The Role of Brain Cyclooxygenase-2 (Cox-2) Beyond Neuroinflammation: Neuronal Homeostasis in Memory and Anxiety
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The Role of Brain Cyclooxygenase-2 (Cox-2) Beyond Neuroinflammation: Neuronal Homeostasis in Memory and Anxiety Diana E. López 1 & Santiago J. Ballaz 2 Received: 25 March 2020 / Accepted: 24 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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-arachidonoylglycerol 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
Introduction Cyclooxygenases (Cox) are a group of heme-containing enzymes that catalyze a rate-limiting conversion of arachidonic acid (AA) to largely bioactive prostaglandins (PGs) through the addition of molecular oxygen [1, 2]. There are two main isoforms of Cox enzymes (i.e., Cox-1 and Cox-2), that differ in their structure. The Cox-1 isoform is a housekeeping enzyme constitutively expressed in all tissues. Although the mitogen-inducible Cox-2 is activated to cause inflammation,
* Santiago J. Ballaz [email protected] 1
Biomedical Sciences Graduate Program, Yachay Tech University, Urcuquí, Ecuador
2
School of Biological Sciences and Engineering, Yachay Tech University, Hacienda San José s/n, San Miguel de Urcuquí, Ecuador
this isoform is also constitutively expressed in certain tissues as in the kidney [3] and in the brain [4]. In the CNS of mammals, the regional Cox activity at
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