Ampakines Reverse Memory Loss In Animal Model Of Huntington's Disease
Now, a study conducted by Prof. Gary Lynch at the University of California, Irvine, has demonstrated the remarkable reversal of memory loss in an animal model of Huntington's disease using a novel class of agents known as ampakines. The experiments were conducted 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 Irvine-based Cortex Pharmaceuticals, produced dramatic improvements in the ability of test animals to create and store memories. These landmark results were published 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, or BNDF, that is essential for maintaining health and the survival of brain tissue. In Huntington's disease mice, the levels of BNDF in the brain are reduced. Prof. Lynch tested whether ampakine-mediated up-regulation of BDNF could restore the deficits in learning in a mouse model of Huntington's disease. The researchers found 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, or LTP in eight-week-old mice. Comparable results were obtained in sixteen-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 perhaps 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 handful 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 Americans, 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), that code for the amino acid glutamine and which together generate polyglutamine. Normal individuals have fewer than 27 repeats, hence 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 a brain growth factor, BDNF, protects neurons and regulates the formation of new brain cells. The mutant Huntington's protein causes under-expression 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 Professor 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 2a study in Alzheimer's disease, and CX1739 is in Phase 2 for sleep apnea. Other ampakines are being tested in Phase 2 trials for attention deficit hyperactivity disorder, schizophrenia, and depression.
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