Targeting cyclooxygenases-1 and -2 in neuroinflammation: Therapeutic implications

Abstract

Neuroinflammation has been implicated in the pathogenesis or the progression of a variety of acute and chronic neurological and neurodegenerative disorders, including Alzheimer's disease. Prostaglandin H synthases or cyclooxygenases (COX -1 and COX-2) play a central role in the inflammatory cascade by converting arachidonic acid into bioactive prostanoids. In this review, we highlighted recent experimental data that challenge the classical view that the inducible isoform COX-2 is the most appropriate target to treat neuroinflammation. First, we discuss data showing that COX-2 activity is linked to anti-inflammatory and neuroprotective actions and is involved in the generation of novel lipid mediators with pro-resolution properties. Then, we review recent data demonstrating that COX-1, classically viewed as the homeostatic isoform, is actively involved in brain injury induced by pro-inflammatory stimuli including Aβ, lipopolysaccharide, IL-1β, and TNF-α. Overall, we suggest revisiting the traditional views on the roles of each COX during neuroinflammation and we propose COX-1 inhibition as a viable therapeutic approach to treat CNS diseases with a marked inflammatory component.

Fig. 1. The metabolic pathway of arachidonic acid (AA)

AA is released from membrane phospholipids by a phospholipase A2 (PLA₂) enzyme and metabolized by COX-1 or COX-2 into PGH2 which is further converted to prostaglandins and thromboxanes by specific terminal synthases. AA can also be metabolized to leukotrienes through lipooxygenases, and to epoxyeicosatrienoic acid (EET) and dihydroxyacids through cytochrome p450 epoxidase. The cyclopentenones PGJ₂ and 15d-PGJ₂ are non-enzymatic degradation products of PGD_2.

Fig. 2. COX-1 and COX-2 distinct roles during the progression of neuroinflammation

Inflammatory stimuli target primarily microglia, the immune resident cells of the brain. They activate pro-inflammatory signaling pathways (NFκB, STAT/JAK) as well as the AA cascade, leading to the release of cytokines, chemokines, reactive oxygen species (ROS), prostaglandins (PG) and thromboxanes (TX). Being predominantly expressed by microglia, COX-1 contributes within seconds to minutes to the local eicosanoid pool at the site of inflammation, before the induction of COX-2. Chemokines and eicosanoids attract leukocytes and later monocytes to the site of inflammation. During the normal progression of neuroinflammation, resolution occurs with a shift from pro-inflammatory eicosanoids to anti-inflammatory cyclopentanone PGs (PGD₂ and 15-dPGJ₂) synthesis. Cyclopentanone PGs attenuate the induction of inflammatory genes. With time, a class switching occurs towards pro-resolving lipid mediators generated by aspirin-acetylated COX-2 and lipooxygenases (LOX) such as (AA)-derived lipoxins and DHA-derived resolvins and neuroprotectins. DHA can also be directly metabolized by COX-2 into anti-inflammatory oxo-derivatives (13-EFOX) in activated macrophages.

Fig. 3. COX-2 derived novel protective lipid mediators

By acetylating COX-2, aspirin inhibits the synthesis of prostaglandins and thromboxanes from AA or EPA, and triggers the generation of epimeric forms of lipoxins (from AA), resolvins E (from EPA), resolvins D and neuroprotectins (from DHA), via lipooxygenases. COX-2 can also directly metabolize DHA to anti-inflammatory oxo-derivatives (13-EFOX), with 17-EFOX being the aspirin-triggered form. 15R-HETE: 15R-hydroxy-eicosatetraenoic acid; 18R-HEPE: 18R-hydroxy-eicosapentaenoic acid; 17R-HDHA: 17R-hydroxy-docosahexaenoic acid.