CNS & neurological disorders drug targets最新文献

Background: A meaningful part of schizophrenia patients suffer from physiosomatic symptoms (formerly named psychosomatic), which are reminiscent of chronic fatigue syndrome and fibromyalgia (FF) and are associated with signs of immune activation and increased levels of tryptophan catabolites (TRYCATs).

Aims: The study aims to examine whether FF symptoms in schizophrenia are associated with the breakdown of the paracellular pathway, zonulin, lowered natural IgM responses to oxidative specific epitopes (OSEs); and whether FF symptoms belong to the behavioral-cognitive-physical-psychosocial- (BCPS)-worsening index consisting of indices of a general cognitive decline (G-CoDe), symptomatome of schizophrenia, and quality of life (QoL)-phenomenome.

Methods: FF symptoms were assessed using the Fibromyalgia and Chronic Fatigue Rating scale in 80 schizophrenia patients and 40 healthy controls and serum cytokines/chemokines, IgA levels to TRYCATs, IgM to OSEs, zonulin and transcellular/paracellular (TRANS/PARA) molecules were assayed using ELISA methods.

Results: A large part (42.3%) of the variance in the total FF score was explained by the regression on the PARA/TRANS ratio, pro-inflammatory cytokines, IgM to zonulin, IgA to TRYCATs (all positively), and IgM to OSEs (inversely). There were highly significant correlations between the total FF score and G-CoDe, symtopmatome, QoL phenomenome, and BCPS-worsening score. FF symptoms belong to a common core shared by G-CoDe, symtopmatome, and QoL phenomenome.

Conclusion: The physio-somatic symptoms of schizophrenia are driven by various pathways, including increased zonulin, breakdown of the paracellular tight-junctions pathway, immune activation with induction of the TRYCAT pathway, and consequent neurotoxicity. It is concluded that FF symptoms are part of the phenome of schizophrenia and BCPS-worsening as well.

Background: Alzheimer's disease (AD) is one of the most common causes of dementia, affecting many old people.

Objectives: By designing and synthesizing intracerebral imaging probes, we tried to provide a new solution for the early diagnosis of AD.

Methods: We designed and synthesized bis-iodine-labeled curcumin, and verified its performance through in vivo and in vitro experiments.

Results: In this study, bis-iodine-labeled curcumin (7, BICUR) was synthesized. In the in vitro mass spectrum binding assay, K_d values of BICUR with Aβ1-40 and Aβ1-42 aggregates were 46.29 nM and 64.29 nM, respectively. Aβ plaques in AD brain adjacent sections were positively stained by BICUR, which was similar to some other curcumin derivatives. The Log P value of BICUR was 1.45. In the biodistribution experiment, BICUR showed the highest initial brain uptake (5.87% compared to the blood concentration) two minutes after the tail vein injection and rapid clearance from the mouse brain. In the acute toxicity experiment, BICUR showed low toxicity, and the LD₅₀ was >100 mg/kg. Moreover, BICUR showed a high stability in vitro (86.68% unchanged BICUR after incubation for 120min in mouse brain homogenate). Besides, BICUR produced an enhanced CT imaging effect that could be sensitively detected in vitro, but it also showed an obvious differentiation from surrounding tissues after intracerebral injection.

Conclusion: All results suggested that BICUR could probably act as a targeted CT imaging agent for Aβ plaques in the brain.

Background: Alzheimer's disease (AD) is one of the most common irreversible degenerative diseases of the central nervous system. Recent studies have found that patients with AD generally experience abnormal glucose metabolism. Xylitol is a functional sugar alcohol, which has been reported to regulate glucose metabolism.

Objective: The present study was designed to determine whether xylitol can alleviate cognitive impairment in AD mice.

Methods: In the current research, 5% xylitol was supplemented in the diet to treat APP/PS1 transgenic AD mice for 2 months. Cognitive ability was measured by the Morris water maze, and anxiety-like behaviors were examined by open-field experiment. Hippocampal cellular apoptosis and mitochondria pathway related apoptotic proteins were tested by TUNEL staining and immunoblotting, respectively. By LC-MS, plasma levels of glucose metabolism intermediates and related amino acids were evaluated.

Results: Results showed that xylitol could significantly ameliorate anxiety-like activity in AD mice by partially regulating expression levels of mitochondrial pathway-related apoptotic proteins. Xylitolregulated glucose metabolism may play an important role in the process.

Conclusion: The current study suggests that xylitol may be a potential candidate for improving neuropsychiatric behavior in AD by regulating the levels of TCA cycle intermediates and related amino acids in glucose metabolism.

Parkinson's disease (PD) is the second most common neurodegenerative disease affecting around 10 million people worldwide. Dopamine agonists that mimic the action of natural dopamine in the brain are the prominent drugs used in the management of PD symptoms. However, the therapy is limited to symptomatic relief with serious side effects. Phytocompounds have become the preferable targets of research in the quest for new pharmaceutical compounds. In addition, current research is directed towards determining a newer specific target for the better treatment and management of PD. Cav-1, a membrane protein present on the caveolae of the plasma membrane, acts as a transporter for lipid molecules in the cells. Cav-1 has been implicated in the pathogenesis of neurodegenerative diseases, like Alzheimer's disease (AD), PD, etc. In this review, we have extensively discussed the role of Cav-1 protein in the pathogenesis of PD. In addition, molecular docking of some selective phytochemical compounds against Cav-1 protein (Q03135) was performed to understand their role. The best phytochemical compounds were screened based on their molecular interaction and binding affinity with the Cav-1 protein model.

Unani system of medicine is based on the use of natural plant products. Unani polyherbal formulations (UPFs) are being prescribed for the treatment of various ailments. The preparations of the UPFs also required the animal products such as honey and umber. UPFs have been reported to cure various diseases but still lack scientific credibility. The Unani system is based on the holistic approach; the synergistic role of the compounds has been suggested to play a protective role against the illness. The present review has compiled the studies carried out on UPFs used to treat various diseases with special reference to neurodegenerative ailments. The exorbitant cost of conventional treatment has led the world to think towards alternative therapy with less cost and no or little side effects compared to conventional treatments. More research is required for UPFs on the experimental models along with the case controlled studies in order to establish UPFs in the mainstream of treatment.

Introduction: The efficacy of oxytocin in the treatment of autism spectrum disorder (ASD) has not been fully characterized. This systematic review and meta-analysis study evaluated randomized controlled trials (RCTs) on the treatment of intranasally administered oxytocin for autism.

Methods: The study was conducted in accordance with the PRISMA statement. Two authors searched Scopus, PubMed/ Medline, Google Scholar, and Web of Science search engines and databases from inception through December 2020. Quality assessment was carried out by with the "ROB-2, Cochrane collaboration's tool". The random-effects model was used for pooled analyses. I2 and Q tests were used to investigate study heterogeneity. The visual inspection of funnel plots along with Egger's regression asymmetry test was used to assess the potential sources of publication bias.

Results: Ten RCTs were selected for the systematic review. No study corroborated the efficacy of oxytocin for the treatment of anxiety and repetitive behavior. One out of 4 studies reported clinical improvement in severity, and 1 out of 6 studies indicated improvement in social function. Our metaanalyses findings suggest that oxytocin shows no significant efficacy in the treatment of anxiety (SMD: -0.168, SE= 0.112; 95% CI: -0.387, 0.050, p = 0.132), repetitive behavior (SMD: -0.078, SE= 0.155; 95% CI: -0.382, 0.225, p = 0.614), social function (SMD: -0.018, SE= 0.133; 95% CI: -0.279, 0.242, p = 0.891) and severity (SMD: -0.084, SE= 132; 95% CI: -0.343, 0.175, p = 0.524) of autism. No significant heterogeneity nor publication bias were observed between studies.

Conclusion: Our findings failed to corroborate the efficacy of oxytocin in the treatment of ASD. Nonetheless, given the several limitations of our study, the results should be interpreted cautiously and stimulate future research on this timely topic.

Neuroinflammation is one of the major pathological factors leading to Alzheimer's disease (AD). The role of microglial cells in neuroinflammation associated with AD has been known for a long time. Recently, astrocytic inflammatory responses have been linked to the neuronal degeneration and pathological development of AD. Lipopolysaccharide (LPS) and Amyloid Beta (Aβ) activate astrocytes and microglial cells via toll-like 4 (TLR4) receptors leading to neuroinflammation. Reactive (activated) astrocytes mainly comprising of A1 astrocytes (A1s) are involved in neuroinflammation, while A2 astrocytes (A2s) possess neuroprotective activity. Studies link low dopamine (DA) levels during the early stages of neurodegenerative disorders with its anti-inflammatory and immuoregulatory properties. DA mediates neuroprotection via inhibition of the A1 astrocytic pathway through blockade of NF-kB and nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3); and promotion of A2 astrocytic pathways leading to the formation of neurotrophic factors like BDNF and GDNF. In this current review, we have discussed the crosstalk between the dopaminergic system in astrocytic TLR4 and NF-kB in addition to NLRP3 inflammasome in the modulation of neuroinflammatory pathologies in cognitive deficits.

Epilepsy and migraine are chronic neurological disorders with shared clinical as well as pathophysiological mechanisms. Epileptic patients are at a higher risk of developing migraine compared to normal individuals and vice versa. Several genetic and environmental risk factors have been reported to be associated with the development of both diseases. Previous studies have already established standard genetic markers involved in various pathways implicated in the pathogenesis of both these comorbid conditions. In addition to genetic markers, epigenetic markers have also been found to be involved in the pathogenesis of epilepsy and migraine. Among the epigenetic markers, miRNAs have been explored at length and have emerged as significant players in regulating the expression of their target genes. miRNAs like miR-22, miR-34a, miR-155, miR-211, and Let-7b play a significant role in neuronal differentiation and seem to be associated with epilepsy and migraine as comorbid conditions. However, the exact shared mechanisms underlying the role of these miRNAs in these comorbid conditions are still unclear. The current review has been compiled with an aim to explore common microRNAs targeting the genes involved in shared molecular pathways leading to epilepsy and migraine as comorbid conditions. The new class of ncRNAs, i.e., tRNA transfer fragments, are also discussed. In addition, their role as potential biomarkers and therapeutic targets has also been evaluated. However, limitations exist, and based on the current literature available, only a few microRNAs seem to be involved in the pathogenesis of both these disorders.

Dementia is a complex syndrome of neurological disorders which is associated with cognitive functions of the body. The present review focuses on the role and application of natural products in the treatment of dementia and related diseases. The studies highlight that there exist some potent synthetic/semisynthetic drugs that can effectively target dementia and related diseases. In contrast, despite the existence of a large library of natural products, only a few of them (galantamine, huperzine A, etc.) have been approved as drugs against dementia. This fact is not discouraging because a large number of natural products, including classes of polyphenols, alkaloids, isothiocyanates, phytocannabinoids, and terpenoids, are in the process of drug development stages against dementia and related diseases. It is because they display some promising and diverse biological activities, including antioxidant, acetylcholinesterase inhibitory activity, and anti-amyloidogenic properties, which are significantly associated with the prevention of dementia syndrome. The studies reported in the literature reveal that bioactive natural products particularly target Alzheimer's and Parkinson's diseases by suppressing the risks responsible for dementia. Huperzine A has been identified as a potent natural product against Alzheimer's disease. Despite the efficient role of natural products in preventing dementia, their direct application as drugs is still limited due to some controversial results obtained from their clinical trials; however, bioassay-guided drug development studies can prove them potential drugs against dementia and related diseases. This review provides useful information for researchers, pharmacologists, and medical doctors.

Background: Waterpipe smoking (WP) exposure involves a negative health impact, including memory deficit, which is attributed to the elevation of oxidative stress. Vitamin E (VitE) in combination with swimming exercise exerts protective effects that prevent memory impairment. In the current study, the modulation of WP-induced memory impairment by the combined effect of VitE and swimming exercise (SE) was investigated.

Methods: Animals were exposed to WP one hour/day, five days per week for four weeks. Simultaneously, VitE (100 mg/kg, six days/week for four weeks) was administered via oral gavage, and the rats were made to swim one hour/day, five days/week for four weeks. Changes in memory were evaluated using radial arm water maze (RAWM), and oxidative stress biomarkers were examined in the hippocampus.

Results: WP exposure induced short-term/long-term memory impairment (p<0.05). This impairment was prevented by a combination of VitE with SE (p<0.05). Additionally, this combination normalized the hippocampal catalase, GPx, and GSH/GSSG ratios that were modulated by WP (p<0.05). The combination further reduced TBARs levels below those of the control group (p<0.05).

Conclusion: WP-induced memory impairments were prevented by the combination of VitE with SE. This could be attributed to preserving the hippocampal oxidative mechanism by combining VitE and SE during WP exposure.