Cyclooxygenase-2, prostaglandin E2, and microglial activation in prion diseases.
Cyclooxygenase (COX) catalyzes the first committed step in the synthesis of prostaglandins (PGs) and is the main target of nonsteroidal anti-inflammatory drugs (NSAIDs). The enzyme exists as constitutive (COX-1) and inducible (COX-2) isoforms, being the latter a major player in inflammation. In the brain, COX-2 expression has been associated with inflammatory and neurodegenerative processes of several human neurological diseases. Prion diseases, or transmissible spongiform encephalopathies, are a heterogeneous group of fatal neurodegenerative disorders, characterized by deposition of the protease-resistant prion protein, astrocytosis, and spongiform degeneration. In addition, an extensive microglial activation supports the occurrence of local chronic inflammatory response. In experimental prion diseases, COX-2 immunoreactivity was found specifically localized to microglial cells and increased with the progression of disease, along with the number of activated microglia. The induction of COX-2 was paralleled by a substantial raise in the brain homogenate PGE(2) levels. In these models, only few scattered COX-1-positive microglia-like cells were detected, suggesting that COX-2 is the major form in prion diseases. In line with the animal models, elevated levels of PGE(2) were found in the cerebrospinal fluid of subjects affected by sporadic, genetic, or variant CJD. In sporadic CJD patients, the most numerous group of patients examined, higher CSF levels of PGE(2) were associated with shorter survival. Although the mechanisms leading to microglial COX-2 expression as well as its potential implication in prion disease pathogenesis remain to be established, PGE(2) levels in the cerebrospinal fluid might represent an important index to predict survival and disease severity.
Department of Cell Biology and Neurosciences, Degenerative and Inflammatory Neurological Diseases Unit, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
Luisa
L
Minghetti
Maurizio
M
Pocchiari
D000818:Animals; D001921:Brain / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000502:physiology*; D015232:Dinoprostone / Q000502:physiology*; D006801:Humans; D017628:Microglia / Q000473:pathology / Q000502:physiology*; D017096:Prion Diseases / Q000473:pathology / Q000503:physiopathology*
D051546:Cyclooxygenase 2; D015232:Dinoprostone