Ettcheto M

References (4)

Title : Licochalcone A: A Potential Multitarget Drug for Alzheimer's Disease Treatment - Olloquequi_2023_Int.J.Mol.Sci_24_
Author(s) : Olloquequi J , Ettcheto M , Cano A , Fortuna A , Bicker J , Sanchez-Lopez E , Paz C , Urena J , Verdaguer E , Auladell C , Camins A
Ref : Int J Mol Sci , 24 : , 2023
Abstract : Licochalcone A (Lico-A) is a flavonoid compound derived from the root of the Glycyrrhiza species, a plant commonly used in traditional Chinese medicine. While the Glycyrrhiza species has shown promise in treating various diseases such as cancer, obesity, and skin diseases due to its active compounds, the investigation of Licochalcone A's effects on the central nervous system and its potential application in Alzheimer's disease (AD) treatment have garnered significant interest. Studies have reported the neuroprotective effects of Lico-A, suggesting its potential as a multitarget compound. Lico-A acts as a PTP1B inhibitor, enhancing cognitive activity through the BDNF-TrkB pathway and exhibiting inhibitory effects on microglia activation, which enables mitigation of neuroinflammation. Moreover, Lico-A inhibits c-Jun N-terminal kinase 1, a key enzyme involved in tau phosphorylation, and modulates the brain insulin receptor, which plays a role in cognitive processes. Lico-A also acts as an acetylcholinesterase inhibitor, leading to increased levels of the neurotransmitter acetylcholine (Ach) in the brain. This mechanism enhances cognitive capacity in individuals with AD. Finally, Lico-A has shown the ability to reduce amyloid plaques, a hallmark of AD, and exhibits antioxidant properties by activating the nuclear factor erythroid 2-related factor 2 (Nrf2), a key regulator of antioxidant defense mechanisms. In the present review, we discuss the available findings analyzing the potential of Lico-A as a neuroprotective agent. Continued research on Lico-A holds promise for the development of novel treatments for cognitive disorders and neurodegenerative diseases, including AD. Further investigations into its multitarget action and elucidation of underlying mechanisms will contribute to our understanding of its therapeutic potential.
ESTHER : Olloquequi_2023_Int.J.Mol.Sci_24_
PubMedSearch : Olloquequi_2023_Int.J.Mol.Sci_24_
PubMedID: 37762479

Title : A novel rhein-huprine hybrid ameliorates disease-modifying properties in preclinical mice model of Alzheimer's disease exacerbated with high fat diet - Espinosa-Jimenez_2023_Cell.Biosci_13_52
Author(s) : Espinosa-Jimenez T , Cano A , Sanchez-Lopez E , Olloquequi J , Folch J , Bullo M , Verdaguer E , Auladell C , Pont C , Munoz-Torrero D , Parcerisas A , Camins A , Ettcheto M
Ref : Cell Biosci , 13 :52 , 2023
Abstract : BACKGROUND: Alzheimer's disease (AD) is characterized by a polyetiological origin. Despite the global burden of AD and the advances made in AD drug research and development, the cure of the disease remains elusive, since any developed drug has demonstrated effectiveness to cure AD. Strikingly, an increasing number of studies indicate a linkage between AD and type 2 diabetes mellitus (T2DM), as both diseases share some common pathophysiological features. In fact, beta-secretase (BACE1) and acetylcholinesterase (AChE), two enzymes involved in both conditions, have been considered promising targets for both pathologies. In this regard, due to the multifactorial origin of these diseases, current research efforts are focusing on the development of multi-target drugs as a very promising option to derive effective treatments for both conditions. In the present study, we evaluated the effect of rhein-huprine hybrid (RHE-HUP), a synthesized BACE1 and AChE inhibitor, both considered key factors not only in AD but also in metabolic pathologies. Thus, the aim of this study is to evaluate the effects of this compound in APP/PS1 female mice, a well-established familial AD mouse model, challenged by high-fat diet (HFD) consumption to concomitantly simulate a T2DM-like condition. RESULTS: Intraperitoneal treatment with RHE-HUP in APP/PS1 mice for 4 weeks reduced the main hallmarks of AD, including Tau hyperphosphorylation, Abeta(42) peptide levels and plaque formation. Moreover, we found a decreased inflammatory response together with an increase in different synaptic proteins, such as drebrin 1 (DBN1) or synaptophysin, and in neurotrophic factors, especially in BDNF levels, correlated with a recovery in the number of dendritic spines, which resulted in memory improvement. Notably, the improvement observed in this model can be attributed directly to a protein regulation at central level, since no peripheral modification of those alterations induced by HFD consumption was observed. CONCLUSIONS: Our results suggest that RHE-HUP could be a new candidate for the treatment of AD, even for individuals with high risk due to peripheral metabolic disturbances, given its multi-target profile which allows for the improvement of some of the most important hallmarks of the disease.
ESTHER : Espinosa-Jimenez_2023_Cell.Biosci_13_52
PubMedSearch : Espinosa-Jimenez_2023_Cell.Biosci_13_52
PubMedID: 36895036

Title : Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP\/PS1 Mice - Viayna_2021_J.Med.Chem_64_812
Author(s) : Viayna E , Coquelle N , Cieslikiewicz-Bouet M , Cisternas P , Oliva CA , Sanchez-Lopez E , Ettcheto M , Bartolini M , De Simone A , Ricchini M , Rendina M , Pons M , Firuzi O , Perez B , Saso L , Andrisano V , Nachon F , Brazzolotto X , Garcia ML , Camins A , Silman I , Jean L , Inestrosa NC , Colletier JP , Renard PY , Munoz-Torrero D
Ref : Journal of Medicinal Chemistry , 64 :812 , 2021
Abstract : The combination of the scaffolds of the cholinesterase inhibitor huprine Y and the antioxidant capsaicin results in compounds with nanomolar potencies toward human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that retain or improve the antioxidant properties of capsaicin. Crystal structures of their complexes with AChE and BChE revealed the molecular basis for their high potency. Brain penetration was confirmed by biodistribution studies in C57BL6 mice, with one compound (5i) displaying better brain/plasma ratio than donepezil. Chronic treatment of 10 month-old APP/PS1 mice with 5i (2 mg/kg, i.p., 3 times per week, 4 weeks) rescued learning and memory impairments, as measured by three different behavioral tests, delayed the Alzheimer-like pathology progression, as suggested by a significantly reduced Abeta42/Abeta40 ratio in the hippocampus, improved basal synaptic efficacy, and significantly reduced hippocampal oxidative stress and neuroinflammation. Compound 5i emerges as an interesting anti-Alzheimer lead with beneficial effects on cognitive symptoms and on some underlying disease mechanisms.
ESTHER : Viayna_2021_J.Med.Chem_64_812
PubMedSearch : Viayna_2021_J.Med.Chem_64_812
PubMedID: 33356266
Gene_locus related to this paper: human-ACHE

Title : Memantine for the Treatment of Dementia: A Review on its Current and Future Applications - Folch_2018_J.Alzheimers.Dis_62_1223
Author(s) : Folch J , Busquets O , Ettcheto M , Sanchez-Lopez E , Castro-Torres RD , Verdaguer E , Garcia ML , Olloquequi J , Casadesus G , Beas-Zarate C , Pelegri C , Vilaplana J , Auladell C , Camins A
Ref : J Alzheimers Dis , 62 :1223 , 2018
Abstract : Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence in the brain of extracellular amyloid-beta protein (Abeta) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. The N-Methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptor, are essential for processes like learning and memory. An excessive activation of NMDARs has been associated with neuronal loss. The discovery of extrasynaptic NMDARs provided a rational and physiological explanation between physiological and excitotoxic actions of glutamate. Memantine (MEM), an antagonist of extrasynaptic NMDAR, is currently used for the treatment of AD jointly with acetylcholinesterase inhibitors. It has been demonstrated that MEM preferentially prevents the excessive continuous extrasynaptic NMDAR disease activation and therefore prevents neuronal cell death induced by excitotoxicity without disrupting physiological synaptic activity. The problem is that MEM has shown no clear positive effects in clinical applications while, in preclinical stages, had very promising results. The data in preclinical studies suggests that MEM has a positive impact on improving AD brain neuropathology, as well as in preventing Abeta production, aggregation, or downstream neurotoxic consequences, in part through the blockade of extrasynaptic NMDAR. Thus, the focus of this review is primarily to discuss the efficacy of MEM in preclinical models of AD, consider possible combinations of this drug with others, and then evaluate possible reasons for its lack of efficacy in clinical trials. Finally, applications in other pathologies are also considered.
ESTHER : Folch_2018_J.Alzheimers.Dis_62_1223
PubMedSearch : Folch_2018_J.Alzheimers.Dis_62_1223
PubMedID: 29254093