both Mn and 15 d-PGJ(2) partially suppressed (p<0.01) the 15 d-PGJ(2)-induced increase in astrocytic Nrf2 protein expression. Mn treatment also decreased (p<0.001) expression of DJ-1, a Parkinson disease-associated protein and a stabilizer of Nrf2, and 15 d-PGJ(2) attenuated Mn-induced astrocytic inhibition of DJ-1 expression. Collectively, these results demonstrate that 15d-PGJ(2) exerts a protective effect in astrocytes against Mn-induced inflammation and oxidative stress by modulating the activation of the NF-κB and Nrf2 signaling pathways.

Topics: Animals; Astrocytes; Cells, Cultured; Chromones; Cytoprotection; Gene Expression Regulation; Intracellular Signaling Peptides and Proteins; Manganese; Morpholines; NF-E2-Related Factor 2; NF-kappa B; Oncogene Proteins; Oxidative Stress; Parkinson Disease; Phosphoinositide-3 Kinase Inhibitors; Prostaglandin D2; Protein Deglycase DJ-1; Rats; Rats, Sprague-Dawley; Signal Transduction; Transcriptional Activation

Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) has been implicated in Parkinson's disease (PD) and is present in neurofibrillary tangles or Lewy bodies. However, the molecular basis for UCH-L1s involvement in proteinacious fibril formation is still elusive, especially in regard to the pathogenicity of the I93M mutation. Here we show that modification of UCH-L1 by cyclopentenone prostaglandins causes unfolding and aggregation. A single thiol group on Cys152 reacts with the alpha,beta-unsaturated carbonyl center in the cyclopentenone ring of prostaglandins, resulting in a covalent adduct. We also show that the PD-associated I93M mutant of UCH-L1 is well-folded, structurally similar to the wild-type protein, and aggregates upon conjugation by cyclopentenone prostaglandins. Our findings suggest a possible mechanistic link between UCH-L1 modification by cyclopentenone prostaglandins and the etiology of neurodegeneration.

Topics: Animals; Cyclopentanes; Humans; Magnetic Resonance Spectroscopy; Mass Spectrometry; Mice; Mutation; Parkinson Disease; Prostaglandin D2; Protein Denaturation; Rats; Rats, Sprague-Dawley; Ubiquitin Thiolesterase