Review Neuroinflammation, COX-2, and ALS—a dual role? Christopher Consilvio, Andrea M. Vincent, and Eva L. Feldman * Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA Received 10 June 2003; revised 10 December 2003; accepted 30 December 2003 Abstract Although the root cause of many neurodegenerative diseases is unknown, neuroinflammation may play a key role in these types of disease, including amyotrophic lateral sclerosis (ALS). In the context of neurodegeneration, it is unclear if the disease is propagated through inflammation, or whether in contrast, evidence of inflammation reflects an attempt to protect against further cellular injury. Inflammatory pathways involving the cyclooxygenase (COX) enzymes and subsequent generation of prostaglandins are potential target sites for treatments to halt the progression of ALS. In the CNS, COX enzymes are localized to neurons, astrocytes, and microglia and can be induced under various conditions. In addition, there appears to be a dual role for the prostaglandin products of COX enzymes in the nervous system. Some prostaglandins promote the survival of neurons, while others promote apoptosis. In this review, the pathways of COX activity and prostaglandin production form the center of the debate regarding the dual nature of neuroinflammation. We will also discuss how this duality may affect future treatments for neurodegenerative diseases such as ALS. D 2004 Elsevier Inc. All rights reserved. Keywords: Neuroinflammation; COX-2; ALS Introduction Neuroinflammation In neurodegenerative diseases such as amyotrophic lat- eral sclerosis (ALS), neuroinflammation is a key event, although the cause and significance of this process is not clear (McGeer and McGeer, 2002). Inflammatory processes occur in the CNS through mechanisms that differ from systemic inflammation, and with distinct cellular effects. There are multiple aspects of neuroinflammation, all work- ing simultaneously. Following exposure to noxious stimuli, components of neuroinflammation include immune cell proliferation, activation of microglia, release of cytokines, and induction of tissue repair enzymes that together limit cellular damage and help regenerate the CNS. However, these same inflammatory mediators are often the primary cause of tissue damage in both acute and chronic CNS pathology. This capacity for the same inflammatory re- sponse to both heal and harm the CNS makes it difficult to assess the significance and potential protective mecha- nisms of neuroinflammation. Complicating this concept even further is the likelihood that both of these protective and damaging processes are occurring at the same time. Some of these processes occur systemically such as leukocytes marginating along postcapil- lary venules around areas of neuroinflammation in ALS (Engelhardt et al., 1989, 1993) followed by the recruitment of a small number of T4 and T8 cells, indicating the involvement of cell-mediated immunity (Kawamata et al., 1992; Troost et al., 1990). Other inflammatory processes are localized reactions. In the localized degenerating areas of neuroinflammation, there is an accumulation of activated microglia that act as phagocytes (Kawamata et al., 1992; Lampson et al., 1990; Troost et al., 1990) as well as a build up of reactive astrocytes (Kawamata et al., 1992; Schiffer et al., 1996). These activated microglia and reactive astrocytes may be the primary means by which a localized neurodegenerative response propagates in the CNS. When stimulated, these cells generate multiple cytokines and enzymes that are involved in the neuroinflammatory response. A further level of complex- ity is introduced because of the dose dependence of cellular responses to inflammatory mediators, with neuroprotection or excitation at one dose but injury at a different concentration 0014-4886/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2003.12.009 * Corresponding author. Department of Neurology, University of Michigan, 4414 Kresge III, 200 Zina Pitcher Place, Ann Arbor, MI 48109. Fax: +1-734-763-7275. E-mail addresses: andreav@umich.edu (A.M. Vincent), efeldman@umich.edu (E.L. Feldman). www.elsevier.com/locate/yexnr Experimental Neurology 187 (2004) 1 – 10