title: PACAP27 prevents Parkinson-like neuronal loss and motor deficits but not microglia activation induced by prostaglandin J2.
abstract: 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.
authors: Department of Biological Sciences, Hunter College, Graduate School and University Center, CUNY, New York, NY 10065, USA.
authors: Kai-Yvonne
authors: KY
authors: Shivers
authors: Department of Radiology, Citigroup Biomedical Imaging Center, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA.
authors: Anastasia
authors: A
authors: Nikolopoulou
authors: Department of Biological Sciences, Hunter College, Graduate School and University Center, CUNY, New York, NY 10065, USA.
authors: Saima Ishaq
authors: SI
authors: Machlovi
authors: Department of Radiology, Citigroup Biomedical Imaging Center, Weill Cornell Medical College of Cornell University, New York, NY 10065, USA.
authors: Shankar
authors: S
authors: Vallabhajosula
authors: Department of Biological Sciences, Hunter College, Graduate School and University Center, CUNY, New York, NY 10065, USA. Electronic address: pereira@genectr.hunter.cuny.edu.
authors: Maria E
authors: ME
authors: Figueiredo-Pereira
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004660:Encephalitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019957:Motor Skills Disorders / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism*; D049268:Positron-Emission Tomography; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; C037112:9-deoxy-delta-9-prostaglandin D2; D015230:Prostaglandin D2
keywords: Microglia; PACAP; PET; PK11195; Parkinson; Prostaglandin J2