Authors :
Presenting Author: Roberta Coa, MD, PhD – AOU Cagliari
Claudia Manca, PhD – Department of Biomedical Sciences, Division of Physiology – University of Cagliari; Elisabetta Murru, PhD – Department of Biomedical Sciences, Division of Physiology – University of Cagliari; Gianfranca Carta, PhD – Department of Biomedical Sciences, Division of Physiology – University of Cagliari; Giovanni Pinna, MD – SC Neurosurgery, Neuroscience and Rehabilitation Department – ARNAS Brotzu; Roberto Sanfilippo, MD – SC Vascular Surgery – AOU Cagliari; Lorenzo Polizzi, MD – Center for the Diagnosis and Treatment of Adult Epilepsy, Neurology Unit – AOU Cagliari; Marco Pistis, MD – Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology – University of Cagliari; Paolo Follesa, PhD – Department of Life and Environmental Sciences, Section of Neuroscience and Anthropology – University of Cagliari; Sebastiano Banni, PhD – Department of Biomedical Sciences, Division of Physiology – University of Cagliari; Monica Puligheddu, MD, PhD – Department of Medical Sciences and Public Health – University of Cagliari
Rationale:
Vagal nerve stimulation (VNS) therapy is a neuromodulation technique with proven efficacy in improving seizure frequency and quality of life of people with Drug-resistant Epilepsy (DRE) (Pérez-Carbonell et al., 2020). The exact molecular mechanism activated by vagal stimulation is still unclear. Previous studies by our group demonstrated in animal models that chronic VNS therapy affects endocannabinoid metabolism and lipid mediator levels. (Banni et al., 2012) This study aims to assess the effect of chronic VNS therapy on lipid bioactive metabolites and fatty acids in subjects with DRE to identify possible circulating metabolic biomarkers of VNS action.
Methods:
Seven subjects affected by DRE (Table) were recruited at the Center for Diagnosis and Treatment of Adult Epilepsy–AOU Cagliari (Ethics Committee PG. 2020/2970). Subjects who refused to sign informed consent, younger than 18, pregnant, or with psychiatric comorbidities were excluded.
A venous blood sampling was performed before VNS implantation (T0), after acute stimulation before the device was turned on, at each step of increasing output current (after two weeks of stimulation at each amperage), and after a period of chronic stimulation (10-14 months).
Venous blood samples were collected into anticoagulant-coated vacutainers (K3-EDTA) and processed for PPARα and SIRT1 gene expression and lipidomic analysis as already described in the literature. (Murru et al., 2018, 2021)
Non-parametric Mann-Whitney tests were performed to evaluate differences between each group and the T0 (expressed as a percentage of change).
Results:
We observed a gradual increase in peroxisome proliferator-activated receptor alpha (PPARα) gene expression, statistically significant at 2 mA stimulation (38% increase from baseline); the levels of PPARα showed a decreasing trend after chronic stimulation. The expression levels of sirtuin1 (SIRT1) showed a gradual increase, significant at 1.25 mA.
The concentration of docosahexaenoic acid (DHA) had a gradually increasing trend with increasing output current until significance after stimulus increase at 2mA: this significant increase was maintained after chronic stimulation. The concentration of the unusual FA-conjugated linoleic acid (CLA) also showed a gradual increase in concentration, which had significance at 2mA but was not maintained after chronic stimulation.
The levels of total saturated FA (SFA) in erythrocytes showed a gradual decrease from baseline, significant at 0.25mA, 1.5mA, 1.75mA, and 2mA, mainly due to two SFAs, namely myristic acid (MA) and palmitic acid (PA).
Conclusions:
This preliminary study demonstrated the action of VNS therapy on energy metabolism in humans, unveiling a new potential mechanism of vagal neuromodulation that has so far been shown only in animal models. These markers act on the endocannabinoid system, which is supposed to play a role in epileptogenesis and whose receptors are expressed in the vagal system. (Kowalski et al., 2020; Vega-García et al., 2021) These mechanisms make these biomarkers of energy metabolism particularly promising in the study of the efficacy of VNS therapy.
Funding: None