Contributions
Abstract: P901
Type: Poster Sessions
Abstract Category: Therapy - Neuroprotection and Repair
Background: Despite multiple approved therapies for treatment of multiple sclerosis (MS), there remains a need for new therapeutic options. Bioelectronic therapy (BET) through vagus nerve stimulation activates protective neuro-immune reflexes that attenuate inflammation, increase Treg populations, and is neuroprotective in the central nervous system (Immunol Rev 248(1):188). We hypothesized that BET may be ameliorative in rodent models of MS. As several reflex pathways are regulated through alpha-7 nicotinic receptors (α7nAChR), we explored whether α7nAChR is required for the beneficial effect of BET in these models.
Objective: Explore mechanisms of action and outcomes of BET on demyelination in a lysolecithin (LPC)-induced MS model.
Methods: To induce a self-limited demyelinating lesion, spinal cords of female mice (BALB/c, C57BL6, and α7nAChR knockout (KO) on C57BL/6 background) were injected between T3-T5 with 1% LPC. BET (0.75 mA, 10 Hz, 60 s) or sham BET was performed immediately post injection, and the mice were euthanized 4 days post injection (dpi). Spinal cord lesion volumes were quantified from luxol blue-stained serial sections. In BALB/c mice, Evans blue extravasation into the injected area at 1 dpi was measured to determine blood-spinal cord barrier (BSCB) leakage, and leukocyte infiltration was measured at 3 dpi via flow cytometry.
Results: BET inhibited demyelinated lesion progression compared to sham. At 4 dpi, mean lesion volume in the BET group was significantly decreased compared to the sham group in both wild type strains (66-71% reduction; p< 0.05). However, the protective effect of BET was abolished in the α7nAChR KO mice. Further, in BALB/c mice, BET significantly reduced BSCB permeability (77% reduction; p< 0.05), and decreased infiltration of leukocytes into the spinal cord compared to sham.
Conclusions: BET reduced demyelination in an α7nAChR-dependent manner, perhaps secondarily to the robust reduction observed in BCSB permeability 1 dpi and subsequent leukocyte infiltration. These data demonstrate a profound effect of BET after a single dose in this model. To further investigate the underlying mechanisms of these neuroprotective effects, additional potential cellular targets such as endothelial cells, astrocytes, oligodendrocytes, and microglia are being explored. Repetitive stimulation with an implanted device will be tested in experimental autoimmune encephalomyelitis to further assess the potential of BET to treat MS.
Disclosure: N. Hamlin is an employee of and owns shares/options in SetPoint Medical, Inc. Y. Levine is an employee of and owns shares/options in SetPoint Medical, Inc. D. Chernoff is an employee of and owns shares/options in SetPoint Medical, Inc., and is a consultant to Crescendo BioScience/Myriad Genetics, Adamas Pharmaceuticals (owns shares), OLLY Nutrition (own shares/options), NAIA Pharma (owns shares/options), and Aquinox Pharma (owns shares/options). This study was funded by SetPoint Medical, Inc.
Abstract: P901
Type: Poster Sessions
Abstract Category: Therapy - Neuroprotection and Repair
Background: Despite multiple approved therapies for treatment of multiple sclerosis (MS), there remains a need for new therapeutic options. Bioelectronic therapy (BET) through vagus nerve stimulation activates protective neuro-immune reflexes that attenuate inflammation, increase Treg populations, and is neuroprotective in the central nervous system (Immunol Rev 248(1):188). We hypothesized that BET may be ameliorative in rodent models of MS. As several reflex pathways are regulated through alpha-7 nicotinic receptors (α7nAChR), we explored whether α7nAChR is required for the beneficial effect of BET in these models.
Objective: Explore mechanisms of action and outcomes of BET on demyelination in a lysolecithin (LPC)-induced MS model.
Methods: To induce a self-limited demyelinating lesion, spinal cords of female mice (BALB/c, C57BL6, and α7nAChR knockout (KO) on C57BL/6 background) were injected between T3-T5 with 1% LPC. BET (0.75 mA, 10 Hz, 60 s) or sham BET was performed immediately post injection, and the mice were euthanized 4 days post injection (dpi). Spinal cord lesion volumes were quantified from luxol blue-stained serial sections. In BALB/c mice, Evans blue extravasation into the injected area at 1 dpi was measured to determine blood-spinal cord barrier (BSCB) leakage, and leukocyte infiltration was measured at 3 dpi via flow cytometry.
Results: BET inhibited demyelinated lesion progression compared to sham. At 4 dpi, mean lesion volume in the BET group was significantly decreased compared to the sham group in both wild type strains (66-71% reduction; p< 0.05). However, the protective effect of BET was abolished in the α7nAChR KO mice. Further, in BALB/c mice, BET significantly reduced BSCB permeability (77% reduction; p< 0.05), and decreased infiltration of leukocytes into the spinal cord compared to sham.
Conclusions: BET reduced demyelination in an α7nAChR-dependent manner, perhaps secondarily to the robust reduction observed in BCSB permeability 1 dpi and subsequent leukocyte infiltration. These data demonstrate a profound effect of BET after a single dose in this model. To further investigate the underlying mechanisms of these neuroprotective effects, additional potential cellular targets such as endothelial cells, astrocytes, oligodendrocytes, and microglia are being explored. Repetitive stimulation with an implanted device will be tested in experimental autoimmune encephalomyelitis to further assess the potential of BET to treat MS.
Disclosure: N. Hamlin is an employee of and owns shares/options in SetPoint Medical, Inc. Y. Levine is an employee of and owns shares/options in SetPoint Medical, Inc. D. Chernoff is an employee of and owns shares/options in SetPoint Medical, Inc., and is a consultant to Crescendo BioScience/Myriad Genetics, Adamas Pharmaceuticals (owns shares), OLLY Nutrition (own shares/options), NAIA Pharma (owns shares/options), and Aquinox Pharma (owns shares/options). This study was funded by SetPoint Medical, Inc.