title: [+]-Huperzine A protects against soman toxicity in guinea pigs.
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× 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.
authors.affiliation: 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.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Yanling
authors.initials: Y
authors.lastname: Wei
authors.forename: Samuel
authors.initials: S
authors.lastname: Oguntayo
authors.forename: Neil
authors.initials: N
authors.lastname: Jensen
authors.forename: Bhupendra P
authors.initials: BP
authors.lastname: Doctor
authors.forename: Madhusoodana P
authors.initials: MP
authors.lastname: Nambiar
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000470:Alkaloids / Q000627:therapeutic use*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001831:Body Temperature / Q000187:drug effects; D002619:Chemical Warfare Agents / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D006168:Guinea Pigs; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage; D011729:Pyridostigmine Bromide / Q000378:metabolism / Q000627:therapeutic use; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D012717:Sesquiterpenes / Q000627:therapeutic use*; D012999:Soman / Q000633:toxicity*; D013237:Stereoisomerism
chemical_list: D000470:Alkaloids; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D012717:Sesquiterpenes; C050426:huperzine A; D012999:Soman; D000110:Acetylcholinesterase; D011729:Pyridostigmine Bromide