Medications for Down syndrome?
Drugs that stimulate the activity of the neurotransmitter norepinephrine in the brain soften the manifestations of cognitive impairment in genetically modified mice with Down syndrome. The results obtained by Stanford University scientists working under the leadership of Ahmad Salehi were published on November 18 in the on-line version of the journal Science Translational Medicine in the article "Cognitive Enhancement Therapy for a Model of Down Syndrome".
Several existing drugs have effects similar to those of norepinephrine, or increase the activity of this neurotransmitter, but none of them has been tested as a treatment for Down syndrome.
This study reflects a growing level of understanding of the brain systems whose malfunction causes cognitive impairment in people with Down syndrome, and improving methods for developing potential treatments for this disease.
The cause of the development of Down syndrome, diagnosed annually in 5,000 newborns in the United States alone, is trisomy of the 21st chromosome. In addition to their characteristic appearance, Down syndrome causes a sharp weakening of intelligence, while the vast majority of them develop symptoms of Alzheimer's disease already in middle age. There are currently no methods for treating cognitive function disorders in Down syndrome, but recently researchers working with an animal model of the disease have identified several potentially effective drugs.
The object of the authors' research was a line of mice with a doubling of the segment of the 16th chromosome containing more than 100 genes that are analogs of genes whose functions are disrupted by doubling of the 21st human chromosome. Such animals exhibit behavioral disorders and brain abnormalities similar to the symptoms of Down's disease in humans. For example, mutant mice, as well as people with Down syndrome, have pronounced abnormalities of the hippocampus, a region that plays an important role in learning and memorization processes.
The results obtained help to better understand the disorders observed in Down syndrome and demonstrate the possibility of drug suppression of their manifestations. The study of the animal brain showed serious disorders in the area of the brain, the so-called blue spot, which provides the hippocampus with norepinephrine. It is believed that this neurotransmitter contributes to the integration of information coming from different sensory organs in the hippocampus.
The experimental mice had problems with performing memorization tasks, impossible without such integration. For example, the researchers trained normal and experimental mice to be afraid of a certain sound, associating it with an electric shock. Hearing this sound, both mice froze, but ordinary mice also froze when placing a box, which they remembered as associated with both sound and electric shock. Mutant mice did not pass this test, which is based on the so-called "learning in context" phenomenon. According to Salehi, children with Down syndrome behave very similarly. If you ask such a child to enter the room through the door and find a toy, prompting its color, he will find it without much difficulty. However, if the next time the child enters the room through another door, and you do not tell him the color of the toy, he will spend a lot of time looking for it.
During the experiments, the drug l-threo-dihydroxyphenylserine (l-threo-dihydroxyphenylserine, l-DOPS), converted by brain cells into norepinephrine, normalized the behavior of experimental animals for several hours, which returned to their previous state with a decrease in the level of the neurotransmitter.
A similar effect was exerted by the drug xamoterol, which activates a certain type of norepinephrine receptors. However, xamoterol is a potent agent used to treat heart failure, so its use in Down syndrome is impractical.
L-DOPS was originally developed in Japan as a remedy for Parkinson's disease. Currently, it is presented on the Asian market as a drug for the treatment of orthostatic hypotension (a sharp, up to fainting, decrease in pressure when moving from a lying position to a standing position and even sitting) and at the same time is undergoing clinical trials in the United States as a cure for orthostatic hypotension, fibromyalgia and hyperactivity and attention deficit syndrome. There are also drugs on the pharmacological market that increase the activity of norepinephrine by blocking its reabsorption. Salehi plans to test on mutant mice one of such drugs, atomoxetine (atomoxetine, Strattera), which has received official approval in the United States as a treatment for hyperactivity and attention deficit disorder.
In addition to compounds that increase the activity of norepinephrine, several other existing drugs are being tested as agents for the treatment of cognitive impairment. For example, the drug memantine, used to treat Alzheimer's disease, also improves cognitive functions in animals with simulated Down syndrome. Memantine is currently undergoing clinical trials involving patients with Down syndrome. Small-scale clinical trials involving people with Down syndrome of another drug, donepezil (Aricept), also used to treat Alzheimer's disease, have shown mixed results.
According to Frances Wiseman from University College London, the treatment of a complex of intellectual disabilities associated with Down syndrome is likely to require multicomponent therapy.
Experts note that it is very difficult to organize large-scale clinical trials of such drugs, since for this it is necessary to develop reliable criteria for assessing the degree of improvement in the ability to learn and memorize, especially those suffering from Down syndrome. In addition, it is quite difficult to attract the necessary number of participants from a relatively small population of sick people to obtain statistically reliable results.
Salehi warns parents against independent attempts to treat children with Down syndrome before the drugs are tested in large clinical trials conducted in accordance with the principles of evidence-based medicine. He emphasizes that the positive effect on the mental development of experimental mice does not guarantee a similar effect when taking drugs by humans.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Technology Review: Potential Treatment for Down Syndrome.
23.11.2009