Anti-inflammatory effects of vagus nerve stimulation in pediatric patients with epilepsy.

Introduction: The neural control of the immune system by the nervous system is critical to maintaining immune homeostasis, whose disruption may be an underlying cause of several diseases, including cancer, multiple sclerosis, rheumatoid arthritis, and Alzheimer's disease. Methods: Here we studied the role of vagus nerve stimulation (VNS) on gene expression in peripheral blood mononuclear cells (PBMCs). Vagus nerve stimulation is widely used as an alternative treatment for drug-resistant epilepsy. Thus, we studied the impact that VNS treatment has on PBMCs isolated from a cohort of existing patients with medically refractory epilepsy. A comparison of genome-wide changes in gene expression was made between the epilepsy patients treated and non-treated with vagus nerve stimulation. Results: The analysis showed downregulation of genes related to stress, inflammatory response, and immunity, suggesting an anti-inflammatory effect of VNS in epilepsy patients. VNS also resulted in the downregulation of the insulin catabolic process, which may reduce circulating blood glucose. Discussion: These results provide a potential molecular explanation for the beneficial role of the ketogenic diet, which also controls blood glucose, in treating refractory epilepsy. The findings indicate that direct VNS might be a useful therapeutic alternative to treat chronic inflammatory conditions.

Myotubularin-related protein protects against neuronal degeneration mediated by oxidative stress or infection.

Microbial infections have been linked to the onset and severity of neurodegenerative diseases such as amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, but the underlying mechanisms remain largely unknown. Here, we used a genetic screen for genes involved in protection from infection-associated neurodegeneration and identified the gene mtm-10. We then validated the role of the encoded myotubularin-related protein, MTM-10, in protecting the dendrites of Caenorhabditis elegans from degeneration mediated by oxidative stress or Pseudomonas aeruginosa infection. Further experiments indicated that mtm-10 is expressed in the AWC neurons of C. elegans, where it functions in a cell-autonomous manner to protect the dendrite degeneration caused by pathogen infection. We also confirm that the changes observed in the dendrites of the animals were not because of premature death or overall sickness. Finally, our studies indicated that mtm-10 functions in AWC neurons to preserve chemosensation after pathogen infection. These results reveal an essential role for myotubularin-related protein 10 in the protection of dendrite morphology and function against the deleterious effects of oxidative stress or infection.

G-Protein-Coupled Receptor SRBC-48 Protects against Dendrite Degeneration and Reduced Longevity Due to Infection.

Increasing evidence suggests that deficient immune modulation and microbial infections underline neurodegeneration, but the mechanisms remain obscure. Here, we show that the G-protein-coupled receptor (GPCR) SRBC-48, which belongs to the class BC serpentine receptors, has a protective role in Caenorhabditis elegans dendrite degeneration caused by Pseudomonas aeruginosa infection. Our results indicate that SRBC-48 functions in a cell-autonomous manner in AWC neurons to protect against infection-associated dendrite degeneration. The absence of SRBC-48 results in a reduced lifespan caused by a pathogen infection early in life that induces dendrite degeneration. The decreased longevity in animals deficient in SRBC-48 is due to uncontrolled activation of immune genes, particularly those regulated by the FOXO family transcription factor DAF-16 that is part of the insulin/insulin-like growth factor (IGF)-1 receptor homolog DAF-2. These results reveal how an infection early in life can not only induce dendrite degeneration but also reduce lifespan.