The Role of Brain Cyclooxygenase-2 (Cox-2) Beyond Neuroinflammation: Neuronal Homeostasis in Memory and Anxiety

Mol Neurobiol. 2020 Dec;57(12):5167-5176. doi: 10.1007/s12035-020-02087-x. Epub 2020 Aug 29.

Abstract

Cyclooxygenases are a group of heme-containing isozymes (namely Cox-1 and Cox-2) that catalyze the conversion of arachidonic acid to largely bioactive prostaglandins (PGs). Cox-1 is the ubiquitous housekeeping enzyme, and the mitogen-inducible Cox-2 is activated to cause inflammation. Interestingly, Cox-2 is constitutively expressed in the brain at the postsynaptic dendrites and excitatory terminals of the cortical and spinal cord neurons. Neuronal Cox-2 is activated in response to synaptic excitation to yield PGE2, the predominant Cox-2 metabolite in the brain, which in turn stimulates the release of glutamate and neuronal firing in a retrograde fashion. Cox-2 is also engaged in the metabolism of new endocannabinoids from 2-arachidonoyl-glycerol to modulate their actions at presynaptic terminals. In addition to these interactions, the induction of neuronal Cox-2 is coupled to the trans-synaptic activation of the dopaminergic mesolimbic system and some serotoninergic receptors, which might contribute to the development of emotional behavior. Although much of the focus regarding the induction of Cox-2 in the brain has been centered on neuroinflammation-related neurodegenerative and psychiatric disorders, some evidence also suggests that Cox-2 release during neuronal signaling may be pivotal for the fine tuning of cortical networks to regulate behavior. This review compiles the evidence supporting the homeostatic role of neuronal Cox-2 in synaptic transmission and plasticity, since neuroinflammation is originally triggered by the induction of glial Cox-2 expression. The goal is to provide perspective on the roles of Cox-2 beyond neuroinflammation, such as those played in memory and anxiety, and whose evidence is still scant.

Keywords: Cyclooxygenase-2; Endocannabinoids; Glutamic acid; Neurogenic inflammation; Neuronal plasticity; Prostaglandins E.

Publication types

  • Review

MeSH terms

  • Animals
  • Anxiety / enzymology*
  • Anxiety / physiopathology*
  • Brain / enzymology*
  • Cyclooxygenase 2 / metabolism*
  • Homeostasis*
  • Humans
  • Inflammation / pathology*
  • Memory / physiology*
  • Neurons / pathology*

Substances

  • Cyclooxygenase 2