Hormone therapy for trisomy
Gonadoliberin restored cognitive function in people with Down syndrome
Alina Suleymanova, PCR.news
Down syndrome (DM) is characterized by mental retardation, impaired sense of smell and puberty. The third chromosome (trisomy) in 21 pairs, which causes the development of pathology, is often found in one newborn out of 800. However, there is still no treatment that compensates for cognitive and olfactory deficits in patients with DM.
It is curious that partly similar symptoms — impaired sense of smell and immaturity of the genitals — are observed in Kallman syndrome and are associated with a deterioration in the secretion of gonadoliberin (gonadotropin-releasing hormone, GnRH) by hypothalamic neurons. In addition, the processes of GnRH-expressing neurons reach areas of the brain whose activity provides cognitive functions. The role of gonadoliberin interested an international team led by scientists from the University of Lille in France.
In the new work, the researchers tried to find out whether disorders in DM are associated with the maturation of the gonadoliberin system. At the first stage, they studied age-related changes in Ts65Dn mice, whose cells carry the third chromosome in the 16th pair, homologous to the 21st pair in the human genome. It turned out that after puberty, such mice coped worse with the task of recognizing odors and objects, and before puberty, their results were comparable to wild-type relatives. Scientists also found underdevelopment of the sexual glands in males and ovulation disorders in females, which generally corresponded to the symptoms in patients with DM.
Developmental abnormalities in Ts65Dn mice were accompanied by the loss of gonadoliberin-secreting neurons and their processes in the hypothalamus and beyond, including the hippocampus and cortex. This affected the production of gonadoliberin — its blood level decreased compared to the wild type.
The expression of the gonadoliberin gene in neurons is regulated by a complex network of microRNAs; some of them are encoded by the loci of chromosome 16 in mice and, accordingly, chromosome 21 in humans. Their influence manifests itself even before puberty. Scientists have found that the synthesis of microRNAs in neurons, especially miR-200, is already disrupted in young Ts65Dn mice. When its expression was increased by introducing a vector into the hypothalamus, the sense of smell and memory improved in adult mice, and the proportion of neurons with active Otx2 increased, which controls the change of critical periods of brain maturation. The restorative effect of miR-200 overexpression could be related to the effect on the expression of target genes involved in myelination and synaptic transmission, both in the hypothalamus and in the hippocampus.
To make sure that the improvement is really caused by the replenishment of gonadoliberin, the researchers conducted a series of manipulations. First, Ts65Dn mice were injected with normal hypothalamic cells of newborn rodents, which neutralized the violation of olfaction and cognitive functions. Then the drug Lutrelef was injected – pure gonadoliberin, which doctors use to treat infertility. The drug entered the blood of mice through pumps sewn into the skin; one group of animals was injected with the drug constantly, the second — impulsively for 10 minutes every 3 hours. The pulse injection, simulating the natural production of the hormone, proved to be effective.
Inspired by the results, the scientists conducted a small pilot study on humans. The experiment involved seven men with Down syndrome aged 20 to 50 years. For 6 months, patients received gonadoliberin impulsively through a pump attached to the forearm.
As a result, cognitive indicators measured by the Montreal Cognitive Scale increased by 10-30% in six out of seven patients. In particular, attention, visual perception and episodic memory improved. According to the MRI results, the improvement affected the functional connections between the brain regions, the difference with the control became smaller. No significant side effects were noted. However, the treatment did not improve the patients' sense of smell.
The authors of the work consider pulse therapy with gonadoliberin to be a promising method of improving cognitive abilities in people with diabetes. They are planning a larger study involving female patients. According to scientists, gonadoliberin may be useful in other neurodegenerative diseases, such as Alzheimer's disease.
Article by Manfredi-Lozano et al. GnRH replacement rescues cognition in Down syndrome is published in the journal Science.
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