A groundbreaking study from the University of the Basque Country (UPV/EHU) has identified a potential therapeutic approach for improving memory in the early stages of dementia. The research, led by Dr. Rafael Rodríguez-Puertas and Dr. Marta Moreno-Rodríguez, demonstrates how the drug WIN55.212-2 could protect the brain and reverse cognitive damage associated with neurodegenerative diseases, particularly Alzheimer’s disease. The findings were published in Neurochemistry and Neurodegeneration.
The UPV/EHU study uncovers how the drug interacts with the brain’s cannabinoid neurotransmitter system to stimulate the cholinergic system, which plays a crucial role in memory and learning. By activating cannabinoid receptors, WIN55.212-2 increases the production of acetylcholine, a neurotransmitter essential for cognitive function. This mechanism of action offers promising prospects for treating cognitive impairment in conditions such as Alzheimer’s and Parkinson’s diseases.
Dr. Rodríguez-Puertas, head of the Neurochemistry and Neurodegeneration group, explained that the team’s research spans over 20 years and builds on previous studies of brain tissue samples from patients at various stages of dementia. Their analysis revealed that in the early stages of Alzheimer’s, damage occurs to the cholinergic system, which regulates memory. Interestingly, they also observed that the cannabinoid system increases as a protective response to this damage.
“The cannabinoid system appears to serve as an initial defense mechanism against the deterioration of the cholinergic system,” said Rodríguez-Puertas. “This suggests that targeting the cannabinoid system could be an effective therapeutic strategy.”
The researchers tested WIN55.212-2 on rodents in the early stages of dementia and found promising results. “The rodents exhibited cognitive behavior similar to healthy animals, successfully learning and remembering spatial orientation,” said Dr. Marta Moreno-Rodríguez. “In essence, the drug seemed to reverse the cognitive damage or provide brain protection.”
One of the major innovations of this study is the development of a novel technique for identifying and localizing lipids in the brain, which helped clarify how WIN55.212-2 works. Using this technique, the team found that treatment with the drug enhanced cannabinoid system activity, restored damaged cholinergic receptors, and increased the production of choline-containing lipids, which are precursors to acetylcholine.
“The activation of cannabinoid receptors and the subsequent increase in acetylcholine levels helped restore the cholinergic system, leading to improved memory function in the rodents,” explained Dr. Rodríguez-Puertas.
The researchers believe that this discovery opens up a potential new drug for treating dementia, especially in its early stages. “Our findings suggest that cannabinoid-based treatments could help enhance the brain’s natural protective mechanisms,” said Rodríguez-Puertas. “In the future, combining cannabinoid drugs with acetylcholine precursors might offer a powerful approach for managing dementia.”
However, while the results in rodents are promising, there are challenges ahead. The WIN55.212-2 molecule, although effective, is a widely used experimental compound that is not commercially exploited. As such, it is not a viable candidate for clinical trials without significant investment. The research team is now focused on identifying and synthesizing similar molecules that could be of interest to the pharmaceutical industry, facilitating the path to clinical testing.
“To move forward with clinical trials, we need molecules that can be commercially developed and manufactured,” said Rodríguez-Puertas. “We are working with partners such as CIC bioGUNE and the University of Vigo to find suitable alternatives.”
The research, which builds on the PhD thesis of Dr. Marta Moreno-Rodríguez, involved extensive analysis of brain tissue samples from the Basque Biobank, the Central University Hospital of Asturias, and the Barrow Neurological Institute in the United States.
With the potential to improve cognitive health in the early stages of dementia, this study offers new hope for the treatment of neurodegenerative diseases, and marks a significant step forward in the quest for effective therapies for Alzheimer’s and similar conditions.
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