Ampakines Reverse Memory Loss in Huntington's Disease

A new study has demonstrated the extraordinary reversal of memory loss in an animal model of Huntington's disease using a unique class of agents known as ampakines. The research was conducted in laboratory mice harboring the genetic mutation found in humans that is responsible for Huntington's disease.

All neurodegenerative diseases share two characteristics: Prognosis is universally poor, and current treatments work marginally at best. Drug development in this area has focused on neuroprotection and upregulation of critical neurotransmitters, but to date no experimental treatments have noticeably outshone the standard of care.

The study was conducted by Prof. Gary Lynch from the University of California, Irvine (USA) in mice harboring the genetic mutation found in humans that is responsible for Huntington's disease. Treating mice with the ampakine molecule CX929, a compound developed by Cortex Pharmaceuticals (Irvine, CA, USA), produced dramatic improvements in the ability of lab animals to create and store memories. These groundbreaking findings were published in March 2009 in the online version of the prestigious journal Proceedings of the National Academy of Sciences (PNAS).

Previous studies by Prof. Lynch have demonstrated that ampakines can increase a growth factor in the brain; know as brain-derived neurotrophic factor (BDNF), essential for maintaining health and the survival of brain tissue. In Huntington's disease mice, the levels of BDNF in the brain are reduced. Prof. Lynch assessed whether ampakine-mediated upregulation of BDNF could restore the deficits in learning in a mouse model of Huntington's disease. The researchers discovered that twice-daily injections of the ampakine normalized BDNF levels, and restored the molecular aspects underlying memory processes such as actin polymerization in dendritic spines, and a process called long-term potentiation (LTP) in eight-week-old mice. Comparable results were obtained in 16-week-old mice with more severe LTP deficits. Treatment with the ampakine did not produce overt side effects in the mice.

Actin polymerization is a key process in the formation of dendrites, which are protrusions emanating from nerve cells that receive signals from other cells. LTP refers to a long-lasting improvement in communication between two adjacent neurons that are simultaneously stimulated. LTP is considered a critical factor in the ability to learn and form memories.

Ampakines are an entirely new class of small-molecule drugs whose effects are possibly best described as "memory amplifiers." Ampakines bind allosterically to the protein on brain cells called the AMPA receptor, which mediates rapid synaptic transmission. Ampakines enhance the activity of the AMPA receptor, causing a rapid change in ion flow within the neuron, which in turn triggers synaptic changes that support memory and cognition.

Huntington's disease is one of a series of progressive, hereditary brain-destroying diseases that result in gradual loss of voluntary muscle control, deterioration of memory and cognition, and severe behavioral disturbances. Memory impairments include altered organization, generally slowed information processing, and the loss of executive function--the ability to plan, think abstractly, and to multi-task. These cognitive symptoms most resemble dementia.

Huntington's affects 30,000 individuals in the United States, with another 150,000 at risk due to a faulty gene known as the "Huntingtin gene" located on chromosome 4. This gene contains repeat nucleotide sequences, cytosine-adenine-guanine [CAG], which code for the amino acid glutamine and which together generate polyglutamine. Normal individuals have fewer than 27 repeats, therefore fewer than 27 glutamines in the relevant peptide. Huntington's patients have many more of these repeats, typically greater than 39 repeat units.

The abnormally long amino acid causes the death of neurons that lead to the classic Huntington's symptoms, but it does not do so directly. It is believed that the brain growth factor, BDNF, protects neurons and regulates the formation of new brain cells. The mutant Huntington's protein causes underexpression of the protective BDNF, which leads progressive death of key neurons in specific areas of the brain.

"We know that BDNF plays an essential role in maintaining the health of the brain," commented Prof. Lynch, who is also a scientific founder of Cortex Pharmaceuticals. "Our studies now demonstrate that we can restore levels of BDNF by treating mice with an Ampakine, which reverses the memory impairments."

Several ampakine molecules are currently in human clinical trials. The most advanced, CX717 is in a phase IIa study in Alzheimer's disease, and CX1739 is in phase II for sleep apnea. Other ampakines are being evaluated in phase II trials for attention deficit hyperactivity disorder, schizophrenia, and depression.

Related Links:
University of California, Irvine
Cortex Pharmaceuticals