Study identifies potential pathway to improve memory in neurodegenerative diseases

Research spanning more than twenty years has led to the Neurochemistry and Neurodegeneration group of the UPV/EHU led by Dr. Rafael Rodríguez-Puertas has identified a promising avenue for the development of new therapies that improve memory in cases of cognitive impairment in neurodegenerative diseases such as Alzheimer’s and Parkinson’s. . The research conducted by Dr. Marta Moreno-Rodríguez in the UPV/EHU group showed that neurotransmitter receptors in the cannabinoid family and certain choline-containing lipids in the brain contribute to cognitive improvement in rats.

The researcher Rodríguez-Puertas explained that “analyses carried out over the years on a very large sample of brain tissue from autopsies of patients who were at different stages of the disease, intriguingly allowed us to see that when the first clinical symptoms of With the onset of Alzheimer’s disease, damage is found in the area initially affected in patients and is caused by one of the interneuronal transmission systems, the cholinergic system (which controls memory and learning and acetylcholine used as a neurotransmitter); In contrast, we saw that another neurotransmission system, the cannabinoid system, increases.” The team also found that as the disease progresses, the cannabinoid system also becomes damaged: “It’s as if this cannabinoid system has an initial protective response to the damage of the cholinergic system and tries to protect the brain,” he said. “It is therefore a therapeutic target that needs to be responded to.”

After testing the effect of the drug WIN55.212-2, which interacts with cannabinoid receptors, on rodents in the early stages of the disease, the team found “that they behaved in the same way as people without brain damage: they learned and remembered spatial orientation in the same way,” explains Marta Moreno. “You could say that the drug somehow reversed the damage or protected the brain.”

A new technique to identify and localize lipids in the brain

The research group was able to understand the mechanism of this cognitive improvement ‘by using a new technique developed and refined by the UPV/EHU research group that allows the identification and anatomical localization of lipids in the brain. we saw that after treatment the activity of the cannabinoid system was increased and also that there was an increase in the activity of the patient’s cholinergic neuronal receptors that were damaged, and also that there was an increase in the synthesis of certain; lipids containing choline, the precursors of acetylcholine, a neurotransmitter that regulates memory and learning in the brain,” explains Rafael Rodríguez. In other words: “It was observed that the cannabinoid receptors were activated and that acetylcholine levels in the brain increased were. The drug restored the cholinergic system and improved memory,” Moreno added.

Rafael Rodríguez believes that “this molecule could become a drug to treat the symptoms of dementia, at least during the initial stages of the disease, because we have already seen that the body itself, physiologically speaking, tries to do something similar”. “With these pharmacological treatments we could help enhance that effect, or perhaps even use a mixed treatment of cannabinoid drugs with acetylcholine precursors,” he suggested.

Looking for similar molecules to move forward with clinical trials

Although the results of the tests on rodents were promising, and the next step would be to study their toxicity and move on to clinical testing on humans, the research team has encountered the obstacle that the molecule is free to use. In other words, ‘it is a synthesis molecule that is widely used in experiments; we did not synthesize it ourselves. It is not a molecule that can be exploited by any particular pharmaceutical company. Toxicology studies and clinical trials represent a major investment for the pharmaceutical industry. industry and this molecule does not offer them the possibility of future commercial exploitation”; therefore they are now working to find and synthesize molecules similar to WIN55.212-2 that could be of interest to the pharmaceutical industry and thus pave the way for the clinical study of this new therapeutic pathway. To this end, they collaborate with CIC bioGUNE and the University of Vigo.

Additional information

This study is the result of many years of continuous work and of researcher Marta Moreno-Rodríguez’s dissertation, written under the supervision of Rafael Rodríguez-Puertas, a permanent doctoral researcher and leader of the Neurochemistry and Neurodegeneration research of the UPV/EHU. group. Marta Moreno currently works at the Barrow Neurological Institute in Arizona (USA).

The tissue samples analyzed over the years came from the Basque Biobank, the Central University Hospital of Asturias and the Barrow Neurological Institute (USA).