Study of pyrrolidine dithiocarbamate on experimental models of Alzheimer's disease in rats

Among non‐communicable diseases, neurological disorders are one of the leading causes of Disability‐Adjusted Life Years (DALY) and Alzheimer's disease is the leading cause in this group. Treatment largely consists of cholinesterase inhibitors. No current therapy is aimed at putting an end to the oxidative and inflammatory attack on the brain, making current pharmacotherapy symptomatic and not curative. The objective of this study was to study the effects of pyrrolidine dithiocarbamate (PDTC), a potent inhibitor of NF‐κB on two experimental models of Alzheimer's disease. Non‐availability of a drug with multiple mechanisms of action (anticholinesterase, anti‐inflammatory, and anti‐oxidant) guided us to perform this study. In the pilot study, to evaluate its minimum effective dose (MED), PDTC was administered at doses of 5, 10 and 20 mg/kg b.w. in the scopolamine model of cognitive deficit. Effectiveness was measured on a battery of neurobehavioral tests (Morris water maze, passive avoidance paradigm, and elevated plus maze). In the intracerebroventricular‐streptozotocin (ICV‐STZ) model of cognitive impairment, PDTC was administered for 28 days (post‐ICV‐STZ) in graded doses of 20, 40 and 80 mg/kg b.w. A battery of neurobehavioral tests were performed. On day 29, cortex and hippocampi were separated for estimation of biochemical parameters (MDA and GSH), acetylcholinesterase, and inflammatory cytokines (TNF‐α, IL‐1β and IL‐10). Finally, H&E, DAPI & GFAP staining of hippocampi was done to assess the effect of the drug. Our research showed the neuroprotective effect of PDTC on ICV‐STZ model of sporadic AD in rats, thus showing its potential as a future therapeutic option. Support or Funding Information All India Institue of Medical Sciences, New DelhiRepresentative image of MWM Track plot. A: Normal control rat, B: STZ rat and C: PDTC 80 ratDAPI and GFAP staining of Hippocampus. A: DAPI stained Normal control whole hippocampus. B: GFAP stained Normal control whole hippocampus. C: DAPI stained Hippocampus CA 3 area in STZ treated rat. D: GFAP stained Hippocampus CA 3 area in STZ treated rat. E: DAPI stained Hippocampus CA 3 area in rat treated with PDTC post‐ICV‐STZ. F: GFAP stained Hippocampus CA 3 area in rat treated with PDTC post‐ICV‐STZ.Representative images of Haematoxylin & Eosin staining done on brain sections showcasing CA 3 region of Hippocampus. A: Normal Control, B: STZ treated rat, C: PDTC treated rat post ICV‐STZ; A,B and C are magnified 20 X. D: Normal Control, E: STZ treated rat, F: PDTC treated rat post ICV‐STZ; D,E and F are magnified 40 X.Effect of PDTC on hippocampal levels of MDA. Data is presented as Mean ±SEM, (n=6), * as compared to NC group, # as compared to STZ group. *** p<0.001, # p<0.05, #: ### p<0.001. MDA: Malondialdehyde, NC: Normal Control, STZ: Streptozotocin, PDTC: Pyrrolidine dithiocarbamate.Effect of PDTC on hippocampal levels of GSH. Data is presented as Mean ±SEM, (n=6), * as compared to NC group, # as compared to STZ group. *** p<0.001, # p<0.05, ## p<0.01. GSH: reduced glutathione, NC: Normal Control, STZ: Streptozotocin, PDTC: Pyrrolidine dithiocarbamateEffect of PDTC on hippocampal levels of acetylcholinesterase. Data is presented as Mean ± SEM, (n=6), * as compared to NC group, # as compared to STZ group. *** p<0.001,, ### p<0.001. GSH: reduced glutathione, NC: Normal Control, STZ: Streptozotocin, PDTC: Pyrrolidine dithiocarbamateEffect of PDTC on hippocampal levels of TNF‐α. Data is presented as Mean ±SEM, (n=6), * as compared to NC group, # as compared to STZ group. *** p<0.001, ### p<0.001. TNF‐ α: Tumor Necrosis Factor ‐ α, NC: Normal Control, STZ: Streptozotocin, PDTC: Pyrrolidine dithiocarbamate.Effect of PDTC on hippocampal levels of IL‐1β. Data is presented as Mean ±SEM, (n=6), * as compared to NC group, # as compared to STZ group. *** p<0.001, ### p<0.001. IL‐1β: Interleukin – β, NC: Normal Control, STZ: Streptozotocin, PDTC: Pyrrolidine dithiocarbamate.Effect of PDTC on hippocampal levels of IL‐1β. Data is presented as Mean ±SEM, (n=6), * as compared to NC group, # as compared to STZ group. *** p<0.001, ### p<0.001. IL‐1β: Interleukin – β, NC: Normal Control, STZ: Streptozotocin, PDTC: Pyrrolidine dithiocarbamate.Effect of PDTC on cortical levels of MDA. Data is presented as Mean ±SEM, (n=6), * as compared to NC group, # as compared to STZ group. *** p<0.001, ## p<0.01. MDA: Malondialdehyde, NC: Normal Control, STZ: Streptozotocin, PDTC: Pyrrolidine dithiocarbamate.Effect of PDTC on cortical levels of GSH. Data is presented as Mean ±SEM, (n=6), * as compared to NC group, # as compared to STZ group. *** p<0.001, ### p<0.001. GSH: reduced glutathione, NC: Normal Control, STZ: Streptozotocin, PDTC: Pyrrolidine dithiocarbamate.Effect of PDTC on cortical levels of GSH. Data is presented as Mean ±SEM, (n=6), * as compared to NC group, # as compared to STZ group. *** p<0.001, ### p<0.001. GSH: reduced glutathione, NC: Normal Control, STZ: Streptozotocin, PDTC: Pyrrolidine dithiocarbamate.Effect of PDTC on cortical levels of TNF‐ α. Data is presented as Mean ±SEM, (n=6), * as compared to NC group, # as compared to STZ group. *** p<0.001, ### p<0.001. TNF‐ α: Tumor Necrosis Factor ‐ α, NC: Normal Control, STZ: Streptozotocin, PDTC: Pyrrolidine dithiocarbamate.Effect of PDTC on cortical levels of IL‐1β. Data is presented as Mean ±SEM, (n=6), * as compared to NC group, # as compared to STZ group. *** p<0.001, # p<0.05. IL‐1β: Interleukin – β, NC: Normal Control, STZ: Streptozotocin, PDTC: Pyrrolidine dithiocarbamate.Effect of PDTC on cortical levels of IL‐10. Data is presented as Mean ±SEM, (n=6), * as compared to NC group, # as compared to STZ group. *** p<0.001, ## p<0.01.. IL‐10: Interleukin – 10, NC: Normal Control, STZ: Streptozotocin, PDTC: Pyrrolidine dithiocarbamate.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .