Current Neuropharmacology - Online First

Although medicinal chemistry is constantly looking for new therapeutic approaches against pathological conditions affecting the central nervous system (CNS), such as neurodegeneration and cancer, this quest has not been fully successful yet. The lack of understanding of all the complex mechanisms underlying these conditions makes the identification of new effective drugs challenging. A wide variety of pathophysiological events are regulated at both nuclear and cytoplasmic levels, and in this context, targeting the shuttle system composed of the karyopherin superfamily and their cargoes may provide an alternative strategy. Molecular recognition is highly specific and strictly related to the presence of special “tag” regions, known as nuclear localization signals, that are localized in the amino acid sequences of cargoes. Importantly, their trafficking is involved in various pathophysiological processes, including CNS diseases. Curiously, although this system has been studied intensively, much remains to be discovered to date. Throughout the years, drug discovery allowed the identification of small molecules and peptides able to target karyopherin-cargo complexes to provide new potential pharmacological treatments. Indeed, the first examples of drug candidates targeting this mechanism that reached clinical trials are appearing in the literature. With this mini-review, this study aims at presenting an updated overview on the most recent reports investigating the use of the karyopherin shuttle system as a new therapeutic target especially for CNS-related diseases.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with multifaceted risk factors, including diet and metabolic dysfunction. The rising prevalence of AD and diabetes has drawn attention to their shared pathophysiological mechanisms. The “cafeteria diet,” characterized by high-fat, high-sugar, and energy-dense foods, has emerged as a significant contributor to metabolic dysfunctions, including obesity and insulin resistance, which are risk factors for both diabetes and neurodegenerative diseases. This study explores the effects of the cafeteria diet on cognitive impairment, AD pathology, and its potential role in exacerbating diabetes-related neurological complications. Animal models were subjected to cafeteria diets, mimicking human dietary patterns, to investigate changes in brain structure, amyloid-beta accumulation, tau hyperphosphorylation, and cognitive function. Additionally, metabolic profiling demonstrated the development of insulin resistance and other hallmarks of diabetes, which were closely correlated with the severity of cognitive deficits. Neuropathological analyses revealed exacerbated amyloid-beta accumulation and increased neuroinflammation, linking dietary-induced diabetes to AD pathophysiology. These findings underscore the critical role of dietary habits in modulating the risk and progression of AD, highlighting the importance of interventions targeting metabolic health to mitigate cognitive decline. This study emphasizes the need for further research to unravel the molecular mechanisms underlying the diet-diabetes-AD axis and develop targeted therapeutic strategies.

Sleep is important to maintain normal physiological functions of the human body. With increased stress in modern society, the number of patients suffering from sleep disorders is gradually increasing. Many studies have shown that general anesthetics induce loss of consciousness by acting on the sleep-wake circuit. In recent years, general anesthesia and other anesthetic agents have been used in the diagnosis and treatment of sleep disorders. This article discusses the mechanism of sleep and sleep disorders, summarizes the effects of anesthetics on sleep and their regulatory mechanisms, and reviews the research progress of using anesthetics in the diagnosis and treatment of sleep disorders.

Epilepsy is a prevalent and severe neurological condition characterized by recurring seizures. It impacts over 70 million individuals worldwide, posing a substantial challenge to public health and placing a heavy burden on society. Glycerophospholipids are an essential component of neuronal cell membranes. Their metabolism is strictly regulated, and maintaining their homeostasis is crucial for the optimal function of the nervous system. Research indicates that disruptions in glycerophospholipid metabolism are commonly detected in patients with epilepsy and animal models. However, the precise molecular mechanisms behind these disruptions remain unclear. Existing evidence indicates that neuroinflammation, oxidative stress, genetic mutations, and ion channel dysfunction are crucial factors contributing to glycerophospholipids imbalance and epilepsy. Further, therapeutic interventions targeting these pathological processes, such as regulating neuroinflammation and oxidative stress or restoring the balance of glycerophospholipid metabolism, may provide new avenues for epilepsy treatment. This review aims to provide an in-depth analysis of the potential mechanisms underlying the relationship between glycerophospholipid metabolism disorders and epilepsy, exploring potential therapeutic targets and diagnostic biomarkers.

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