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[+]-Huperzine A Protects Against Soman Toxicity in Guinea Pigs

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Abstract

The chemical warfare nerve agent (CWNA) soman irreversibly inhibits acetylcholinesterase (AChE) causing seizure, neuropathology and neurobehavioral deficits. Pyridostigmine bromide (PB), the currently approved pretreatment for soman, is a reversible AChE inhibitor that does not cross the blood–brain barrier (BBB) to protect against central nervous system damage. [−]-Huperzine A, a natural reversible AChE inhibitor, rapidly passes through the BBB and has numerous neuroprotective properties that are beneficial for protection against soman. However, [−]-Huperzine A is toxic at higher doses due to potent AChE inhibition which limits the utilization of its neuroprotective properties. [+]-Huperzine A, a synthetic stereoisomer of [−]-Huperzine A and a weak inhibitor of AChE, is non-toxic. In this study, we evaluated the efficacy of [+]-Huperzine A for protection against soman toxicity in guinea pigs. Pretreatments with [+]-Huperzine A, i.m., significantly increased the survival rate in a dose-dependent manner against 1.2× LD50 soman exposures. Behavioral signs of soman toxicity were significantly reduced in 20 and 40 mg/kg [+]-Huperzine A treated animals at 4 and 24 h compared to vehicle and PB controls. Electroencephalogram (EEG) power spectral analysis showed that [+]-Huperzine A significantly reduces soman-induced seizure compared to PB. [+]-Huperzine A (40 mg/kg) preserved higher blood and brain AChE activity compared to PB in soman exposed animals. These data suggest that [+]-Huperzine A protects against soman toxicity stronger than PB and warrant further development as a potent medical countermeasure against CWNA poisoning.

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Abbreviations

AChE:

Acetylcholinesterase

BBB:

Blood-brain barrier

BChE:

Butyrylcholinesterase

CNS:

Central nervous system

CWNA:

Chemical warfare nerve agent

DTNB, 5′:

5′-Dithiobis(2-nitrobenzoic acid)

EEG:

Electroencephalogram

Iso-OMPA:

Tetra monoisopropyl pyrophosphortetramide

LD50 :

50% lethal dose

NMDA:

N-methyl-d-aspartate

PB:

Pyridostigmine bromide

2-PAM:

2-Pralidoxime

Soman:

O-pinacolyl methylphosphonofluoridate

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Acknowledgments

This work was supported by funding from Defense Threat Reduction Agency (DTRA) Grant #1.E0003_08_WR_C. The technical assistance from Collaborative Research Facility, USAMRICD is greatly acknowledged.

Conflict of interest

The authors have no financial or personal conflicts of interest.

Author information

Authors and Affiliations

  1. Blast-Induced Neurotrauma Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD, 20910, USA

    Ying Wang, Yanling Wei, Samuel Oguntayo, Bhupendra P. Doctor & Madhusoodana P. Nambiar

  2. Collaborative Research Facility, US Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, Aberdeen, MD, 21010, USA

    Neil Jensen

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  1. Ying Wang
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  2. Yanling Wei
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  3. Samuel Oguntayo
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  4. Neil Jensen
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  5. Bhupendra P. Doctor
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  6. Madhusoodana P. Nambiar
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Correspondence to Madhusoodana P. Nambiar.

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Disclosure: The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Army, the Navy, or the Department of Defense, USA.

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Wang, Y., Wei, Y., Oguntayo, S. et al. [+]-Huperzine A Protects Against Soman Toxicity in Guinea Pigs. Neurochem Res 36, 2381–2390 (2011). https://doi.org/10.1007/s11064-011-0564-5

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  • DOI: https://doi.org/10.1007/s11064-011-0564-5

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