Increased Expression of 15-Hydroxyprostaglandin Dehydrogenase in Spinal Astrocytes During Disease Progression in a Model of Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is an adult-onset, progressive, and fatal neurodegenerative disease caused by selective loss of motor neurons. Both ALS model mice and patients with sporadic ALS have increased levels of prostaglandin E2 (PGE2). Furthermore, the protein levels of microsomal PGE synthase-1 and cyclooxygenase-2, which catalyze PGE2 biosynthesis, are significantly increased in the spinal cord of ALS model mice. However, it is unclear whether PGE2 metabolism in the spinal cord is altered. In the present study, we investigated the protein level of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a key enzyme in prostaglandin metabolism, in ALS model mice at three different disease stages. Western blotting revealed that the 15-PGDH level was significantly increased in the lumbar spinal cord at the symptomatic stage and end stage. Immunohistochemical staining demonstrated that 15-PGDH immunoreactivity was localized in glial fibrillary acidic protein (GFAP)-positive astrocytes at the end stage. In contrast, 15-PGDH immunoreactivity was not identified in NeuN-positive large cells showing the typical morphology of motor neurons in the anterior horn. Unlike 15-PGDH, the level of PGE2 in the spinal cord was increased only at the end stage. These results suggest that the significant increase of PGE2 at the end stage of ALS in this mouse model is attributable to an imbalance of the synthetic pathway and 15-PGDH-dependent scavenging system for PGE2, and that this drives the pathogenetic mechanism responsible for transition from the symptomatic stage.

Generation of Cellular Reactive Oxygen Species by Activation of the EP2 Receptor Contributes to Prostaglandin E2-Induced Cytotoxicity in Motor Neuron-Like NSC-34 Cells

“…PGE2 is known to be a potent proinflammatory mediator that is increased in postmortem brain tissue, cerebrospinal fluid, and serum from patients with sporadic ALS [6,29] and in both the cerebral cortex and spinal cord in the G93A mutant SOD1 transgenic mouse model of ALS [7,30]. A previous study from our laboratory showed that the PGE2induced cytotoxicity is mediated by activation of EP2 in differentiated NSC-34 cells [21].…”

“…Among them, PGE2 plays a pivotal role in the degeneration of motor neurons in humans and transgenic models of ALS. PGE2 is increased in cerebrospinal fluid from patients with sporadic ALS [6] and in the spinal cord of ALS model mice [7]. We have revealed that the level of microsomal PGE synthase-1 (mPGES-1), the enzyme catalyzing the final step of PGE2 biosynthesis, is significantly increased in motor neurons in the mouse model of ALS [8].…”

Regulation of the 20S proteasome by a novel family of inhibitory proteins

“…Mutations in NQO1 have been correlated with an increased risk of Alzheimer's disease (Bian, Zhao et al, 2008, Tsvetkov, Adamovich et al, 2011, while changes in PGDH expression have been linked to tumor growth in multiple cancers (Tai, Tong et al, 2007, Wolf, O'Kelly et al, 2006, as well as late-stage neurodegenerative disease (Miyagishi, Kosuge et al, 2017).…”

Bidens pilosa Extract Administered after Symptom Onset Attenuates Glial Activation, Improves Motor Performance, and Prolongs Survival in a Mouse Model of Amyotrophic Lateral Sclerosis

“…Immunohistochemistry. Immunohistochemistry was performed as described elsewhere [19,20]. Briefly, anaesthetised animals were perfused with 4% paraformaldehyde in phosphate-buffered saline (PBS).…”