CNS & neurological disorders drug targets最新文献

Parkinson's disease (PD) is a neurodegenerative disease characterized by both motor and non-motor symptoms. A progressive neuronal loss and the consequent clinical impairment lead to deleterious effects on daily living and quality of life. Despite effective symptomatic therapeutic approaches, no disease-modifying therapies are currently available. Emerging evidence suggests that adopting a healthy lifestyle can improve the quality of life of PD patients. In addition, modulating lifestyle factors can positively affect the microstructural and macrostructural brain levels, corresponding to clinical improvement. Neuroimaging studies may help to identify the mechanisms through which physical exercise, dietary changes, cognitive enrichment, and exposure to substances modulate neuroprotection. All these factors have been associated with a modified risk of developing PD, with attenuation or exacerbation of motor and non-motor symptomatology, and possibly with structural and molecular changes. In the present work, we review the current knowledge on how lifestyle factors influence PD development and progression and the neuroimaging evidence for the brain structural, functional, and molecular changes induced by the adoption of positive or negative lifestyle behaviours.

Previous studies show changes in lipid metabolism in epilepsy. The aim of this study was to investigate the association between lipid profile and clinical variables in adult patients with epilepsy (APE). Seventy-two APE participated in this pilot study at an outpatient neurology service. The lipid profile (total cholesterol, low-density lipoprotein (LDL) cholesterol, very-low-density lipoproteins (VLDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides), age at disease onset, disease duration, seizures frequency, and the number of antiseizure medications (ASM) used were investigated. Data were analyzed using the Chi-square, Fisher, Mann-Whitney, Spearman coefficient, and logistic regression tests. There were significant differences in HDL (p = 0.0023) and total cholesterol (p = 0.0452) levels in connection with the number of ASM used. There was a significant difference in seizure control among the different numbers of ASM used (p = 0.0382). Higher HDL values were found in females (p = 0.0170). The logistic regression showed that only the number of ASM used was associated with seizure control (p = 0.0408; OR = 2.800; 95% CI = 1.044; 7.509). The number of ASM taken and not the lipid profile was associated with seizure control in APE.

Background: The management of neurodegenerative diseases can be frustrating for clinicians, given the limited progress of conventional medicine in this context.

Aim: For this reason, a more comprehensive, integrative approach is urgently needed. Among various emerging focuses for intervention, the modulation of central nervous system energetics, oxidative stress, and inflammation is becoming more and more promising.

Methods: In particular, electrons leakage involved in the mitochondrial energetics can generate reactive oxygen-free radical-related mitochondrial dysfunction that would contribute to the etiopathology of many disorders, such as Alzheimer's and other dementias, Parkinson's disease, multiple sclerosis, stroke, and amyotrophic lateral sclerosis (ALS).

Results: In this context, using agents, like acetyl L-carnitine (ALCAR), provides mitochondrial support, reduces oxidative stress, and improves synaptic transmission.

Conclusion: This narrative review aims to update the existing literature on ALCAR molecular profile, tolerability, and translational clinical potential use in neurodegeneration, focusing on ALS.

Alzheimer's disease (AD) represents the most prevalent type of neurodegenerative dementia and the sixth leading cause of death worldwide. The so-called "non-calcemic actions" of vitamin D have been increasingly described, and its insufficiency has already been linked to the onset and progression of the main neurological diseases, including AD. Immune-mediated Aβ plaque's phagocytosis and clearance, immune response, oxidative stress, and mitochondrial function are all influenced by vitamin D, and these functions are considered relevant in AD pathogenesis. However, it has been shown that the genomic vitamin D signaling pathway is already impaired in the AD brain, making things more complicated. In this paper, we aim to summarise the role of vitamin D in AD and review the results of the supplementation trials in AD patients.

Background & objectives: Despite much clinical and laboratory research that has been performed to explore the mechanisms of Parkinson's disease (PD), its pathogenesis remains elusive to date. Therefore, this study aimed to identify possible regulators of neurodegeneration by performing microarray analysis of the zebrafish PD model's brain following rotenone exposure.

Methods: A total of 36 adult zebrafish were divided into two groups: control (n = 17) and rotenonetreated (n = 19). Fish were treated with rotenone water (5 μg/L water) for 28 days and subjected to locomotor behavior analysis. Total RNA was extracted from the brain tissue after rotenone treatment. The cDNA synthesized was subjected to microarray analysis and subsequently validated by qPCR.

Results: Administration of rotenone has significantly reduced locomotor activity in zebrafish (p < 0.05), dysregulated dopamine-related gene expression (dat, th1, and th2, p < 0.001), and reduced dopamine level in the brain (p < 0.001). In the rotenone-treated group, genes involved in cytotoxic T lymphocytes (gzm3, cd8a, p < 0.001) and T cell receptor signaling (themis, lck, p < 0.001) were upregulated significantly. Additionally, gene expression involved in microgliosis regulation (tyrobp, p < 0.001), cellular response to IL-1 (ccl34b4, il2rb, p < 0.05), and regulation of apoptotic process (dedd1, p < 0.001) were also upregulated significantly.

Conclusion: The mechanisms of T cell receptor signaling, microgliosis regulation, cellular response to IL-1, and apoptotic signaling pathways have potentially contributed to PD development in rotenonetreated zebrafish.

Reactive oxygen species (ROS)-induced oxidative stress triggers the vicious cycle leading to the degeneration of dopaminergic neurons in the nigra pars compacta. ROS produced during the metabolism of dopamine is immediately neutralized by the endogenous antioxidant defense system (EADS) under physiological conditions. Aging decreases the vigilance of EADS and makes the dopaminergic neurons more vulnerable to oxidative stress. As a result, ROS left over by EADS oxidize the dopamine-derived catechols and produces a number of reactive dopamine quinones, which are precursors to endogenous neurotoxins. In addition, ROS causes lipid peroxidation, uncoupling of the electron transport chain, and DNA damage, which lead to mitochondrial dysfunction, lysosomal dysfunction, and synaptic dysfunction. The mutations in genes such as DNAJC6, SYNJ1, SH3GL2, LRRK2, PRKN, and VPS35 caused by ROS have been associated with synaptic dysfunction and the pathogenesis of Parkinson's disease (PD). The available drugs that are used against PD can only delay the progression of the disease, but they produce various side effects. Through their antioxidant activity, flavonoids can substantiate the EADS of dopaminergic neurons and disrupt the vicious cycle incepted by oxidative stress. In this review, we show how the oxidative metabolism of dopamine generates ROS and dopamine-quinones, which then exert unrestrained OS, causing mutations in several genes involved in the proper functioning of mitochondrion, synapse, and lysosome. Besides, we also present some examples of approved drugs used for the treatment of PD, therapies in the clinical trial phase, and an update on the flavonoids that have been tested to boost the EADS of dopaminergic neurons.

Epilepsy, characterized by recurrent seizures and abnormal brain discharges, is the third most common chronic disorder of the Central Nervous System (CNS). Although significant progress has been made in the research on antiepileptic drugs (AEDs), approximately one-third of patients with epilepsy are refractory to these drugs. Thus, research on the pathogenesis of epilepsy is ongoing to find more effective treatments. Many pathological mechanisms are involved in epilepsy, including neuronal apoptosis, mossy fiber sprouting, neuroinflammation, and dysfunction of neuronal ion channels, leading to abnormal neuronal excitatory networks in the brain. CK2 (Casein kinase 2), which plays a critical role in modulating neuronal excitability and synaptic transmission, has been shown to be associated with epilepsy. However, there is limited research on the mechanisms involved. Recent studies have suggested that CK2 is involved in regulating the function of neuronal ion channels by directly phosphorylating them or their binding partners. Therefore, in this review, we will summarize recent research advances regarding the potential role of CK2 regulating ion channels in epilepsy, aiming to provide more evidence for future studies.

Alzheimer's disease (AD) is a commonly reported neurodegenerative disorder associated with dementia and cognitive impairment. The pathophysiology of AD comprises Aβ, hyperphosphorylated tau protein formation, abrupt cholinergic cascade, oxidative stress, neuronal apoptosis, and neuroinflammation. Recent findings have established the profound role of immunological dysfunction and microglial activation in the pathogenesis of AD. Microglial activation is a multifactorial cascade encompassing various signalling molecules and pathways such as Nrf2/NLRP3/NF-kB/p38 MAPKs/ GSK-3β. Additionally, deposited Aβ or tau protein triggers microglial activation and accelerates its pathogenesis. Currently, the FDA-approved therapeutic regimens are based on the modulation of the cholinergic system, and recently, one more drug, aducanumab, has been approved by the FDA. On the one hand, these drugs only offer symptomatic relief and not a cure for AD. Additionally, no targetedbased microglial medicines are available for treating and managing AD. On the other hand, various natural products have been explored for the possible anti-Alzheimer effect via targeting microglial activation or different targets of microglial activation. Therefore, the present review focuses on exploring the mechanism and associated signalling related to microglial activation and a detailed description of various natural products that have previously been reported with anti-Alzheimer's effect via mitigation of microglial activation. Additionally, we have discussed the various patents and clinical trials related to managing and treating AD.

The endovascular treatment of posterior circulation aneurysms, although challenging, has been well-established due to various factors that limit the surgical approach in most cases. Flow diversion has also been utilized in the treatment of such aneurysms, although its effectiveness and safety still require evaluation. Numerous studies have examined the outcomes and complication rates in patients treated with FD, resulting in varying findings. This review aimed to summarize the most recent literature concerning the effectiveness of flow diversion devices in posterior circulation aneurysms. Additionally, it highlights reports that compare results in the posterior versus anterior circulation, as well as flow diversion versus stent-assisted coiling.

Parkinson's disease (PD) is a debilitating neurological disorder characterized by progressively worsening motor dysfunction. Currently, available therapies merely alleviate symptoms, and there are no cures. Consequently, some researchers have now shifted their attention to identifying the modifiable risk factors of PD, with the intention of possibly implementing early interventions to prevent the development of PD. Four primary risk factors for PD are discussed including environmental factors (pesticides and heavy metals), lifestyle (physical activity and dietary intake), drug abuse, and individual comorbidities. Additionally, clinical biomarkers, neuroimaging, biochemical biomarkers, and genetic biomarkers could also help to detect prodromal PD. This review compiled available evidence that illustrates the relationship between modifiable risk factors, biomarkers, and PD. In summary, we raise the distinct possibility of preventing PD via early interventions of the modifiable risk factors and early diagnosis.