Huperzine A and Alzheimer's disease

Extracts of the club moss Huperzia serrata have been used for centuries in traditional Chinese medicine to treat conditions including inflammation, fever, and schizophrenia. Plants such as this one from the lycopod family existed as far back as 400 million years ago, according to fossil records. The plant's names in Chinese are qian ceng ta, “thousand-laid pagodas” (referring to its multileafed structure), and jin bu huan, “more valuable than gold” (Pharmacol. Biochem. Behav. 2003;75:675–86).

The plant is approved for the treatment of Alzheimer's disease in China, and is sold as a dietary supplement in the United States. The process of extraction was made publicly available in 1986 but is not patented, so neither pharmaceutical nor supplement manufacturers have thus far been willing to invest in the clinical studies that would be needed for Food and Drug Administration approval.

Rationale for Use

Huperzine A is a potent, selective, reversible inhibitor of acetylcholinesterase. In vitro studies have shown that huperzine A's acetylcholinesterase-inhibiting activity exceeds that of tacrine and galantamine, and animal studies have found that the compound has greater bioavailability and crosses the blood-brain barrier more easily than tacrine or donepezil (Curr. Med. Chem. 2000;7:355–74).

It also is selective for brain acetylcholinesterase, rather than peripheral acetylcholinesterase, which limits its potential for cholinergic adverse effects. Other properties of huperzine A include protection against oxidative stress, which is thought to be involved in the progression of Alzheimer's disease, and regulation of apoptotic proteins.

In an animal model, it also showed protective effects against transient cerebral ischemia and reperfusion (Pharmacol. Biochem. Behav. 2006;83:603–11).

Furthermore, the compound helps prevent glutamate-induced neuronal cell death, a capacity that has led to its use not only in Alzheimer's disease but also as a prophylactic agent against organophosphate nerve gases such as soman (Neurotoxicology 2002;23:1–5).

The Chinese Experience

Most of the clinical studies involving huperzine A have taken place in China. In one randomized trial at the Zhejiang Supervision and Detection Station of Drug Abuse, Zhejiang Medical University, Hangzhou, China, 103 patients with DSM III-R diagnoses of Alzheimer's disease received 200 μg of huperzine or placebo orally twice daily for 8 weeks.

On multiple evaluations including the Wechsler memory scale, Mini-Mental State Examination (MMSE), and Hasegawa dementia scale, 29 (58%) of the huperzine-treated patients showed significant improvements in memory as well as in cognitive and behavioral functions, compared with 19 (36%) of placebo-treated patients (Zhongguo Yao Li Xue Bao 1995;16:391–5). The average improvement in the huperzine-treated group on the MMSE was 3 points, compared with an improvement of 0.4 points in the placebo group.

Diarrhea, anorexia, and hyperactivity each were reported in about 10% of patients receiving both active and placebo treatment.

Another study conducted in 15 centers in China randomized 202 patients with possible or probable Alzheimer's disease initially to receive 100 μg huperzine twice daily or placebo. Dosages were adjusted up to 200 μg twice daily according to patient response.

A total of 37.8% of patients in the huperzine group improved by 4 points or more on the MMSE, compared with 10.1% in the placebo group. Improvements of 10% in activities of daily living were seen in 32.7% of those on the active treatment, compared with 17.2% of those receiving placebo. Positive effects on symptoms of depression, delusions, and repetitive activities also were seen (Zhonghua Yi Xue Za Zhi 2002;82:941–4).

The NIH Trial

In the first trial outside of China, the National Institute on Aging currently is conducting a phase II clinical trial evaluating huperzine A in doses of 200 μg or 400 μg twice a day among patients with Alzheimer's disease. The aims of the study are to determine if huperzine improves cognitive function, global clinical status, activities of daily living, and behavior, and to evaluate the tolerability of the supplement. Additionally, the study is investigating the relationship between blood cholinesterase activity and cognitive function.

In an interview, principal investigator Dr. Paul Aisen said, “We think it's a very promising treatment for Alzheimer's disease. Based on our work so far and the Chinese literature, we hope this will be more effective and better tolerated than existing treatments. We're optimistic.”

Dr. Aisen, professor of neurology and medicine and director of the memory disorders program at Georgetown University, Washington, said that he and his colleagues confirmed the compound's safety and its “excellent” cholinesterase inhibition in phase I tests. He added that laboratory tests have shown that huperzine exhibits N-methyl-d-aspartate antagonism similar to that shown by memantine, and that it appears to have some very promising neuroprotective activities.

This article was originally published by www.internalmedicinenews.com