Rofecoxib Attenuates the Pathogenesis of Amyotrophic Lateral Sclerosis by Alleviating Cyclooxygenase-2-Mediated Mechanisms

Abstract

Cyclooxygenase-2 (COX-2) is reported to be activated during the course of amyotrophic lateral sclerosis (ALS) development and progression. However, the roles of COX-2 in aggravating ALS and the underlying mechanism have been largely overlooked. To reveal the mechanisms, the canonical SOD1 G93A mouse model was used as an experimental model for ALS in the current study. In addition, a specific inhibitor of COX-2 activity, rofecoxib, was orally administered to SOD1 G93A mice. With this in vivo approach, we revealed that COX-2 proinflammatory signaling cascades were inhibited by rofecoxib in SOD1 G93A mice. Specifically, the protein levels of COX-2, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α were elevated as a result of activation of astrocytes and microglia during the course of ALS development and progression. These proinflammatory reactions may contribute to the death of neurons by triggering the movement of astrocytes and microglia to neurons in the context of ALS. Treatment with rofecoxib alleviated this close association between glial cells and neurons and significantly decreased the density of inflammatory cells, which helped to restore the number of motor neurons in SOD1 G93A mice. Mechanistically, rofecoxib treatment decreased the expression of COX-2 and its downstream signaling targets, including IL-1β and TNF-α, by deactivating glial cells, which in turn ameliorated the progression of SOD1 G93A mice by postponing disease onset and modestly prolonging survival. Collectively, these results provide novel insights into the mechanisms of ALS and aid in the development of new drugs to improve the clinical treatment of ALS.

In Silico Exploration of Metabolically Active Peptides as Potential Therapeutic Agents against Amyotrophic Lateral Sclerosis

“…Ozone could activate NF-κB and phosphatases [ 77 ], and ozone-driven cellular oxidation has been linked to fatty acid oxidation, acting as a signal traducer for Nrf2/Keap1/ARE system activation with crosstalk of Nrf2/NF-kB and AMPK/FOXO/mTOR/Sir1 pathway, which shifted cytokine activation from pro-inflammatory to anti-inflammatory and immunoregulatory effects on intestinal microbiota and regulatory T lymphocytes [ 78 ]. Activation of astrocytes and microglia cause high expression of IL-1β, COX-2, and TNF-α at the onset and during the progression of ALS in SOD1 G93A mice, and that treatment with non-steroidal anti-inflammatory drugs (NSAIDs), rofecoxib or celecoxib, markedly inhibited the expression of COX-2 [ 68 , 79 , 80 ].…”

Anti-Inflammatory Effects of Miyako Bidens pilosa in a Mouse Model of Amyotrophic Lateral Sclerosis and Lipopolysaccharide-Stimulated BV-2 Microglia

“…Recombinant human erythropoietin has also been reported to prolong the life span and protect the motor neurons of G93A mice [ 40 ]. Moreover, rofecoxib, an anti-inflammatory drug, has been reported to decrease the expression of TNF-α and IL-1β in the spinal cord and to prolong survival in G93A mice [ 41 ], suggesting that it may be important to reduce pro-inflammatory cytokines in ALS therapy. Consistent with the effects of erythropoietin and rofecoxib, we found that MBP selectively suppressed the upregulation of pro-inflammatory cytokines with no influence on anti-inflammatory cytokine expression in the spinal cord of G93A mice at an early symptomatic stage ( Figure 1 ).…”

The Diverse Roles of Reactive Astrocytes in the Pathogenesis of Amyotrophic Lateral Sclerosis

“…The levels of PGE2 in the CSF of most ALS patients are elevated 10-fold [128][129][130][131][132]. Cyclooxygenase 2 (COX2) catalyzes the conversion of arachidonic acid to PGE2; thus, blocking COX2 specifically with celecoxib or rofecoxib may slow down the development and progression of ALS [133,134].…”