sEH Enzyme Could Be a Potential Drug Target Against Alzheimer's
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A UB study published in the journal Neurotherapeutics has validated a new pharmacological target for Alzheimer's disease. The results show that inhibition of the soluble epoxide hydrolase enzyme (sEH) in murine models of the disease decreases the neuroinflammatory process, thereby improving the body’s endogenous response and reducing the deterioration and death of neurons that they cause this type of dementia. These results confirm the role of this enzyme in the evolution of Alzheimer's and point to its inhibition as a potential therapeutic strategy for this pathology and also for others with neuroinflammation.
The new work is led by professors from the Faculty of Pharmacy and Food Sciences Mercè Pallàs (Institute of Neurosciences), Santiago Vázquez (Institute of Biomedicine of the UB, IBUB), Carles Galdeano (IBUB) and Christian Griñán-Ferré Institute of Neurosciences). Experts from the Barcelona Institute for Biomedical Research (IIBB) —Center of the CSIC and IDIBAPS—, the Autonomous University of Barcelona, the University of Santiago de Compostela and the University of California-Davis also took part. .
Strategy focused on inflammatory processes
Drugs currently used to treat Alzheimer’s disease have very limited efficacy and only in mild stages of the disease. Therapeutic strategies in recent years have been specifically aimed at counteracting molecular pathways such as amyloid beta accumulation and plaque formation in the brain characteristic of this pathology. In this study, researchers have used a new approach related to inflammatory processes that help trigger this disease and modulate its pathogenesis. “It is vitally important to expand research in therapy for Alzheimer’s disease towards new pharmacological targets, preferably related to the pathophysiological pathways of the disease. In this case, our interest was directed towards the sEH,
The enzyme sEH is present throughout the body and is relatively abundant in the murine and human brain. It causes epoxyacetroatenoic acids (TSEs) —molecules that reduce the inflammatory response in pathological conditions such as hypertension or diabetes— to lose their anti-inflammatory activity, and even cause inflammation. Based on this background, the researchers analyzed the effects of sEH inhibition on two animal models of Alzheimer's disease, one considered familial Alzheimer's and a second linked to disease progression with advanced age. . In the first part of the work, it was shown that the expression of this enzyme is increased in both animal models — compared to the control group — and also in brain samples from Alzheimer’s patients.
Drugs with neuroprotective effects
Once it was determined that the enzyme sEH could be a new therapeutic target, the researchers proceeded to validate it using three structurally different sEH inhibitors, one of which has been designed and synthesized by the Santiago Vázquez group. The results showed that all the compounds used, regardless of their chemical structure, were able to prevent cognitive impairment in both animal models. “Oral treatment with the different drugs prevented cognitive impairment and reduced all markers of the disease, such as the accumulation of amyloid plaques, tau phosphorylation, etc. In addition, it was shown that the inhibition of sEH reduced neuroinflammation, endoplasmic reticulum stress and oxidative stress ", Mercè Pallàs points out.
In addition, the new therapeutic strategy may have implications for the treatment of other pathologies. "The fact that sEH inhibition leads to an increase in endogenous anti-inflammatory defenses throughout the body means that inhibitors of this enzyme could be an appropriate, effective and safe therapy in pathologies that cause inflammation," concludes Santiago Vázquez . The researcher advances that new sEH inhibitors patented by the University of Barcelona are already being evaluated not only in models of Alzheimer's disease, but also in models of diseases with an important inflammatory component, such as the Niemann-Pick of type C, in neuropathic pain or in acute pancreatitis.
Reference: Christian Griñán-Ferré, et al. (2020). Pharmacological Inhibition of Soluble Epoxide Hydrolase as a New Therapy for Alzheimer’s Disease. Neurotherapeutics DOI: https://doi.org/10.1007/s13311-020-00854-1
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