CNS & neurological disorders drug targets最新文献

Introduction: Alzheimer's disease (AD) lacks effective biomarkers and diseasemodifying therapies. This study explored transcriptomic dysregulation, immune-metabolic crosstalk, and drug repurposing opportunities in AD.

Methods: Transcriptomic datasets (GSE109887, GSE5281) were harmonized using batch correction. Differentially expressed genes (DEGs) were identified, and Weighted Gene Co-Expression Network Analysis (WGCNA) prioritized AD-associated modules. Machine learning (RF+LDA) validated diagnostic genes across external cohorts (GSE29378, GSE122063). Functional enrichment, immune infiltration (CIBERSORT), single-cell analysis (AlzData), Mendelian randomization (MR), and drug repurposing (DSigDB/CB-Dock2) were employed.

Results: WGCNA identified the yellow module as most AD-relevant. Machine learning prioritized 15 diagnostic genes (e.g., CASP6, LDHA, CHRM1), achieving AUCs of 0.941 (training) and 0.715- 0.910 (validation). Single-cell analysis confirmed their dysregulation in AD brains. MR revealed FIBP as a protective factor, inversely linked to AD risk. Immune profiling showed increased naive B cells and M1 macrophages in AD. Ketamine exhibited the highest drug enrichment (fold enrichment = 49.12), with strong binding to CASP6 (-5.3 kcal/mol), CHRM1 (-7.8 kcal/mol), and LDHA (-6.7 kcal/mol).

Discussion: CASP6, LDHA, and CHRM1 underpin immune-metabolic dysregulation in AD. Ketamine targets these genes, suggesting therapeutic potential. FIBP's protective role and naive B-cell shifts offer novel mechanistic insights.

Conclusion: This integrative study identifies robust diagnostic biomarkers and nominates ketamine for repurposing in AD. Experimental validation of ketamine's neuroprotective effects and FIBP's role is warranted.

Alzheimer's disease (AD) is a leading source of dementia, evidenced by cognitive debility, tau neurofibrillary tangles, and amyloid-β plaques. Recent studies emphasize the gut-brain axis as a vital element in the pathogenesis of Alzheimer's disease, involving microbial, neuronal, immunological, and hormonal mechanisms. The composition of gut microbiota dysbiosis is determined by growth in intestinal barrier permeability and activation of immune cells, which causes impaired function of the blood-brain barrier that stimulates neural injury, neuronal loss, neuroinflammation, and eventually AD. Various studies have reported that the gut microbiota plays a crucial role in brain function and changes in individual behavior, as well as in bacterial amyloid formation. Growing experimental and clinical data specify the conspicuous role of intestinal dysbiosis and microbiota- host interactions in AD. The importance of this paper is the focus on the potential association of AD and gut microbiota and also a discussion of the therapeutic modalities of inhibiting gut dysbiosis.

Introduction: This systematic review aimed to provide an updated overview of studies using anticholinesterases with in vivo activity for the treatment of Alzheimer's disease.

Methods: A systematic review was conducted using searches in the following databases: PubMed, SciELO (Scientific Electronic Library Online), Web of Science, LILACS (Latin American and Caribbean Literature in Health Sciences), as well as gray literature, through the CAPES and Google Scholar databases of national and international journals. The research was registered on the International Prospective Register of Systematic Reviews (PROSPERO) platform under registration number: CRD42024482117 and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol.

Results: A total of 1,191 articles were identified in the databases, of which 11 were selected to compose this systematic review, as they met the previously pre-defined selection criteria. The selected articles were published between 2019 and 2023. The substance most commonly used to induce Alzheimer's was scopolamine. As for administration routes, the most used was intraperitoneal. Some of the methods used to evaluate cognitive processes in rats and mice were- Elevated Plus Maze (EPM), Morris water maze (MWZ), Y maze, and passive avoidance tests.

Discussion: The reviewed studies demonstrated that the evaluated anticholinesterase agents exhibited anti-Alzheimer activity in animal models, with notable cognitive effects observed in behavioral tests.

Conclusion: The data indicated that the analyzed anticholinesterase agents have therapeutic potential for Alzheimer's disease, justifying the continuation of preclinical research and future clinical investigations.

Introduction: JNK3 is a specific isoform of c-Jun N-terminal kinase, mainly found in the brain, and is highly sensitive to stress-associated signals in the central nervous system. It has been reported that JNK3 plays a crucial role in neurite formation and cognition. During pathological states such as Alzheimer's disease, cerebral ischemia, Traumatic brain injury (TBI), Parkinson's disease, and epilepsy, it is found to be in a hyperactivated form. Hyperphosphorylation of amyloid precursor protein (APP) and tau leads to toxic Aβ42 and neurofibrillary tangles. Excess Aβ activates JNK3 signaling, causing neuronal loss. JNK3 also contributes to mitochondrial dysfunction, Oxidative stress, neuroinflammation, and apoptosis, driving AD progression.

Methods: This study aims to identify possible therapeutics based on their physicochemical, ADMET, toxicity, and drug-likeness properties. Moreover, we utilized Molecular docking and Molecular dynamics (MD) simulation to reveal possible inhibitors against JNK3.

Results: Based on the highest binding affinity against JNK3, the best compounds, Myricetin and Kaempferol, were subjected to an MD simulation study. RMSD analysis indicated that the JNK3- Kampferol complex showed more stability; at the same time, myricetin formed more hydrogen bonds with JNK3. Moreover, both compounds exhibited favorable ADMET properties.

Discussion: This study identified Kaempferol and myricetin as potential inhibitors that target JNK3 through molecular docking and MD simulation studies. Both compounds demonstrated favorable ADMET profiles, supporting their promise as safe, orally available drug candidates.

Conclusion: Therefore, Kaempferol and myricetin emerge as promising candidates for further investigations in both in vitro and in vivo studies to treat Alzheimer's disease and other neurodegenerative disorders.

Introduction: Alzheimer's disease (AD), a debilitating neurodegenerative disorder, presents a growing global health challenge due to limited therapeutic options. Ergosterol, known for its neuroprotective and antioxidant properties, suffers from poor bioavailability. This study aimed to develop ergosterol-loaded nanoliposomes (ER-NL-2) and evaluate their safety, antioxidant potential, and therapeutic efficacy in animal models of AD.

Methods: ER-NL-2 was formulated using the ultrasonic thin-film dispersion method and characterized via dynamic light scattering (DLS), zeta potential, and TEM. Acute oral toxicity was assessed in Wistar rats and Swiss mice (2000 mg/kg). Two AD models were employed: Streptozotocin (STZ)- induced in Swiss albino mice and AlCl₃-induced in Wistar albino rats. Behavioral studies included actophotometer and elevated plus maze tests. Antioxidant assays measured SOD, CAT, GSH, and LPO levels. Histopathological analysis of brain tissue was conducted.

Results: ER-NL-2 exhibited a mean droplet size of ~180 nm, PDI <0.3, and zeta potential of -27.9 mV. TEM confirmed spherical morphology. Toxicity studies showed no abnormalities. In both AD models, ER-NL-2 improved locomotor activity and reduced transfer latency. Biochemical analyses revealed elevated SOD, CAT, GSH and reduced LPO levels. Histopathology showed preserved neuronal integrity and reduced neurofibrillary tangles in treated groups.

Discussion: ER-NL-2 demonstrated neuroprotective efficacy through behavioral, biochemical, and histological endpoints, confirming its antioxidative mechanism and brain safety profile. It was comparable to standard therapy (donepezil).

Conclusion: ER-NL-2 is a safe and promising nanocarrier for Alzheimer's treatment with significant neuroprotective and antioxidant properties. Further studies are warranted to explore its pharmacokinetics and clinical applicability.

Several organosulfur compounds exhibit anti-Parkinson's disease (PD) activities. PD is a progressive and chronic neurodegenerative condition that causes motor and non-motor symptoms that severely reduce quality of life. A selective loss of dopaminergic neurons in the substantia nigra, in addition to several neuropathological mechanisms, has been implicated in PD. The present therapeutic techniques are mostly focused on providing symptomatic relief and frequently have significant side effects, which underscores the pressing need for innovative medicines that address the underlying causes of disease. Several organosulfur compounds, both synthesized and naturally occurring analogues, have gained attention as potential anti-PD molecules because of their wide range of biological activities, which include anti-inflammatory, neuroprotective, and antioxidant capabilities. Several organosulfur compounds have been shown to have potential neuroprotective benefits in preclinical research on PD. Their ability to attenuate neuroinflammation, oxidative stress, apoptosis, and mitochondrial dysfunction, which are central to PD pathogenesis via modulation of cellular pathways and endogenous antioxidant defenses, provides multifaceted approaches to neuroprotection in PD. Thus, the current review provides the state of the art on the potential therapeutic effects of organosulfur compounds in PD. The natural and synthetic sources of anti-PD organosulfur compounds, including their physical properties, chemical properties, structure-activity relationship (SAR), and therapeutic effects in PD, were discussed. The challenges and future directions of organosulfur compounds as potential anti-PD drugs and their clinical trial prospects were also highlighted. This is aimed at paving the way for the development of more effective and sustainable treatment strategies for PD.

Introduction: Neurosarcoidosis is a rare and severe manifestation of sarcoidosis, whose natural history still lacks a comprehensive and theoretical understanding. Therefore, we aimed to conduct a qualitative systematic review of the literature on the clinical-epidemiologic, diagnostic, and therapeutic assessment of patients with neurosarcoidosis.

Methods: A qualitative systematic literature review was conducted in accordance with the PRISMA protocol. The search was conducted between January 1954 and December 2024 in the following databases: PubMed, Scopus, Web of Science, CAPES Journal Portal, and the Virtual Health Library (VHL). Articles were selected if they had at least one of the selected descriptors in the title or abstract, were written in English, Portuguese, or Spanish, and dealt with the clinical-epidemiologic, diagnostic, and therapeutic aspects of neurosarcoidosis. Review articles, experimental studies, and short communications were excluded from the analysis.

Results: Seventy-four articles with 551 cases of neurosarcoidosis were included. The majority of studies were case reports, followed by cohort studies conducted in European countries. The methodological quality of most studies was "good".

Discussion: Patients with neurosarcoidosis are primarily women Caucasian ethnicity with a mean age of 43.5 years. The disease most commonly involves the cranial nerves (especially cranial nerve II), followed by aseptic meningitis, panhypopituitarism, ocular changes, and diabetes insipidus. The most common laboratory findings were cerebrospinal fluid abnormalities, hypogonadotropic hypogonadism, hyperprolactinemia, and hypothyroidism. The most common neuroimaging changes were meningeal enhancement and pituitary destruction. The treatment of choice was glucocorticoids in conjunction with or without immunosuppressants, with methotrexate and azathioprine being the most commonly used.

Conclusion: This review identified that manifestations such as cranial nerve alterations, aseptic meningitis, and pituitary infiltrations are frequent patterns in neurosarcoidosis, generally associated with laboratory and imaging findings that aid in the diagnosis. Systematizing these data provides a broad view of the disease and may contribute to early diagnosis and effective therapy. Nevertheless, longitudinal studies with larger samples are needed to better understand its natural history and clinical outcomes in the medium and long term.

Neuroinflammation, characterised by an overactive immune system in the brain and spinal cord, has now been tied to several neurodegenerative diseases. Here, immune cells invade into the brain, activating astrocytes and microglia. Neuroinflammation is a common symptom of many neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This inflammatory reaction occurs within the central nervous system (CNS). Neurological dysfunction results from the inflammatory response, which arises in reaction to any kind of brain injury. Regulating neuroinflammation can be useful for controlling brain disorders associated with neuroinflammation. Several targeted drug delivery systems attempt to treat neuroinflammation caused by neurodegenerative illnesses or brain tumours by targeting the microglia and other immune cells in the central nervous system. Therefore, biodegradable and biocompatible NPs (nanoparticles) could be developed as a treatment for neurodegenerative diseases caused by neuroinflammation or as a less invasive means of transporting other drugs across the blood-brain barrier. Numerous applications of gold nanoparticles (AuNPs) in the treatment of neurological diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), are studied in this article. To prevent neuroinflammation and microglia over-activation, some NPs have recently been found to be effective anti-inflammatory medication carriers that cross the blood-brain barrier.

Introduction: Sodium benzoate (NaBen), a D-amino acid oxidase inhibitor, has been demonstrated to possess antipsychotic and cognition-enhancing effects in animal models. However, the clinical findings in patients with schizophrenia and dementia are mixed and inconclusive.

Objectives: To further improve its therapeutic potential, a novel crystalline polymorph of NaBen (abbreviated as Ω-NaBen) was developed. This study evaluated the physicochemical properties and central nervous system (CNS) effects of Ω-NaBen and investigated its therapeutic potential.

Methods: The novel crystalline structure of Ω-NaBen was confirmed by thermogravimetric analysis, differential scanning calorimetry, and X-ray powder diffractometry. Water solubility test and stability test were performed to compare its physicochemical properties. The CNS exposure and Damino acids levels in brain subregions of Ω-NaBen- and non-Ω-NaBen-treated male mice were determined with LC-MS/MS. Therapeutic effects of Ω-NaBen in the MK-801-induced mouse model were assessed by the open field test, novel object recognition test, and three-chamber social test.

Results: Our findings indicated that Ω-NaBen had a unique crystalline structure and showed better aqueous solubility and crystal stability, either with or without clozapine, compared with amorphous NaBen. Ω-NaBen also showed improved CNS exposure and induced higher levels of D-serine or/and D-alanine in the brain. In MK-801-treated mice, Ω-NaBen displayed enhanced effects in alleviating hyperactivity and stronger potency in relieving cognitive impairment. It also improved efficacy in relieving social deficit, a negative symptom model of schizophrenia.

Conclusion: Our study demonstrated Ω-NaBen's promising potential as a novel CNS therapeutic due to its favorable physicochemical properties, CNS exposure, and neurochemical and behavioral effects.

Persistent swelling in the brain, internal tau bundles, and external Amyloid-Beta (Aβ) deposits are characteristics of Alzheimer's Disease (AD), an ongoing neurodegenerative illness. Microglia are the main immune cells in the CNS (Central Nervous System). They keep the brain stable by keeping an eye on the immune system and removing apoptotic cells and protein clusters through a process called phagocytosis. However, in AD, microglia exhibit dysregulated phagocytic activity, resulting in either insufficient Aβ clearance or exacerbated inflammatory responses, both of which contribute to neurodegeneration. This review examines key molecular pathways, such as those mediated by TREM2 (Triggering Receptor Expressed on Myeloid cells), APOE (Apolipoprotein E), and CD33 (Cluster of Differentiation), that govern microglial activation and influence their neuroprotective or neurotoxic functions. We further explore therapeutic strategies to modulate microglial phagocytosis, pharmacological agents (such as minocycline, pioglitazone, rifampicin, etc.), some natural agents, gene-editing tools, and nanomedicine, which aim to optimise microglial response and reduce the neuroinflammatory burden in AD. Despite promising advances, challenges persist in achieving targeted, effective modulation of microglial function due to microglial heterogeneity, limited model fidelity, and potential off-target effects. This review underscores the importance of refining microglia-targeted interventions and developing combinatory approaches that enhance microglial homeostasis to mitigate AD pathology and progression.