Researchers have found that the marketed Alzheimer’s disease drug, memantine, could also help hold back progression of Huntington’s disease. Studies showed that while normal synaptic activity in nerve cells protects the brain from misfolded proteins in Huntington’s disease, excessive extrasynaptic activity boosts the effects of the aberrant protein aggregates.
The research is published in Nature Medicine in a paper titled “Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin.”
Led by Stuart Lipton, M.D., Ph.D., at the Burnham Institute for Medical Research, collaborators at Burnham, the University of British Columbia’s Centre for Molecular Medicine and Therapeutics, and the University of California, San Diego investigated the link between Huntington’s disease, the excessive extrasynaptic excitatory brain activity seen in the disease, and the formation of abnormal huntingtin aggregate in the brain. They observed that even though normal synaptic receptor activity rendered nerve cells more resistant to the mutant protein, excessive extrasynaptic activity contributed to increased cell death.
When Dr. Lipton’s team administered the NMDA glutamate receptor blocker, memantine, to a mouse model of Huntington’s disease, they found low doses blocked NMDA receptors found outside the synapse and reduced the severity of the disease in the mice. Benefits included reduced neuronal death and behavioral deficits.
Conversely a high dose of memantine that blocked NMDA receptors both on the synapse and outside the synapse increased the number of huntingtin protein clumps and worsened the disease. International human trials with memantine are now being planned in Huntington’s disease, following positive results from a small-scale human study.
“We show here, for the first time, that electrical activity controls protein folding, and if you have a drug that can adjust the electrical activity to the correct levels, you can protect against misfolding,” states Dr. Lipton, director of the Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research at Burnham.
Memantine is an NMDA glutamate receptor blocker, developed by German company, Merz, and now marketed worldwide by various licensees. The drug was first sanctioned for the treatment of Alzheimer’s disease in 2002.