👤 Lucielli Savegnago

This research investigated the potential therapeutic role of α-(phenylselanyl) acetophenone (PSAP) in the comorbidity of chronic pain and depression triggered by partial sciatic nerve ligation (PSNL). Male Swiss mice underwent PSNL surgery, and after a four-week period, they received either PSAP (1-50 mg/kg, administered intragastrically) or imipramine (IMI) (50 mg/kg) 30 min prior to behavioral assessments. Both PSAP and IMI effectively alleviated PSNL-induced hypersensitivity to pain and depressive-like symptoms, as demonstrated in forced swim and allodynia tests. Additionally, PSAP counteracted the elevated levels of lipid peroxidation and reactive oxygen species observed in the cortex and hippocampus following PSNL. These neuroprotective effects appear to be linked to PSAP's anti-inflammatory properties, as it downregulated the expression of pro-inflammatory markers such as NF-κB p65, TNF-α, and IDO mRNA in the affected brain regions. Furthermore, PSAP restored hippocampal BDNF mRNA levels, which had been diminished by nerve injury. Since inflammation is a common pathway in both chronic pain and depression, the findings indicate that PSAP holds promise as a treatment for this comorbid condition. Show less

The incorporation of selenium into tacrine derivatives has been explored as a novel strategy to enhance therapeutic efficacy while minimizing toxicity in the treatment of neurodegenerative diseases such as Alzheimer's. This study utilized computational and experimental approaches, including Density Functional Theory (DFT), molecular docking, pharmacokinetic profiling, and toxicological predictions, to evaluate the potential of these derivatives. The selenium-modified compounds demonstrated improved electronic properties, such as narrower HOMO-LUMO gaps and optimized electronegativity, resulting in enhanced stability and reactivity. Pharmacokinetic analyses revealed favorable absorption, distribution, and blood-brain barrier penetration, while toxicological assessments indicated reduced hepatotoxicity and skin sensitization risks compared to tacrine. Molecular docking and dynamic simulations highlighted strong and stable interactions of the derivatives with critical enzymes, including acetylcholinesterase (AChE) and beta-secretases (BACE1 and BACE2). Compounds Show less

Alzheimer's Disease (AD) is the most common form of dementia, affecting almost 50 million of people around the world, characterized by a complex and age-related progressive pathology with projections to duplicate its incidence by the end of 2050. AD pathology has two major hallmarks, the amyloid beta (Aβ) peptides accumulation and tau hyperphosphorylation, alongside with several sub pathologies including neuroinflammation, oxidative stress, loss of neurogenesis and synaptic dysfunction. In recent years, extensive research pointed out several therapeutic targets which have shown promising effects on modifying the course of the disease in preclinical models of AD but with substantial failure when transposed to clinic trials, suggesting that modulating just an isolated feature of the pathology might not be sufficient to improve brain function and enhance cognition. In line with this, there is a growing consensus that an ideal disease modifying drug should address more than one feature of the pathology. Considering these evidence, β-secretase (BACE1), Glycogen synthase kinase 3β (GSK-3β) and acetylcholinesterase (AChE) has emerged as interesting therapeutic targets. BACE1 is the rate-limiting step in the Aβ production, GSK-3β is considered the main kinase responsible for Tau hyperphosphorylation, and AChE play an important role in modulating memory formation and learning. However, the effects underlying the modulation of these enzymes are not limited by its primarily functions, showing interesting effects in a wide range of impaired events secondary to AD pathology. In this sense, this review will summarize the involvement of BACE1, GSK-3β and AChE on synaptic function, neuroplasticity, neuroinflammation and oxidative stress. Additionally, we will present and discuss new perspectives on the modulation of these pathways on AD pathology and future directions on the development of drugs that concomitantly target these enzymes. Show less