New drug shows neuroprotective and anti-inflammatory effects in murine models of Alzheimer's

Alzheimer's disease, the most common cause of dementia, is currently incurable. The current drugs available have very limited efficacy and only in mild stages of the disease. A team from the University of Barcelona has developed a promising therapeutic candidate to treat this disease, which affects more than 800,000 people in Spain. According to a study published in the journal ACS Pharmacology & Translational Science, the new drug has been shown to have neuroprotective and anti-inflammatory effects in two murine models of the disease. The patent for the compound has been licensed to a pharmaceutical company to start the preclinical and clinical trials necessary for its approval.

This study is led by Mercè Pallàs, from the UB's Faculty of Pharmacy and Food Sciences and the Institute of Neurosciences (UBNeuro), and Santiago Vázquez, from the same faculty and the UB Institute of Biomedicine (IBUB). The paper is also signed by UB researchers Christian Griñán Ferré, Julia Jarne Ferrer, Javier Sánchez and Sandra Codony. Experts from the Institute of Biomedical Research of Barcelona (IIBB) — a CSIC and the August Pi i Sunyer Biomedical Research Institute (IDIBAPS) centre —, the Neurodegenerative Diseases Area of the Centre for Biomedical Research Network (CIBERNED) and the University of Bonn (Germany) have also participated.

​​​​A new approach against neuroinflammation

The study is the culmination of seven years of research in which researchers have used a new approach, based on the inflammatory processes that contribute to triggering the disease and modulating its progression. "Strategies that have been tried unsuccessfully over the past ten years have specifically targeted beta-amyloid accumulation and plaque formation in the brain, but there is evidence that neuroinflammation is a major cause of Alzheimer's disease. Addressing inflammatory processes has therefore become a promising therapeutic strategy", the authors explain.

The new compound is an inhibitor of soluble epoxide hydrolase (sEH), an enzyme involved in the regulation of several physiological processes, including inflammation and pain response.

In the context of Alzheimer's disease, inhibition of this enzyme can increase levels of epoxyeicosatrienoic acids (EETs) — bioactive molecules that are endogenous anti-inflammatories — and thus reduce neuroinflammation and promote neuroprotection."

Mercè Pallàs, researcher at CIBERNED

The results of the study show that treatment with the new compound had neuroprotective effects in two mouse models of Alzheimer's disease, culminating in improved spatial and working memory and an improved neural network. "This could help preserve neuronal function and reduce neuronal death associated with Alzheimer's disease", says Santiago Vázquez.

These neuroprotective effects are due to the increase in EET acids, which are also involved in improving cerebral blood flow, which is crucial for maintaining brain health. "Inhibition of sEH may therefore contribute to improved cerebral perfusion and protection against ischaemic damage", the researchers note.

Simultaneous effect on several anti-inflammatory pathways

The advantage of this new drug over other anti-inflammatory compounds — which have failed in clinical trials and have not reached patients due to ineffectiveness — is that TSE augmentation has been shown to reduce transcription and levels of multiple pro-inflammatory markers while enhancing anti-inflammatory cytokines. "This global approach, which affects several inflammatory pathways simultaneously rather than acting on just one, results in a neuroprotective effect that is sufficient to ameliorate the symptomatology and pathology of Alzheimer's disease", the researchers stress.

In fact, in the study the authors show that the compound is effective compared to ibuprofen — an anti-inflammatory drug — whose action is of little significance in the animal model of familial Alzheimer's disease in which it has been tested. For the researchers, this is a "very important" competitive advantage over other potential drugs.

Modifying disease progression

The study also shows that treatment with the sEH inhibitor not only prevents the progression of the disease, but is able to modify its course. According to the researchers, the treatment maintains the cognitive-enhancing effects even one month after the drug is stopped in the mice. "More importantly, the integrity of the neuronal network and the dendrite count (a component of neurons) were preserved, suggesting that the treatment is not only symptomatic, but modifies disease progression in the mouse model".

Clinical translation challenges

Despite these encouraging results, the road to clinical application of this compound is still long and complex. The development of a new drug involves a rigorous process involving multiple stages: from initial research and pre-clinical testing to clinical trials with patients and, finally, approval by health authorities. During this process, the drug must pass stringent safety and efficacy regulations, a requirement that often requires decades of research and considerable financial investment.
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In this sense, the patent for the compound has been licensed to a US pharmaceutical company to promote its progress in the preclinical and clinical trials phase. Members of the research team, led by professors Santiago Vázquez and Mercè Pallàs, are following the project within the company as expert consultants. "This collaboration will allow us to continue participating, as the UB, in the development of the new compound for the treatment of pathologies related to neuroinflammation", the researchers conclude.​​​​​​