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

• Published in: Neurochemical research Vol. 36; no. 12; pp. 2381 - 2390
• Main Authors: Wang, Ying, Wei, Yanling, Oguntayo, Samuel, Jensen, Neil, Doctor, Bhupendra P., Nambiar, Madhusoodana P.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.12.2011; Springer Nature B.V
• Subjects: Acetylcholinesterase - metabolism; Alkaloids - therapeutic use; Animals; Biochemistry; Biomedical and Life Sciences; Biomedicine; Blood-Brain Barrier - metabolism; Body Temperature - drug effects; Cell Biology; Chemical Warfare Agents - toxicity; Cholinesterase Inhibitors - therapeutic use; Guinea Pigs; Male; Neurochemistry; Neurology; Neuroprotective Agents - administration & dosage; Neurosciences; Original Paper; Pyridostigmine Bromide - metabolism; Pyridostigmine Bromide - therapeutic use; Seizures - chemically induced; Seizures - prevention & control; Sesquiterpenes - therapeutic use; Soman - toxicity; Stereoisomerism; Neuroprotection; Chemical warfare; Seizure; Huperzine A; Acetylcholinesterase
• ISSN: 0364-3190; 1573-6903
• DOI: 10.1007/s11064-011-0564-5

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× LD 50 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.