👤 Antoni Camins

Inflammation plays a key role in the development of neurodegenerative disorders that are currently incurable. Licochalcone A (LCA) has been described as an emerging anti-inflammatory drug with multiple therapeutical properties that could potentially prevent neurodegeneration. However, its neuroprotective mechanism remains unclear. Here, we investigated if LCA prevents cognitive decline induced by Lipopolysaccharide (LPS) and elucidated its potential benefits. For that, 8-week-old C57BL6/J male mice were intraperitonially (i.p.) treated with saline solution or LCA (15 mg/kg/day, 3 times per week) for two weeks. The last day, a single i.p injection of LPS (1 mg/kg) or saline solution was administered 24 h before sacrifice. The results revealed a significant reduction in mRNA expression in genes involved in oxidative stress (Sod1, Cat, Pkm, Pdha1, Ndyfv1, Uqcrb1, Cycs and Cox4i1), metabolism (Slc2a1, Slc2a2, Prkaa1 and Gsk3b) and synapsis (Bdnf, Nrxn3 and Nlgn2) in LPS group compared to saline. These findings were linked to memory impairment and depressive-like behavior observed in this group. Interestingly, LCA protected against LPS alterations through its anti-inflammatory effect, reducing gliosis and regulating M1/M2 markers. Moreover, LCA-treated animals showed a significant improvement of antioxidant mechanisms, such as citrate synthase activity and SOD2. Additionally, LCA demonstrated protection against metabolic disturbances, downregulating GLUT4 and P-AKT, and enhanced the expression of synaptic-related proteins (P-CREB, BDNF, PSD95, DBN1 and NLG3), leading all together to dendritic spine preservation. In conclusion, our results demonstrate that LCA treatment prevents LPS-induced cognitive decline by reducing inflammation, enhancing the antioxidant response, protecting against metabolic disruptions and improving synapsis related mechanisms. Show less

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, β-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. Intraperitoneal treatment with RHE-HUP in APP/PS1 mice for 4 weeks reduced the main hallmarks of AD, including Tau hyperphosphorylation, Aβ 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. Show less

An active lifestyle involving regular exercise reduces the deleterious effects of the aging process. At the cerebral level, both synaptic plasticity and neurogenesis are modulated by exercise, although the molecular mechanisms underlying these effects are not clearly understood. In the mature nervous system, the canonical Wnt (Wnt/β-catenin) signaling pathway is implicated in neuroprotection and synaptic plasticity. Here, we examined whether the Wnt pathway could be modulated in adult male rat hippocampus by long-term moderate exercise (treadmill running) or enrichment (handling/environmental stimulation). Sedentary animals showed higher protein levels of the Wnt antagonist, Dkk-1, the lowest levels being found in the exercised group. Although there was no evidence of any changes in activation of the LRP6 receptor, the total levels of LRP6 were higher in exercised and enriched animals. Analysis of some of the components implicated in the phosphorylation of β-catenin, which leads ultimately to its proteasomal degradation, revealed higher levels and activation of Axin1 and GSK-3α/β respectively in sedentary animals. However neither different phosphorylated forms nor total β-catenin protein levels differed between the experimental groups. Higher protein levels of Axin2 and the antiapoptotic protein, Bcl-2, were found with exercise and handling, whereas the proapototic, Bax, was unaffected. Thus, our results suggest activation of the Wnt pathway not only with moderate exercise, but also with the handling of the animals. Show less