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.

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.

Neurologic injury continues to be a debilitating worldwide disease with high morbidity and mortality. The systemic sequelae of a neural insult often lead to prolonged hospital stays and challenging nutritional demands that contribute to poorer prognoses. Clinical management of a given condition should prioritize preserving the homeostatic parameters disrupted by inflammatory response cascades following the primary insult. This focused review examines the reciprocal relationship between electrolyte disturbance and neurologic injury. A prolonged electrolyte imbalance can significantly impact morbidity and mortality in neurologic injuries. A detailed overview of the major electrolytes and their physiologic, iatrogenic, and therapeutic implications are included. The pathophysiology of how dysnatremias, dyskalemias, dyscalcemias, and dysmagnesemias occur and the symptoms they can induce are described. The manifestations in relation to traumatic brain injury, status epilepticus, and acute ischemic stroke are addressed. Each type of injury and the strength of its association with a disruption in either sodium, potassium, calcium, or magnesium is examined. The value of supplementation and replacement is highlighted with an emphasis on the importance of early recognition in this patient population. This review also looks at the current challenges associated with correcting imbalances in the setting of different injuries, including the relevant indications and precautions for some of the available therapeutic interventions. Based on the findings of this review, there may be a need for more distinct clinical guidelines on managing different electrolyte imbalances depending on the specified neurologic injury. Additional research and statistical data on individual associations between insult and imbalance are needed to support this potential future call for context-based protocols.

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: 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.

Parkinson's disease is the second most common neurodegenerative disease affecting millions of people worldwide. Despite the crucial threat it poses, currently, no specific therapy exists that can completely reverse or halt the progression of the disease. Parkinson's disease pathology is driven by neurodegeneration caused by the intraneuronal accumulation of alpha-synuclein (α-syn) aggregates in Lewy bodies in the substantia nigra region of the brain. Parkinson's disease is a multiorgan disease affecting the central nervous system (CNS) as well as the autonomic nervous system. A bidirectional route of spreading α-syn from the gut to CNS through the vagus nerve and vice versa has also been reported. Despite our understanding of the molecular and pathophysiological aspects of Parkinson's disease, many questions remain unanswered regarding the selective vulnerability of neuronal populations, the neuromodulatory role of the locus coeruleus, and alpha-synuclein aggregation. This review article aims to describe the probable factors that contribute to selective neuronal vulnerability in Parkinson's disease, such as genetic predisposition, bioenergetics, and the physiology of neurons, as well as the interplay of environmental and exogenous modulators. This review also highlights various therapeutic strategies with cell transplants, through viral gene delivery, by targeting α-synuclein and aquaporin protein or epidermal growth factor receptors for the treatment of Parkinson's disease. The application of regenerative medicine and patient-specific personalized approaches have also been explored as promising strategies in the treatment of Parkinson's disease.

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: A limited subgroup of multiple sclerosis (MS) patients present with a longterm disease evolution characterized by a limited disease progression, known as benign MS (BMS). Chitinase 3-like-1 (CHI3L1) levels are sensitive to inflammatory processes and may play a role in the pathogenesis of MS. In this observational, cross-sectional study, we aimed to evaluate the implications of serum CHI3L1 and inflammatory cytokines in BMS patients treated with interferon β-1b for over a decade.

Methods: We collected serum samples from 17 BMS patients and 17 healthy controls (HC) to measure serum CHI3L1 levels and a Th17 panel of inflammatory cytokines. Serum levels of CHI3L1 were analysed using the sandwich ELISA method and the Th17 panel was assessed using the multiplex XMap technology on a Flexmap 3D Analyzer.

Results: Serum CHI3L1 levels did not differ significantly from HC. We identified a positive correlation between CHI3L1 levels and relapses during treatment.

Conclusion: Our findings suggest that there are no differences in serum CHI3L1 levels between BMS patients and HC. However, serum CHI3L1 levels are sensitive to clinical inflammatory activity and may be associated with relapses in BMS patients.

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.