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Journal of Molecular Neuroscience

, Volume 63, Issue 1, pp 115–122 | Cite as

Inhibitor of Endocannabinoid Deactivation Protects Against In Vitro and In Vivo Neurotoxic Effects of Paraoxon

  • Karen L. G. Farizatto
  • Sara A. McEwan
  • Vinogran Naidoo
  • Spyros P. Nikas
  • Vidyanand G. Shukla
  • Michael F. Almeida
  • Aaron Byrd
  • Heather Romine
  • David A. Karanian
  • Alexandros Makriyannis
  • Ben A. Bahr
Article

Abstract

The anticholinesterase paraoxon (Pxn) is related to military nerve agents that increase acetylcholine levels, trigger seizures, and cause excitotoxic damage in the brain. In rat hippocampal slice cultures, high-dose Pxn was applied resulting in a presynaptic vulnerability evidenced by a 64% reduction in synapsin IIb (syn IIb) levels, whereas the postsynaptic protein GluR1 was unchanged. Other signs of Pxn-induced cytotoxicity include the oxidative stress-related production of stable 4-hydroxynonenal (4-HNE)-protein adducts. Next, the Pxn toxicity was tested for protective effects by the fatty acid amide hydrolase (FAAH) inhibitor AM5206, a compound linked to enhanced repair signaling through the endocannabinoid pathway. The Pxn-mediated declines in syn IIb and synaptophysin were prevented by AM5206 in the slice cultures. To test if the protective results in the slice model translate to an in vivo model, AM5206 was injected i.p. into rats, followed immediately by subcutaneous Pxn administration. The toxin caused a pathogenic cascade initiated by seizure events, leading to presynaptic marker decline and oxidative changes in the hippocampus and frontal cortex. AM5206 exhibited protective effects including the reduction of seizure severity by 86%, and improving balance and coordination measured 24 h post-insult. As observed in hippocampal slices, the FAAH inhibitor also prevented the Pxn-induced loss of syn IIb in vivo. In addition, the AM5206 compound reduced the 4-HNE modifications of proteins and the β1 integrin activation events both in vitro and in vivo. These results indicate that Pxn exposure produces oxidative and synaptic toxicity that leads to the behavioral deficits manifested by the neurotoxin. In contrast, the presence of FAAH inhibitor AM5206 offsets the pathogenic cascade elicited by the Pxn anticholinesterase.

Keywords

Paraoxon Anticholinesterase Synaptic decline AM5206 Neuroprotection Excitotoxicity 

Notes

Acknowledgements

This material is based upon work supported by the US Army Research Office and the Department of Defense Research and Education Program under grant number W911NF-15-1-0432 (BAB). The research was also supported by National Institutes of Health (NIH) grants DA009158 (AM), DA003801 (AM), and DA007215 (AM) and in part by National Institutes of Health-Research Initiative for Scientific Enhancement (NIH-RISE) grant 5R25GM077634-04 (UNCP). The funding agencies had no role in study design, data collection and analysis, or decision to publish. We thank Jeannie Hwang, Christopher Long, Kathlyn Stephens, and Wynne Kelly for excellent assistance in the laboratory.

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Karen L. G. Farizatto
    • 1
  • Sara A. McEwan
    • 1
    • 2
  • Vinogran Naidoo
    • 1
    • 3
  • Spyros P. Nikas
    • 4
  • Vidyanand G. Shukla
    • 4
  • Michael F. Almeida
    • 1
  • Aaron Byrd
    • 1
  • Heather Romine
    • 1
  • David A. Karanian
    • 5
  • Alexandros Makriyannis
    • 4
  • Ben A. Bahr
    • 1
    • 5
  1. 1.Biotechnology Research and Training CenterUniversity of North Carolina—PembrokePembrokeUSA
  2. 2.Robert Wood Johnson Medical SchoolRutgers UniversityNew BrunswickUSA
  3. 3.Department of Human BiologyUniversity of Cape TownCape TownSouth Africa
  4. 4.Center for Drug DiscoveryNortheastern UniversityBostonUSA
  5. 5.Neurosciences ProgramUniversity of ConnecticutStorrsUSA

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