COX-2 as a multifunctional neuronal modulator - Nature

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Like the rooster's crow at sunrise,. COX-2 serves as part of the body's alarm clock for infection or injury, alerting it to systemic changes and helping it prepare to ...
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© 2001 Nature Publishing Group http://medicine.nature.com

COX-2 as a multifunctional neuronal modulator

© 2001 Nature Publishing Group http://medicine.nature.com

COX-2 is involved in prostaglandin synthesis and expressed throughout the nervous system, where it participates in pain sensitivity and in synaptic plasticity. Microsomal prostaglandin E synthase, expressed throughout the nervous system microvasculature, may be another important player in neural aspects of the inflammatory response.

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ike the rooster’s crow at sunrise, COX-2 serves as part of the body’s alarm clock for infection or injury, alerting it to systemic changes and helping it prepare to respond. Infectious diseases stimulate production of IL-1β and other factors, leading to upregulation of COX-2 and production of prostaglandins. Prostaglandin production participates in enhancing pain sensitivity, anorexia, lethargy and fever in response to injury or infection. The pro-inflammatory COX-2 enzyme is activated by IL-1β, a bloodborne cytokine that targets the IL-1β type I receptor expressed on endothelial cells (Fig. 1). However, it has been a mystery as to what happens at the blood–brain barrier during systemic inflammation, as IL-1β is unable to cross this barrier. In the 22 March issue of Nature, Ek et al. 1 report that IL1β stimulates production of prostaglandin E2 (PGE 2), a lipophilic pro-inflammatory mediator that can diffuse into the brain parenchyma. In the same issue, Samad et al. 2 report that IL-1β plays a major role in inducing COX-2 expression throughout the spinal cord and other regions of the central nervous system (CNS), and that its activation leads to elevated levels of PGE 2 in the CNS. Biosynthesis of PGE2 requires the enzyme prostaglandin E synthase (PGES). Ek et al.1 cloned the microsomal form of PGES (mPGES) from rat and investigated its expression in the CNS after injection of IL-1β. The authors were able to detect expression of PGES in the cerebral blood vessels up to five hours after IL-1β administration, which matches the time course for PGE 2 induction. The induction of PGES was preceded by induction of COX-2 expression. Using an elegant dual in situ hybridization technique, they demonstrated that COX-2 and mPGES mRNAs colocalized within the same vascular endothelial cells and also in perivascular macrophages. Ek et al. showed that most of the endothelial cells expressing mPGES mRNA and COX-2 mRNA also

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NICOLAS G. BAZAN expressed the type I IL-1β receptor. They propose that during the inflammatory response, circulating IL-1β induces synthesis of PGE2, which acts on prostaglandin E receptors in the nervous system parenchyma to induce cellular responses. These findings suggest that mPGES may be explored as an anti-inflammatory drug target (Fig. 1), due to its strategic location on the neural microvasculature and its early activation. Towards this end, researchers will have to determine whether these types of drugs interfere with mPGES functions in other cells. One concern about these studies is the relatively high dose of IL1β injected by Ek et al.1. Samad et al.2 report that IL-1β levels do not rise significantly up to six hours after peripheral inflammation. In any case, other cytokines may also be involved. Other cells of the neural tissue, such as microglia, may produce IL-1β in response to peripheral inflammation. Also, microglia upregulate COX-2 expression in response to a number of proinflammatory conditions. Little is known about the identity of the circulating factors that communicate between the bloodstream and the nervous system cells that lie beyond the blood–brain barrier. Samad et al.2 investigated the extent of IL-1β–dependent COX-2 induction in pain induction in response to inflammatory signals. Previous studies have shown that local peripheral injury promotes induction of COX-2 expression by the ipsilateral neurons of the lumbar spinal cord where sciatic nerve signals converge3,4. Samad et al.2 demonstrate that 12–24 hours after COX-2 induction, it is expressed in the rest of the spinal cord and in various brain regions. COX-2 converts free arachidonic acid (AA) to the intermediate prostaglandin H2 (PGH2) (Fig. 1). AA is released from membrane lipids primarily by phospholipases A2 and its ex-

pression was not found to be upregulated in the nervous system in response to peripheral inflammation, indicating that constitutive activity of these enzymes is sufficient to supply AA to COX-2 (ref. 2). In spite of this new knowledge, many questions still remain about the significance of neuronal COX-2. One of these questions is whether there are differences between physiological and pathological COX-2. In contrast to the pathological induction of COX-2 that occurs in many organs, the brain expresses COX-2 under normal physiological conditions. COX-2 levels increase during developmental synaptic remodeling5 and upregulation of synaptic activity6. Moreover, COX-2 is involved in the coupling of synaptic plasticity with cerebral blood flow7. Neuronal tissue may produce IL-β in response to perhipheral inflammation (Fig. 1). However, it is unclear which circulating factor communicates between the blood stream and the nervous system. The physiological or pathological outcomes of COX-2 activity appear to depend upon its level of expression. Low levels of COX-2 are produced during normal cell function5–7, whereas COX-2 overexpression is associated with pathological conditions8,9. A single seizure causes a 10-fold increase in COX-2 expression, whereas status epilepticus-like conditions (repeated seizures), caused by the injection of the neurotoxin kainic acid into experimental animals, results in a 70-fold induction in the hippocampus 8. Repeated seizures cause extensive cellular damage. In addition, upregulation of COX2, through prostaglandins, sensitizes peripheral nociceptive nerve terminals to inflamation and contributes to pain. But how can COX-2 overexpression exert pathological consequences? One possibility is that COX-2 interacts with different substrates to generate different products 10, which in turn activate different receptors 11. The effects of COX-2 may also depend on its local-

NATURE MEDICINE • VOLUME 7 • NUMBER 4 • APRIL 2001

© 2001 Nature Publishing Group http://medicine.nature.com

NEWS & VIEWS

© 2001 Nature Publishing Group http://medicine.nature.com

challenge, however, to pharmacologically modulate COX-2 function in pathological situations without disrupting its normal function. Microsomal PGES should also be assessed as a specific drug target that may have only limited side effects, due to its specific localization to the bloodbrain barrier.

Fig. 1 Regulatory checkpoints of peripheral pain hypersensitivity and of systemic inflammation. In the nervous system, endothelial cells are surrounded by a basal membrane, astrocytic feet and pericytes, and this composes the blood–brain barrier. Local peripheral inflammation causes the release of IL-1β into the bloodstream, where it interacts with the IL-1 receptors expressed on the surface of endothelial cells. This leads to the induction of COX-2 and microsomal prostaglandin E (PGE) synthase (mPGES) genes. COX-2 converts arachidonic acid (AA) to the short-lived PGH2 intermediate that is converted to PGE2 by PGES. PGE2 is then released into the parenchyma, where it interacts with EP receptors. Local peripheral inflammation also activates signals that induce neuronal IL-1β expression and COX-2 upregulation in both spinal cord and brain. COX-2 expression is also modulated by other receptors such as glutamate receptors. PGE2 can interact with either synaptic PGE2 receptors or be carried through the cerebrospinal fluid (CSF) to interact with distal EP receptors. Anti-inflammatory drugs can be designed to interfere with any step in this pathway, including 1) inhibitors of mPGE 2 synthase, 2) inhibitors of central IL-1β synthesis, 3) IL-1 receptor antagonists, 4) inhibitors of IL-1 receptor-triggered signaling, 5) inhibitors of COX-2 transcription, 6) selective COX-2 inhibitors, and 7) PGE2 receptor antagonists. Arrows to double helixes depict signaling to regulatory regions of genes.

ization within the neuron. Synaptic plasticity studies suggest that COX-2 functions in dendritic arborization and spines, as well as in perinuclear locations 6. COX-2, therefore, may act at different sub-cellular locations on different types of receptors. Prostaglandin receptors, for example, are expressed in the nuclear membrane. The effects of these receptors on expression of other genes under normal or pathological conditions remain to be determined. It is also unclear whether normal and pro-inflammatory conditions selectively modify DNA-binding proteins, affecting their ability to interact with COX-2 gene regulatory elements and regulate its expression. Future studies should include a determination of how other messengers of the inflammatory response affect gene expression 12. In cases of peripheral pain hypersensitivity13 and inflammatory acute-

phase reactions14, IL-1β receptor signaling cascades induce COX-2 and mPGES gene expression, whereas production of glutamate, for example, activates COX2 through a different signaling cascade (Fig. 1). The AA-COX-2 inflammatory pathways may play important roles in pathogenesis of other acute conditions, such as stroke and head injury, or of neurodegenerative diseases such as Alzheimer disease and glaucoma. The involvement of the COX substrate AA in other pathways, such as lipoxygenation, and its effects on other cells, such as microglia, should also be investigated (Fig. 1). Interfering with the rooster’s crow may disrupt the harmony of the normal daily schedule. Likewise, altered COX-2 expression levels may disrupt cellular homeostasis. Elucidation of COX-2 regulatory pathways will lead to the development of new anti-inflammatory agents. It will be a major

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1. Ek, M. et al. Pathway across the blood-brain barrier. Nature 410, 430–431 (2001). 2. Samad, T.A. et al. An interleukin-1β-mediated induction of COX-2 in the central nervous system contributes to inflammatory pain hypersensitivity. Nature 410, 471–475 (2001). 3. Beiche, F., Scheuerer, S., Brune, K., Geisslinger, G. & Goppelt-Struebe, M. Up-regulation of cyclooxygenase-2 mRNA in the rat spinal cord following peripheral inflammation. FEBS Lett. 390, 165–169 (1996). 4. Hay, C.H., Trevethick, M.A., Wheeldon, A., Bowers, J.S. & de Belleroche, J.S. The potential role of spinal cord cyclooxygenase-2 in the development of Freund’s complete adjuvant-induced changes in hyperalgesia and allodynia. Neurosci. 78, 843–850 (1997). 5. Yamagata, K., Andreasson, K.I., Kaufmann, W.E., Barnes, C.A. & Worley P.F. Expression of a mitogen-inducible cyclooxygenase in brain neurons: regulation by synaptic activity and glucocorticoids. Neuron 11, 371–386 (1993). 6. Kaufmann, W.E., Worley, P.F., Pegg, J., Bremer, M. & Isakson, P. COX-2, a synaptically induced enzyme, is expressed by excitatory neurons at postsynaptic sites in rat cerebral cortex. Proc. Natl. Acad. Sci. USA 93, 2317–2321 (1996). 7. Niwa, K, Araki, E., Morham, S.G., Ross, M.E. & Iadecola, C. Cyclooxygenase-2 contributes to functional hyperemia in whisker-barrel cortex. J. Neurosci. 20, 763–770 (2000). 8. Marcheselli, V.L. & Bazan, N.G. Sustained induction of prostaglandin endoperoxide synthase-2 by seizures in hippocampus. J. Biol. Chem. 271, 24794–24799 (1996). 9. Breder, C.D. & Saper, C.B. Expression of inducible cyclooxygenase mRNA in the mouse brain after systemic administration of bacterial lipopolysaccharide. Brain Res. 713, 64–69 (1996). 10. Kozak, K.R., Rowlinson, S.W. & Marnett, L.J. Oxygenation of the endocannabinoid, 2-arachidonylglycerol, to glyceryl prostaglandins by cyclooxygenase-2. J. Biol. Chem. 275, 33744–33749 (2000). 11. Ek, M, Arias, C., Sawchenko, P. & EricssonDahlstrand, A. Distribution of the EP3 prostaglandin E 2 receptor subtype in the rat brain: relationship to sites of interleukin-1-induced cellular responsiveness. J. Comp. Neurol. 428, 5–20 (2000). 12. Bazan, N.G. Inflammation: a signal terminator. Nature 374, 501–502 (1995). 13. Woolf, C.J. & Salter, M.W. Neuronal plasticity: increasing the gain in pain. Science 288, 1765–1768 (2000). 14. Rothwell, N., Allan, S. & Toulmond, S. The role of interleukin 1 in acute neurodegeneration and stroke: pathophysiological and therapeutic implications. J. Clin. Invest. 100, 2648–2652 (1997).

Neuroscience Center and Department of Ophthalmology School of Medicine Louisiana State University Health Sciences Center New Orleans, Louisiana, USA Email: [email protected] 415