CNS & neurological disorders drug targets最新文献

Autism Spectrum Disorder is a neurodevelopmental disorder characterized by impaired social and communication skills, repetitive behaviors, and/or restricted interests with a prevalence of as high as 1% of children. Autism spectrum has strongly associated with genetic factors and exhibits wide clinical and heterogeneous genetic architecture. Most genes associated with Autism are involved in neuronal and synaptic development. The neuroligin3, the sex-linked gene on the X chromosome, was the first gene to be associated with a monogenic form of Autism. Neuroligin3 is a postsynaptic cell adhesion protein involved in synapse transmission, brain formation, and neuronal development. In this review, we provide recent findings on different mutations in the Neuroligin3 gene linked to Autism spectrum disorder and their molecular pathway effect. We also give the behavioral, and synaptic alterations reported in the Neuroligin3 animal model of Autism and the potential therapeutic strategies targeting the biological processes and the main symptoms of autism spectrum disorder. In addition, we discuss the use of novel technologies like induced pluripotent stem cells from Autistic patients that have the potential to differentiate in human neurons and therefore have a variety of applications in therapy and biomedical studies to search specific biomarkers, and develop systems for screening chemical molecules in human cells to discover target therapies.

Traumatic brain injury (TBI) is a major healthcare problem and a common cause of mortality and morbidity. Clinical and preclinical research suggests sex-related differences in short- and longterm outcomes following TBI; however, males have been the main focus of TBI research. Females show a protective response against TBI. Female animals in preclinical studies and women in clinical trials have shown comparatively better outcomes against mild, moderate, or severe TBI. This reflects a favorable protective nature of the females compared to the males, primarily attributed to various protective mechanisms that provide better prognosis and recovery in the females after TBI. Understanding the sex difference in the TBI pathophysiology and the underlying mechanisms remains an elusive goal. In this review, we provide insights into various mechanisms related to the anatomical, physiological, hormonal, enzymatic, inflammatory, oxidative, genetic, or mitochondrial basis that support the protective nature of females compared to males. Furthermore, we sought to outline the evidence of multiple biomarkers that are highly potential in the investigation of TBI's prognosis, pathophysiology, and treatment and which can serve as objective measures and novel targets for individualized therapeutic interventions in TBI treatment. Implementations from this review are important for the understanding of the effect of sex on TBI outcomes and possible mechanisms behind the favorable response in females. It also emphasizes the critical need to include females as a biological variable and in sufficient numbers in future TBI studies.

Neurodegenerative diseases (NDDs), such as Alzheimer's and Parkinson's, are the most frequent age-related illnesses affecting millions worldwide. No effective medication for NDDs is known to date and current disease management approaches include neuroprotection strategies with the hope of maintaining and improving the function of neurons. Such strategies will not provide a cure on their own but are likely to delay disease progression by reducing the production of neurotoxic chemicals such as reactive oxygen species (ROS) and related inflammatory chemicals. Natural compounds such as flavonoids that provide neuroprotection via numerous mechanisms have attracted much attention in recent years. This review discusses evidence from different research models and clinical trials on the therapeutic potential of one promising flavonoid, apigenin, and how it can be helpful for NDDs in the future prospects. We have also discussed its chemistry, mechanism of action, and possible benefits in various examples of NDDs.

Aging is a gradual decline of physiological function and tissue homeostasis and, in many instances, is related to increased (neuro)-degeneration, together with inflammation, becoming one of the most important risks for developing neurodegenerative diseases. Certain individual nutrients or foods in combination may counteract aging and associated neurodegenerative diseases by promoting a balance between the pro- and anti-inflammatory responses. Thus, nutrition could represent a powerful modulator of this fine balance, other than a modifiable risk factor to contrast inflammaging. This narrative review explores from a broad perspective the impact of nutrition on the hallmarks of aging and inflammation in Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic Lateral Sclerosis Syndrome (ALS), starting from nutrients up to single foods and complex dietary patterns.

Spinal cord injury (SCI) is an intractable and poorly prognostic neurological disease, and current treatments are still unable to cure it completely and avoid sequelae. Extracellular vesicles (EVs), as important carriers of intercellular communication and pharmacological effects, are considered to be the most promising candidates for SCI therapy because of their low toxicity and immunogenicity, their ability to encapsulate endogenous bioactive molecules (e.g., proteins, lipids, and nucleic acids), and their ability to cross the blood-brain/cerebrospinal barriers. However, poor targeting, low retention rate, and limited therapeutic efficacy of natural EVs have bottlenecked EVs-based SCI therapy. A new paradigm for SCI treatment will be provided by engineering modified EVs. Furthermore, our limited understanding of the role of EVs in SCI pathology hinders the rational design of novel EVbased therapeutic approaches. In this study, we review the pathophysiology after SCI, especially the multicellular EVs-mediated crosstalk; briefly describe the shift from cellular to cell-free therapies for SCI treatment; discuss and analyze the issues related to the route and dose of EVs administration; summarize and present the common strategies for EVs drug loading in the treatment of SCI and point out the shortcomings of these drug loading methods; finally, we analyze and highlight the feasibility and advantages of bio-scaffold-encapsulated EVs for SCI treatment, providing scalable insights into cell-free therapy for SCI.

Anxiety is a common mental illness that affects a large number of people around the world, and its treatment is often based on the use of pharmacological substances such as benzodiazepines, serotonin, and 5-hydroxytyrosine (MAO) neurotransmitters. MAO neurotransmitters levels are deciding factors in the biological effects. This review summarizes the current understanding of the MAO system and its role in the modulation of anxiety-related brain circuits and behavior. The MAO-A polymorphisms have been implicated in the susceptibility to generalized anxiety disorder (GAD) in several investigations. The 5-HT system is involved in a wide range of physiological and behavioral processes, involving anxiety, aggressiveness, stress reactions, and other elements of emotional intensity. Among these, 5-HT, NA, and DA are the traditional 5-HT neurons that govern a range of biological activities, including sleep, alertness, eating, thermoregulation, pains, emotion, and memory, as anticipated considering their broad projection distribution in distinct brain locations. The DNMTs (DNA methyltransferase) protein family, which increasingly leads a prominent role in epigenetics, is connected with lower transcriptional activity and activates DNA methylation. In this paper, we provide an overview of the current state of the art in the elucidation of the brain's complex functions in the regulation of anxiety.

Background: Foods rich in flavonoids are associated with a reduced risk of various chronic diseases, including Alzheimer's disease (AD). In fact, growing evidence suggests that consuming flavonoid- rich foods can beneficially affect normal cognitive function. Animal models have shown that many flavonoids prevent the development of AD-like pathology and improve cognitive deficits.

Objective: Identifying the molecular causes underlying the memory-enhancing effect of flavonoid-rich foods makes it possible to provide the best diet to prevent cognitive decline associated with aging and Alzheimer's disease. Based on the most recent scientific literature, this review article critically examines the therapeutic role of dietary flavonoids in ameliorating and preventing the progression of AD and enhancement of memory with a focus on the role of the BDNF signaling pathway.

Methods: The databases of PubMed, Web of Science, Google Scholar, and Scopus were searched up to March 2023 and limited to English language. Search strategies were using the following keywords in titles and abstracts: (Flavonoid-rich foods OR Flavonoids OR Polyphenols); AND (Brain-Derived Neurotrophic Factor OR BDNF OR CREB OR) AND (Alzheimer's disease OR memory OR cognition OR).

Results: Flavonoid-rich foods including green tea, berries, curcumin and pomegranate exert their beneficial effects on memory decline associated with aging and Alzheimer's disease mostly through the direct interaction with BDNF signaling pathway.

Conclusion: The neuroprotective effects of flavonoid-rich foods through the CREB-BDNF mechanism have the potential to prevent or limit memory decline due to aging and Alzheimer's disease, so their consumption throughout life may prevent age-related cognitive impairment.

Introduction: Vortioxetine is a multimodal antidepressant drug that has been reported to have a positive impact on cognition, social function, and fatigue. Nevertheless, it has not been widely studied. Our objective was to explore the effects of vortioxetine on these and other parameters in patients with multiple sclerosis (MS) and depression.

Patients and methodology: This observational case series study included patients with MS and depression who received treatment with vortioxetine for at least 6 months. The patient history of depression and depressive symptoms was assessed. A neuropsychiatric evaluation was carried out using different scales, both before and after treatment.

Results: Of the 25 patients who enrolled in the study, 17 completed the treatment. Significant improvements were observed in health status (EQ-5D; p = 0.002), mood (Beck's Depression Inventory, BDI-II; p = 0.006), anxiety (State-Trait Anxiety Inventory, STAI-State; p = 0.021, and STAI-Trait; p = 0.011), and in the general health test (Short Form Health Survey, SF-36) for the vitality (p = 0.028) and mental health (p = 0.025) domains of the patients who completed the treatment. However, no statistically significant differences were observed in the cognitive tests related to attention, information processing speed, or fatigue.

Conclusion: In this population, vortioxetine treatment was effective in reducing the symptoms of depression and improving anxiety, vitality, and mental health. In contrast, it did not produce any improvement in cognition or fatigue but an increase in sample size would be necessary to confirm these results.

Background: Locomotion problems in Parkinson's syndrome are still a research and treatment difficulty. With the recent introduction of brain stimulation or neuromodulation equipment that is sufficient to monitor activity in the brain using electrodes placed on the scalp, new locomotion investigations in patients having the capacity to move freely have sprung up.

Objective: This study aimed to find rat models and locomotion-connected neuronal indicators and use them all over a closed-loop system to enhance the future and present treatment options available for Parkinson's disease.

Methods: Various publications on locomotor abnormalities, Parkinson's disease, animal models, and other topics have been searched using several search engines, such as Google Scholar, Web of Science, Research Gate, and PubMed.

Results: Based on the literature, we can conclude that animal models are used for further investigating the locomotion connectivity deficiencies of many biological measuring devices and attempting to address unanswered concerns from clinical and non-clinical research. However, translational validity is required for rat models to contribute to the improvement of upcoming neurostimulation-based medicines. This review discusses the most successful methods for modelling Parkinson's locomotion in rats.

Conclusion: This review article has examined how scientific clinical experiments lead to localised central nervous system injuries in rats, as well as how the associated motor deficits and connection oscillations reflect this. This evolutionary process of therapeutic interventions may help to improve locomotion- based treatment and management of Parkinson's syndrome in the upcoming years.

Background: Alzheimer's disease is a degenerative disease of the central nervous system, and its characteristic pathological changes are closely associated with Aβ deposition and neurofibrillary tangles. Many studies have found that malignant changes in the myelin sheath and oligodendrocyte (OL) are accompanied by the occurrence and development of AD. Therefore, any method that can resist myelin sheath and OL disorders may be a potential strategy for AD.

Objective: To investigate the effects and mechanism of Scutellaria baicalensis Georgi stem and leaf flavonoids (SSFs) on the myelin sheath degeneration induced by Aβ_25-35 combined with AlC1₃ and RHTGF-β₁ (composite Aβ) in rats.

Methods: A rat AD model was established by intracerebroventricular injection of composite Aβ. The Morris water maze was used to screen the memory impairment rat model. The successful model rats were divided into the model group and the 35, 70, and 140 mg/kg SSFS groups. The myelin sheath changes in the cerebral cortex were observed with an electron microscope. The expression of the oligodendrocyte- specific protein claudin 11 was detected with immunohistochemistry. The protein expression levels of myelin oligodendrocyte glycoprotein (MOG), myelin-associated glycoprotein (MAG) and myelin basic protein (MBP), sphingomyelin synthase-1 (SMS1), and sphingomyelinase-2 (SMPD2) were assayed by Western blotting.

Results: The intracerebroventricular injection of composite Aβ caused degeneration of the myelin sheath structure and was accompanied by the decreased claudin 11, MOG, MAG, MBP, and SMS1, and increased SMPD2 protein expression in the cerebral cortex. However, 35, 70, and 140 mg/kg SSFs can differentially ameliorate the above abnormal changes induced by composite Aβ.

Conclusion: SSFs can alleviate myelin sheath degeneration and increase the protein expression of claudin 11, MOG, MAG, and MBP, and the effective mechanism may be related to the positive regulation of SMS1 and SMPD2 activities.