Increased Expression of the Pro- Inflammatory Enzyme Cyclooxygenase-2 in Amyotrophic Lateral Sclerosis Gabrielle Almer, MD, 1 Christelle Gue ´gan, PhD, 1 Peter Teismann, PhD, 1 Ali Naini, PhD, 1 Gorazd Rosoklija, MD, PhD, 2 Arthur P. Hays, MD, 2 Caiping Chen, MD, 1 and Serge Przedborski, MD, PhD 1,2 Mutations in the copper/zinc superoxide dismutase (mSOD1) gene are associated with a familial form of amyotrophic lateral sclerosis (ALS), and their expression in transgenic mice produces an ALS-like syndrome. Recent observations suggest a role for inflammatory-related events in the progression and propagation of the neurodegenerative process in ALS. Consistent with this view, the present study demonstrates that, during the course of the disease, the expression of cyclooxygenase type 2 (Cox-2), a key enzyme in the synthesis of prostanoids, which are potent mediators of inflamma- tion, is dramatically increased. In both early symptomatic and end-stage transgenic mSOD1 mice, neurons and, to a lesser extent, glial cells in the anterior horn of the spinal cord exhibit robust Cox-2 immunoreactivity. Cox-2 mRNA and protein levels and catalytic activity are also significantly increased in the spinal cord of the transgenic mSOD1 mice. The time course of the spinal cord Cox-2 upregulation parallels that of motor neuronal loss in transgenic mSOD1 mice. We also show that Cox-2 activity is dramatically increased in postmortem spinal cord samples from sporadic ALS patients. We speculate that Cox-2 upregulation, through its pivotal role in inflammation, is instrumental in the ALS neurode- generative process and that Cox-2 inhibition may be a valuable therapeutic avenue for the treatment of ALS. Ann Neurol 2001;49:176 –185 Amyotrophic lateral sclerosis (ALS) is the most frequent neuromuscular disorder in adults and is characterized mainly by progressive muscle wasting and weakness. 1 Mutations in the gene for the free-radical–scavenging enzyme copper/zinc superoxide dismutase (SOD1) are associated with a familial form of ALS (FALS) 2 that is clinically and pathologically indistinguishable from the most common sporadic form of this fatal neurodegen- erative disorder. Moreover, transgenic mice that express mutant SOD1 (mSOD1) develop an adult-onset para- lytic condition that reproduces the clinical and patholog- ical hallmarks of ALS. 3–5 We 6 and others 7,8 have found that the level of mSOD1 expression markedly modulates the age of onset of symptoms but has no or minimal effect on the type of symptoms or the rate of progression of the disease. This suggests that, while mSOD1 is a pivotal factor in the initiation of motor neuron disease, additional factors contribute to the propagation of the neurodegenerative process. The elucidation of such fac- tors is of major importance because it may open new therapeutic avenues aimed at stopping or slowing the progression of ALS. There is mounting evidence that inflammatory- related events could be among the factors that promote progression and propagation of motor neuron degener- ation in ALS. For instance, in addition to the dramatic loss of motor neurons, which predominates in the an- terior horn, the gray matter of the spinal cord is also the site of a robust glial reaction in both humans and transgenic mice. 9 –13 Although gliosis may in some in- stances be associated with beneficial effects, many more situations come to mind in which gliosis may be dele- terious. 14,15 Consistent with this view, we have dem- onstrated that inducible nitric oxide synthase (iNOS) is upregulated in activated microglia in the spinal cord of transgenic mSOD1 mice, 13 whereby surrounding cells, especially neurons, can be flooded with high amounts of iNOS-derived NO and other reactive oxygen species (ROS). 16 Factors such as the pro-inflammatory cyto- kine interleukin-6 (IL-6) and interleukin-1 (IL-1) may also mediate some of the glial-related deleterious effects. IL-6 and IL-1 levels are elevated in the cere- brospinal fluid 17 and spinal cord, respectively, of ALS patients. 18 IL-1 and tumor necrosis factor- levels are also increased in the spinal cord of experimental mod- els of ALS, 18,19 and inhibition of IL-1 activation is associated with clinical benefits in transgenic mSOD1 mice. 20 From the Departments of 1 Neurology and 2 Pathology, Columbia University, New York, NY. Received Apr 19, 2000, and in revised form Jul 18. Accepted for publication Sep 6, 2000. Address correspondence to Dr Przedborski, Departments of Neurol- ogy and Pathology, BB-307, Columbia University, 650 West 168th Street, New York, NY 10032. E-mail: SP30@Columbia.edu 176 © 2001 Wiley-Liss, Inc.