An Ampakine Upregulates BDNF

An ampakine, a modulator of glutamate receptors, reduced memory and learning problems in HD mice.

Dr. Gary Lynch and colleagues have been researching memory deficits in the HD knock-in mouse and investigating whether a class of drugs called ampakines could ameliorate them.   In their latest study, an ampakine upregulated BDNF and improved memory deficits in the HD knock-in mouse model.

Brain derived neurotrophic factor (BDNF)  is downregulated in the brains of HD patients and in mouse models of the disease.  BDNF protects neurons and facilitates the growth of new ones.  It also plays an important role in long term memory.  BDNF signaling is part of a system of synaptic changes that encode long term memories.   It promotes theta burst stimulation which in turn induces actin polymerization which stabilizes long term potentiation.  Long term potentiation involves a change in the electrical properties of neurons and is a necessary component of memory.

Dr Lynch and colleagues have found that actin polymerization and long term potentiation are both impaired in the HD knock-in mice.  It seems likely then that the decrease in BDNF in Huntington’s Disease could be responsible for the memory problems that HD patients experience.  BDNF does not cross the blood barrier so a therapeutic strategy to address the problem would involve discovering or developing a drug that increases it.

SSRI (serotonin reuptake inhibitor) antidepressants are known to increase BDNF and one of them, citalopram (Celexa), is currently in clinical trials to see if it improves cognition.  Another possible drug is an ampakine.  Ampakines are a class of drugs which bind to AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) type glutmate receptors which mediate synaptic transmission in the central nervous system.

The researchers used an ampakine that has a short half life (the time it takes for a drug to lose half of its pharmacological activity).  A short half life can mean fewer side effects but lesser effectiveness.  In this case, the ampakine stimulated BDNF which has a much longer half life.   They found that twice daily injections of the ampakine upregulated BDNF, normalized actin polymerization, and stabilized long term potentiation in the knock in mice.  Memory deficits were rescued in while motor behavior remained unchanged.

 

In this study, the focus was on memory and other symptoms in the mice.  Further studies are needed to determine if ampakines have a neuroprotective effect and actually treat the disease itself.  This is a possibility, but even if they do not, a treatment to improve cognition in HD patients is not currently available and would be a welcome addition to symptomatic treatments. 

The ampakine used in the study is owned by Cortex Pharmaceuticals which was co-founded by Dr. Lynch.  Cortex has a different ampakine currently in a Phase IIb clinical trial for Alzheimer’s and a portfolio of s variety of structurally different ampakines.   Some of their other ampakines are in clinical trials for depression, ADHD, and respiratory distress.  If ampakines continue to look promising for HD, the information gained from trials with other diseases can speed the time necessary to move through the drug pipeline for Huntington’s.  
 

Marsha L. Miller, Ph.D.

“Brain-derived neurotrophic factor (BDNF), is reduced in Huntington’s disease. We know that BDNF plays an essential role in maintaining the health of the brain and our studies now demonstrate that we can restore levels of BDNF by treating mice with an AMPAKINE, which reverses the memory impairments.” - Dr. Gary Lynch

Up-regulating BDNF with an ampakine rescues synaptic plasticity and memory in Huntington's disease knockin mice

Danielle A.Simmons, Christopher S. Rex, Vijay Pandyarajan, Vidm Fedulov, Christine M. Gall, and Gary Lynch

abstract

Cognitive problems occur in asymptomatic gene carriers of Huntington's disease (HD), and mouse models of the disease exhibit impaired learning and substantial deficits in the cytoskeletal changes that stabilize long-term potentiation (LTP). The latter effects may be related to the decreased production of brain-derived neurotrophic factor (BDNF) associated with the HD mutation. This study asked whether up-regulating endogenous BDNF levels with an ampakine, a positive modulator of AMPA-type glutamate receptors, rescues plasticity and reduces learning problems in HD (CAG140) mice. Twice-daily injections of a short half-life ampakine normalized BDNF levels, activity-driven actin polymerization in dendritic spines, and LTP stabilization in 8-week-old mutants. Comparable results were obtained in 16-week-old HD mice with more severe LTP deficits. Ampakine treatments had no measurable effect on the decreased locomotor activity observed in the mutants but offset their impairments in long-term memory. Given that ampakines are well tolerated in clinical trials and were effective in this study after brief exposures, these results suggest a novel strategy for chronic treatment of the cognitive difficulties that occur in the early stages of HD.

press release: Studies in Animals Demonstrate AMPAKINE Molecules Reverse Memory Loss in Huntington’s Disease

Irvine, CA (March 6, 2009) — Cortex Pharmaceuticals, Inc. (NYSE Alternext US (COR)) announced that preclinical studies from the laboratory of Professor Gary Lynch at the University of California Irvine, one of the scientific founders of the company, demonstrated that AMPAKINE? molecules show promise in the treatment of memory loss in Huntington’s disease. The studies were performed in mice harboring the genetic mutation found in humans that is responsible for Huntington’s disease. The related results demonstrated that treating mice with CX929, a High Impact AMPAKINE, produced dramatic increases in the brain’s chemical processes for creating and storing memories. These studies were published in the early online version of the prestigious, peer-reviewed journal, Proceedings of the National Academy of Sciences (PNAS).

Huntington's disease is a progressive, hereditary brain disease that affects men and women alike, and affects 30,000 patients in the U.S., with another 150,000 at risk. It is caused by the death of specific brain cells and is characterized by the gradual development of involuntary muscle movements, progressive deterioration of cognitive processes and memory (dementia), and severe behavioral disturbances. The memory impairments include altered organization, generally slowed processing of information by the brain, and executive function – that is, the ability to plan, abstract thinking and multi-tasking.

“One protein in particular, brain-derived neurotrophic factor (BDNF), is reduced in Huntington’s disease. We know that BDNF plays an essential role in maintaining the health of the brain,” commented Professor Lynch. “And our studies now demonstrate that we can restore levels of BDNF by treating mice with an AMPAKINE, which reverses the memory impairments.”

Mark A. Varney, President and CEO stated that, “Professor Lynch’s studies in mice support the rationale for Cortex to develop AMPAKINE molecules to address the memory deficits in patients suffering from Huntington’s disease. Also, the link to BDNF may play an important role in other neurodegenerative diseases such, as Alzheimer’s Disease.”

Proceedings of the National Academy of Sciences of the United States 2009 Mar 24;106(12):4906-11.