Skip to main content

Advertisement

SpringerLink
Log in

Time Course, Behavioral Safety, and Protective Efficacy of Centrally Active Reversible Acetylcholinesterase Inhibitors in Cynomolgus Macaques

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Galantamine hydrobromide and (−)huperzine A, centrally active reversible acetylcholinesterase inhibitors, are potentially superior to the current standard, pyridostigmine bromide, as a pretreatment for organophosphorus chemical warfare nerve agent intoxication. Galantamine, huperzine, and pyridostigmine were compared for time course of acetylcholinesterase inhibition in 12 cynomolgus macaques. Although both galantamine and huperzine shared a similar time course profile for acetylcholinesterase inhibition, huperzine was 88 times more potent than galantamine. The dose for 50% acetylcholinesterase inhibition (ID50) was 4.1 ug/kg for huperzine, 362 ug/kg for galantamine, and 30.9 ug/kg for pyridostigmine. In a safety assessment, galantamine, huperzine, and pyridostigmine were examined using an operant time-estimation task. Huperzine and pyridostigmine were devoid of behavioral toxicity, whereas galantamine was behaviorally toxic at doses producing peak acetylcholinesterase inhibition of about 50% and higher. Following pretreatment with galantamine, huperzine or pyridostigmine, monkeys were challenged with the median lethal dose of soman at the time of peak acetylcholinesterase inhibition and evaluated for overt signs of soman toxicity (cholinergic crisis, convulsions). Both huperzine and galantamine were equally effective at preventing overt signs of soman toxicity, but neither drug was capable of preventing soman-induced neurobehavioral disruption. In contrast, three of four pyridostigmine-pretreated animals exposed to soman exhibited convulsions and required therapy. Full functional recovery required 3–16 days. The degree of acetylcholinesterase inhibition was lower for pyridostigmine, but rates of recovery of acetylcholinesterase activity following soman challenge were comparable for all drug pretreatments. Huperzine may be the more promising centrally active reversible acetylcholinesterase inhibitor due to its greater potency and superior safety profile.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Shih TM, Duniho SM, McDonough JH (2003) Control of nerve agent-induced seizures is critical for neuroprotection and survival. Toxicol Appl Pharmacol 188(2):69–80

    Article  CAS  PubMed  Google Scholar 

  2. McDonough JH Jr, Shih TM (1997) Neuropharmacological mechanisms of nerve agent-induced seizure and neuropathology. Neurosci Biobehav Rev 21(5):559–579

    Article  CAS  PubMed  Google Scholar 

  3. Ashani Y, Peggins JO, Doctor BP (1992) Mechanism of inhibition of cholinesterases by huperzine A. Biochem Biophys Res Commun 184(2):719–726

    Article  CAS  PubMed  Google Scholar 

  4. Damar U, Gersner R, Johnstone JT, Schachter S, Rotenberg A (2016) Huperzine A as a neuroprotective and antiepileptic drug: a review of preclinical research. Expert Rev Neurother 16(6):671–680

    Article  CAS  PubMed  Google Scholar 

  5. Park P, Schachter S, Yaksh T (2010) Intrathecal huperzine A increases thermal escape latency and decreases flinching behavior in the formalin test in rats. Neurosci Lett 470:6–9

    Article  CAS  PubMed  Google Scholar 

  6. Yu D, Thakor DK, Han I, Ropper AE, Haragopal H, Sidman RL, Zafonte R, Schachter SC, Teng YD (2013) Alleviation of chronic pain following rat spinal cord compression injury: sustainable efficacy from multimodal actions of Huperzine A. Proc Natl Acad Sci USA 110(8):E746–E755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bialer M, Johannessen SI, Levy RH, Perucca E, Tomson T, White HS (2015) Progress report on new antiepileptic drugs: a summary of the Twelfth Eilat Conference (EILAT XII). Epilepsy Res 111:85–141

    Article  PubMed  Google Scholar 

  8. Gersner R, Ekstein D, Dhamne SC, Schachter SC, Rotenberg A (2015) Huperzine A prophylaxis against pentylenetetrazole-induced seizures in rats is associated with increased cortical inhibition. Epilepsy Res 117:97–103

    Article  CAS  PubMed  Google Scholar 

  9. Grunwald J, Raveh L, Doctor BP, Ashani Y (1994) Huperzine A as a pretreatment candidate drug against nerve agent toxicity. Life Sci 54(14):991–997

    Article  CAS  PubMed  Google Scholar 

  10. Lallement G, Veyret J, Masqueliez C, Aubriot S, Burckhart MF, Baubichon D (1997) Efficacy of huperzine in preventing soman-induced seizures, neuropathological changes and lethality. Fundam Clin Pharmacol 11(5):387–394

    Article  CAS  PubMed  Google Scholar 

  11. Myers TM, Sun W, Saxena A, Doctor BP, Bonvillain AJ, Clark MG (2010) Systemic administration of the potential countermeasure huperzine reversibly inhibits central and peripheral acetylcholinesterase activity without adverse cognitive-behavioral effects. Pharmacol Biochem Behav 94(3):477–481

    Article  CAS  PubMed  Google Scholar 

  12. Lallement G, Demoncheaux JP, Foquin A, Baubichon D, Galonnier M, Clarençon D, Dorandeu F (2002) Subchronic administration of pyridostigmine or huperzine to primates: compared efficacy against soman toxicity. Drug Chem Toxicol 25(3):309–320

    Article  CAS  PubMed  Google Scholar 

  13. Corey-Bloom J (2003) Galantamine: a review of its use in Alzheimer’s disease and vascular dementia. Int J Clin Pract 57(3):219–223

    CAS  PubMed  Google Scholar 

  14. Albuquerque EX, Pereira EF, Aracava Y, Fawcett WP, Oliveira M, Randall WR, Hamilton TA, Kan RK, Romano JA Jr, Adler M (2006) Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents. Proc Natl Acad Sci USA 103(35):13220–13225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hilmas CJ, Poole MJ, Finneran K, Clark MG, Williams PT (2009) Galantamine is a novel post-exposure therapeutic against lethal VX challenge. Toxicol Appl Pharmacol 240(2):166–173

    Article  CAS  PubMed  Google Scholar 

  16. Thomsen T, Kewitz H (1990) Selective inhibition of human acetylcholinesterase by galanthamine in vitro and in vivo. Life Sci 46(21):1553–1558

    Article  CAS  PubMed  Google Scholar 

  17. Wang BS, Wang H, Wei ZH, Song YY, Zhang L, Chen HZ (2009) Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer’s disease: an updated meta-analysis. J Neural Transm 116(4):457–465

    Article  CAS  PubMed  Google Scholar 

  18. Sidell FR, Takafuji ET, Franz DR (eds) (1997) Medical aspects of chemical and biological warfare. Department of the Army, Office of the Surgeon General, Borden Institute, Falls Church

    Google Scholar 

  19. Gordon RK, Haigh JR, Garcia GE, Feaster SR, Riel MA, Lenz DE, Aisen PS, Doctor BP (2005) Oral administration of pyridostigmine bromide and huperzine A protects human whole blood cholinesterases from ex vivo exposure to soman. Chem Biol Interact 157–158:239–246

    Article  PubMed  Google Scholar 

  20. Zhang Y, Huo M, Zhou J, Xie S (2010) PKSolver: an add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Methods Progr Biomed 99(3):306–314

    Article  Google Scholar 

  21. Adams NL (1990) The intramuscular lethality of soman (GD) in the cynomolgus monkey. USAMRICD-TR-90-6, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD, AD A224887

  22. von Bredow J, Corcoran K, Maitland G, Kaminskis A, Adams N, Wade J (1991) Efficacy evaluation of physostigmine and anticholinergic adjuncts as a pretreatment for nerve agent intoxication. Fundam Appl Toxicol 17(4):782–789

    Article  Google Scholar 

  23. Maelicke A, Schrattenholz A, Samochocki M, Radina M, Albuquerque EX (2000) Allosterically potentiating ligands of nicotinic receptors as a treatment strategy for Alzheimer’s disease. Behav Brain Res 113(1–2):199–206

    Article  CAS  PubMed  Google Scholar 

  24. Schilstrom B, Ivanov VB, Wiker C, Svensson TH (2007) Galantamine enhances dopaminergic neurotransmission in vivo via allosteric potentiation of nicotinic acetylcholine receptors. Neuropsychopharmacology 32(1):43–53

    Article  PubMed  Google Scholar 

  25. Maelicke A, Samochocki M, Jostock R, Fehrenbacher A, Ludwig J, Albuquerque EX, Zerlin M (2001) Allosteric sensitization of nicotinic receptors by galantamine, a new treatment strategy for Alzheimer’s disease. Biol Psychiatry 49(3):279–288

    Article  CAS  PubMed  Google Scholar 

  26. Wang D, Noda Y, Zhou Y, Mouri A, Mizoguchi H, Nitta A, Chen W, Nabeshima T (2007) The allosteric potentiation of nicotinic acetylcholine receptors by galantamine ameliorates the cognitive dysfunction in beta amyloid25-35 I.c.v.-injected mice: involvement of dopaminergic systems. Neuropsychopharmacology 32(1):1261–1271

    Article  CAS  PubMed  Google Scholar 

  27. Woodruff-Pak DS, Vogel RW 3rd, Wenk GL (2001) Galantamine: effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning. Proc Natl Acad Sci USA 98(4):2089–2094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang H, Tang XC (1998) Anticholinesterase effects of huperzine A, E2020 and tacrine in rats. Acta Pharmacol Sin 19:27–30

    CAS  Google Scholar 

  29. Cheng DH, Tang XC (1998) Comparative studies of huperzine A, E2020, and tacrine on behavior and cholinesterase activities. Pharmacol Biochem Behav 60:377–386

    Article  CAS  PubMed  Google Scholar 

  30. TangXC, KindelGH, Kozikowski AP, Hanin I (1994) Comparison of the effects ofnatural and synthetic huperzine-A on rat brain cholinergic function in vitro and in vivo. J Ethnopharmacol 44:147–155

    Article  Google Scholar 

  31. Tang XC, DeSarno P, Sugaya K, Giacobini E (1989) Effect of Huperzine A, a new cholinesterase inhibitor, on the central cholinergic systemof the rat. J Neurosci Res 24:276–285

    Article  CAS  PubMed  Google Scholar 

  32. Harris LW, Talbot BG, Lennox WJ, Anderson DR, Solana RP (1991) Physostigmine (alone and together with adjunct) pretreatment against soman, sarin, tabun and VX intoxication. Drug Chem Toxicol 14(3):265–281

    Article  CAS  PubMed  Google Scholar 

  33. Lennox WJ, Harris LW, Talbot BG, Anderson DR (1985) Relationship between reversible acetylcholinesterase inhibition and efficacy against soman lethality. Life Sci 37(9):793–798

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors sincerely thank Andrew Bonvillain, David Kahler, and Rachel Gray for technical support.

Funding

This research was supported by the Defense Threat Reduction Agency—Joint Science and Technology Office, Medical S&T Division.

Author information

Authors and Affiliations

  1. Department of Psychology, University of Colorado Denver, Denver, CO, 80217, USA

    Lindsey R. Hamilton

  2. Neurobehavioral Toxicology Branch, Analytical Toxicology Division, United States Army Medical Research Institute of Chemical Defense (USAMRICD), 2900 Ricketts Point Rd, Aberdeen Proving Ground, Aberdeen, MD, 21010, USA

    Todd M. Myers

  3. Departments of Neurology Beth Israel Deaconess Medical Center, Massachusetts General Hospital, Harvard Medical School, Consortia for Improving Medicine with Innovation and Technology, 125 Nashua Street, 3rd Floor, Boston, MA, 02114, USA

    Steven C. Schachter

Authors
  1. Lindsey R. Hamilton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Steven C. Schachter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Todd M. Myers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Steven C. Schachter.

Ethics declarations

Conflict of interest

Dr. Schachter is inventor on a patent for the use of huperzine for treatment of epilepsy, which is licensed by Harvard Medical School to Biscayne Pharmaceuticals, Inc., in which he holds less than 5% equity and for which he serves as chair of the scientific advisory board. The remaining authors have no conflicts of interest.

Disclaimer

The views expressed in this article are those of the authors and do not reflect the official policy of the Department of Army, Department of Defense, or the U.S. Government.

Ethical Approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hamilton, L.R., Schachter, S.C. & Myers, T.M. Time Course, Behavioral Safety, and Protective Efficacy of Centrally Active Reversible Acetylcholinesterase Inhibitors in Cynomolgus Macaques. Neurochem Res 42, 1962–1971 (2017). https://doi.org/10.1007/s11064-016-2120-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-016-2120-9

Keywords

Search

Navigation