AI Article Synopsis
- ALS is a serious neurodegenerative disease leading to motor neuron death, with increased levels of cPLA2α observed in affected patients and mice.
- Treatment with an antisense oligonucleotide targeting cPLA2α showed promise in reducing its levels and delaying symptom onset in transgenic mice before disease symptoms appeared.
- The reduction of cPLA2α not only preserved motor neuron function but also inhibited the activation of glial cells and decreased pro-inflammatory markers associated with the progression of ALS.
Article Abstract
Background: Amyotrophic lateral sclerosis (ALS) is a fatal multifactorial neurodegenerative disease characterized by selective death of motor neurons in the cortex, brainstem, and spinal cord. Cytosolic phospholipase A2 alpha (cPLA2α) upregulation and activation in the spinal cord of patients with sporadic ALS and in the spinal cord of human mutant SOD1G93A (hmSOD1) transgenic mice were recently reported.
Methods: cPLA2α upregulation in the brainstem and spinal cord was reduced by brain infusion of a specific antisense oligonucleotide against cPLA2α (AS), and the effect was evaluated on disease progression and brain cell activation.
Results: We found that the elevation of cPLA2α protein expression in the spinal cord was first detected at 6-week-old hmSOD1 mice and remained elevated during their whole life span. Reduction of the elevated expression of cPLA2α in the spinal cord of hmSOD1 mice by brain infusion of an AS at week 15 (shortly before the appearance of the disease symptoms), for a duration of 6 weeks, delayed the loss of motor neuron function in comparison with hmSOD1 mice and with sense brain-infused hmSOD1 mice. To characterize the effect of cPLA2α upregulation on different processes taking place at the appearance of the disease symptoms, mice were brain infused with AS or with sense at week 15 for 3-4 weeks. The AS treatment that reduced cPLA2α upregulation in the spinal cord of AS-treated hmSOD1 mice (as analyzed at week 18-19) prevented the reduction in the number of the neurons (detected by NeuN) and inhibited astrocyte activation (detected by GFAP) and microglia activation (detected by Iba-1 and by CD40). In addition, AS treatment blunted the upregulation of the proinflammatory enzyme-inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) detected in hmSOD1 mice.
Conclusions: Since specific reduction of cPLA2α in the brainstem and spinal cord significantly attenuated the development of the disease, cPLA2α may offer an efficient target for treatment of ALS.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4888471 | PMC |
| http://dx.doi.org/10.1186/s12974-016-0602-y | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Inhibition of RIPK1-driven necroptosis ameliorates inflammatory hyperalgesia caused by lipopolysaccharide: involvement of TLR-, NLRP3-, and caspase-11-mediated signaling pathways.
Cell Mol Biol (Noisy-le-grand)
January 2025
Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, Türkiye.
Article Synopsis
- Recent research indicates that blocking the RIPK1/RIPK3/MLKL necrosome can help reduce inflammatory pain linked to conditions like demyelination in the central nervous system.
- This study tests necrostatin-1s (Nec-1s), a specific RIPK1 inhibitor, on LPS-induced inflammatory pain in male mice, assessing pain sensitivity through hot plate tests and examining related protein changes.
- Results show that Nec-1s not only prevents LPS-induced pain relief but also reverses the activation of key proteins and signals involved in inflammation and demyelination, suggesting that RIPK1 inhibitors could be a promising treatment for managing inflammatory pain.
Artificial enforcement of the unfolded protein response (UPR) reduces disease features in multiple preclinical models of ALS/FTD.
Mol Ther
January 2025
Program of Cellular and Molecular Biology, Biomedical Sciences Institute (ICBM), Universidad de Chile, Santiago, Chile; Biomedical Neuroscience, Faculty of Medicine, Universidad de Chile, Santiago, Chile; FONDAP Center for Geroscience, Brain Health and Metabolism, Santiago, Chile; Buck Institute for Research on Aging, Novato, CA, USA. Electronic address:
Amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) are part of a spectrum of diseases that share several causative genes, resulting in a combinatory of motor and cognitive symptoms and abnormal protein aggregation. Multiple unbiased studies have revealed that proteostasis impairment at the level of the endoplasmic reticulum (ER) is a transversal pathogenic feature of ALS/FTD. The transcription factor XBP1s is a master regulator of the unfolded protein response (UPR), the main adaptive pathway to cope with ER stress.
View Article and Find Full Text PDFFerroptosis-related genes participate in the microglia-induced neuroinflammation of spinal cord injury via NF-κB signaling: evidence from integrated single-cell and spatial transcriptomic analysis.
J Transl Med
January 2025
Division of Spine, Department of Orthopedics, Tongji Hospital affiliated to Tongji University, Tongji University School of Medicine, Shanghai, 200065, China.
Background: Ferroptosis and immune responses are critical pathological events in spinal cord injury (SCI), whereas relative molecular and cellular mechanisms remain unclear.
Methods: Micro-array datasets (GSE45006, GSE69334), RNA sequencing (RNA-seq) dataset (GSE151371), spatial transcriptome datasets (GSE214349, GSE184369), and single cell RNA sequencing (scRNA-seq) datasets (GSE162610, GSE226286) were available from the Gene Expression Omnibus (GEO) database. Through weighted gene co-expression network analysis and differential expression analysis in GSE45006, we identified differentially expressed time- and immune-related genes (DETIRGs) associated with chronic SCI and differentially expressed ferroptosis- and immune-related genes (DEFIRGs), which were validated in GSE151371.
Transcription factor AP-2 Beta, a potential target of repetitive Transspinal magnetic stimulation in spinal cord injury treatment, reduced inflammation and alleviated spinal cord injury.
Exp Neurol
January 2025
Department of Rehabilitation Medicine, The First Hospital of China Medical University, Shenyang, China. Electronic address:
Spinal cord injury (SCI) is a neurodegenerative disease, with a high disability rate. According to the results of mRNA-seq, transcription factor AP-2 Beta (TFAP2B) is a potential target of repetitive Transspinal Magnetic Stimulation (rTSMS) in SCI treatment. Our results demonstrated that rTSMS significantly improved motor function and promoted neuronal survival post-SCI.
View Article and Find Full Text PDFBaicalin ameliorates neuroinflammation by targeting TLR4/MD2 complex on microglia via PI3K/AKT/NF-κB signaling pathway.
Neuropharmacology
January 2025
National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, The Key Laboratory of Medicinal Resources and Natural Pharmaceutical Chemistry, The Ministry of Education, College of Life Sciences, Shaanxi Normal University, Xi'an, Shaanxi 710119, China. Electronic address:
This study aims to elucidate the target and mechanism of baicalin, a clinically utilized drug, in the treatment of neuroinflammatory diseases. Neuroinflammation, characterized by the activation of glial cells and the release of various pro-inflammatory cytokines, plays a critical role in the pathogenesis of various diseases, including spinal cord injury (SCI). The remission of such diseases is significantly dependent on the improvement of inflammatory microenvironment.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!