Andres Urrutia

Introduction: Organophosphate (OP) based nerve agent weapons are a large concern in today’s geopolitical climate due to their lethality. Death from exposure is typically cardiac/respiratory arrest secondary to cholinergic over-stimulation which leads to parasympathomimetic symptoms^1,2. However, for physicians, there is a significantly higher likelihood of running into OP based pesticides or fertilizers either in agricultural communities or research. While current treatment has centered around keeping patients alive, it has done a poor job of combating long term side-effects related to neuroinflammation in regions of the brain such as the amygdala, hippocampus, striatum and cortex³. Current treatment is Atropine for lethal cholinergic effects, benzodiazepines for seizures and Pyridostigmine serves as the current, reversible acetylcholinesterase (AcHE) inhibitor of choice^4,5. Reversible sequestration of AcH is critical for survival of neural pathways in the brain. Galantamine has been shown to be superior to Pyridostigmine in multiple animal models for sequestration of neural AcH, preventing memory loss issues, cognitive delays, and mitigation of fear responses^5,6. Methods: Mice, guinea pig, rat, and macaque animal models were utilized for testing. Mice were exposed to LPS (neuroinflammatory substance) and galantamine with water maze tests being utilized to calculate error rate⁴. Guinea pig spatial learning was measured post OP exposure with light and dark maze tests to judge completion times. Macaque models were prophylactically given Galantamine prior to Soman (OP) exposure to show a timeline for seizure prevention while rat models were also placed in mazes and time to completion as well as throughput errors were measured. Results: For Macaques exposed to Soman, length of seizures was universally indicative of neurologic damage. When administered as prophylaxis prior to exposure, Galantamine was effective at preventing neural pathway destruction and reversing damage done if administered within 15-20 minutes of exposure⁷. In all models exposed to neuroinflammatory substances, less throughput mistakes were made and completion of maze times were faster in those exposed to Galantamine^7-9. Down-regulation of pro-inflammatory factors were seen in frozen brain fractions of guinea pigs, and less reactive gliosis indicative of neural injury was noted upon GFAP staining³. Conclusions: Galantamine is superior to Pyridostigmine in prevention of OP induced neuroinflammatory effects and destruction of neuronal pathways in the brain. While the mechanism remains unclear through either upregulation of survival factors or downregulation of pro-inflammatory factors, multiple animal models showed increased survivability and less neural pathway destruction related side effects.

1.  Sources: Golime, R., Palit, M., Acharya, J. et al. Neuroprotective Effects of Galantamine on Nerve Agent-Induced Neuroglial and Biochemical Changes. Neurotox Res 33, 738–748 (2018).
2. Naughton, S. and Terry, A., 2020. Neurotoxicity In Acute And Repeated Organophosphate Exposure.
3. Liu H-Y, Jin B-R. Comparative efficacy and safety of cognitive enhancers for treating vascular cognitive impairment: systematic review and Bayesian network meta-analysis. Neural Regeneration Research. 2019;14(5):805. doi:10.4103/1673-5374.249228.
4. Liu Y, Zhang Y, Zheng X, et al. Galantamine improves cognition, hippocampal inflammation, and synaptic plasticity impairments induced by lipopolysaccharide in mice. Journal of Neuroinflammation. 2018;15(1). doi:10.1186/s12974-018-1141-5.
5. Flannery BM, Bruun DA, Rowland DJ, et al. Persistent neuroinflammation and cognitive impairment in a rat model of acute diisopropylfluorophosphate intoxication. Journal of Neuroinflammation. 2016;13(1). doi:10.1186/s12974-016-0744-y.
6. Sarah Mackenzie Ross, I. C. McManus, Virginia Harrison & Oliver Mason (2013) Neurobehavioral problems following low-level exposure to organophosphate pesticides: a systematic and meta-analytic review, Critical Reviews in Toxicology, 43:1, 21-44, DOI: 10.3109/10408444.2012.738645
7. Hamilton LR, Schachter SC, Myers TM. Time Course, Behavioral Safety, and Protective Efficacy of Centrally Active Reversible Acetylcholinesterase Inhibitors in Cynomolgus Macaques. Neurochemical Research. 2016;42(7):1962-1971. doi:10.1007/s11064-016-2120-9.
8. Mamczarz J, Pescrille JD, Gavrushenko L, et al. Spatial learning impairment in prepubertal guinea pigs prenatally exposed to the organophosphorus pesticide chlorpyrifos: Toxicological implications. NeuroToxicology (2017).
9. Li-Ping Liang, Jennifer N Pearson-Smith, Jie Huang, Pallavi McElroy, Brian J Day, Manisha Patel, Neuroprotective Effects of AEOL10150 in a Rat Organophosphate Model, Toxicological Sciences, Volume 162, Issue 2, April 2018, Pages 611–621.