Abstract FR550: Galantamine May Exert Its Beneficial Effects in SLE Hypertension Through Divergent Pathways

The cholinergic anti-inflammatory pathway, which includes stimulation of the vagus and splenic nerves and activation of splenic immune cells, is an intrinsic mechanism for suppressing inflammation in chronic diseases like systemic lupus erythematosus (SLE) and hypertension. We have confirmed in published and preliminary studies that short- and long-term systemic administration of galantamine, an acetylcholinesterase inhibitor that increases efferent vagus nerve activity, prevents blood pressure rises in SLE mice, reduces albuminuria, lowers splenic and renal inflammation, decreases renal injury markers, and improves survival. Given controversy over the spleen’s role in this pathway and the possibility that the beneficial effects of intraperitoneal galantamine in the kidney are due to local responses, we tested whether splenectomy would eliminate galantamine’s effect. We hypothesized that galantamine benefits would not be present in splenectomized SLE mice. Female NZBWF1 (SLE) and NZW (control) mice were splenectomized at 31 weeks, allowed to recover for two weeks, and administered galantamine (4 mg/kg/day, IP) for 14 days. At the end of the study (35 weeks), plasma and urine were collected, and mean arterial pressure (MAP) was measured via carotid catheters in conscious mice over two days. Mice were then euthanized, and kidneys were collected. Disease severity was assessed by plasma dsDNA autoantibody titers (ELISA), and kidney inflammation/injury markers were measured by western blot and ELISA. Galantamine did not alter MAP (135±3 vs. 142±4; n=3-10, p=0.4574) or dsDNA antibodies (4.6e5±2.3e5 vs. 5.5e5±1.9e5; n=3-8, p=0.8041) in splenectomized SLE mice compared to sham SLE mice that received galantamine. Although galantamine tended to decrease the urinary albumin-to-creatinine ratio (2485.93±1105.11 vs. 1.64±0.68; n=3-10, p=0.2576), urinary KIM-1-to-creatinine ratio (36.48±15.93 vs. 13.04±0.92; n=3-10, p=0.4514), urinary NGAL-to-creatinine ratio (788.1±438.4 vs. 61.5±7.8; n=3-10, p=0.1910), and renal TNF-α (9.5e7±3.0e7 vs. 1.4e8±1.2e7; n=3-7, p=0.1445) in splenectomized mice compared to shams, none reached significance. These results suggest galantamine’s benefits on MAP and autoimmunity may require the spleen, while its effects on kidney inflammation/injury may be spleen-independent. Further studies are needed to confirm galantamine's actions through the vagus nerve and/or through local acetylcholinesterase inhibition in the kidney.