CNS & neurological disorders drug targets最新文献

Introduction: Neuroinflammation derived from the activation of the microglia is considered a vital pathogenic factor of Alzheimer's Disease (AD). T-006, a tetramethylpyrazine derivative, has been found to alleviate cognitive deficits via inhibiting tau expression and phosphorylation in AD transgenic mouse models. Recently, T-006 has been proven to dramatically decrease the levels of total Amyloid β (Aβ) peptide and Glial Fibrillary Acidic Protein (GFAP) and suppress the expression of ionized calcium binding adaptor molecule-1 (Iba-1) in APP/PS1 mice. Therefore, we have further investigated the effects of T-006 on neuroinflammation in AD-like pathology.

Methods: The anti-inflammatory effects of T-006 and its underlying mechanisms were evaluated in Lipopolysaccharide (LPS)-induced AD rats. The potential protective effects against LPS-activated microglia-mediated neurotoxicity were also measured.

Results: T-006 significantly improved the cognitive impairment in LPS-induced AD rats by inhibiting the microglia/astrocyte activation. Further cellular assays found that T-006 significantly reserved the anomalous elevation of inflammatory cytokines in LPS-induced BV2 microglial cells in a concentration-dependent manner, while T-006 treatment alone showed no effects on the normal cultured cells. T-006 also reduced the levels of Toll-like Receptor 4 (TLR4)/Myeloid Differentiation protein-88 (MyD88)/NF-κB signaling-related proteins in BV2 cells exposed to LPS stimulation. TAK242, which selectively inhibits TLR4, slightly lessened the effects of T-006 in LPS-treatment BV2 cells without significance. Importantly, T-006 protected neurons against LPS-induced neuroinflammation by inhibiting the Reactive Oxygen Species (ROS) production and maintaining mitochondrial function.

Conclusion: T-006 inhibited TLR4-mediated MyD88/NF-κB signaling pathways to suppress neuroinflammation in the LPS-induced AD rat model.

Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by social communication deficits and repetitive behaviors. Emerging evidence highlights the significant role of glial cells, particularly astrocytes and microglia, in the pathophysiology of ASD. Glial cells are crucial for maintaining homeostasis, modulating synaptic function, and responding to neural injury. Dysregulation of glial cell functions, including altered cytokine production, impaired synaptic pruning, and disrupted neuroinflammatory responses, has been implicated in ASD. Molecular mechanisms underlying these disruptions involve aberrant signaling pathways, such as the mTOR pathway, and epigenetic modifications, leading to altered gene expression profiles in glial cells. Moreover, microglial activation and reactive astrocytosis contribute to an inflammatory environment that exacerbates neural circuit abnormalities. Understanding these molecular mechanisms opens avenues for therapeutic interventions. Current therapeutic approaches targeting glial cell dysfunction include anti-inflammatory agents, modulators of synaptic function, and cell-based therapies. Minocycline and ibudilast have shown potential for modulating microglial activity and reducing neuroinflammation. Additionally, advancements in gene editing and stem cell therapy hold promise for restoring normal glial function. This abstract underscores the importance of glial cells in ASD. It highlights the need for further research to elucidate the complex interactions between glial dysfunction and ASD pathogenesis, aiming to develop targeted therapies that can ameliorate the clinical manifestations of ASD.

Background: Gliomas are the most frequent, heterogeneous group of tumors arising from glial cells, characterized by difficult monitoring, poor prognosis, and fatality. Tissue biopsy is an established procedure for tumor cell sampling that aids diagnosis, tumor grading, and prediction of prognosis.

Materials and methods: We studied and compared the levels of liquid biopsy markers in patients with different grades of glioma. Also, we tried to prove the potential association between glioma and specific blood group antigens.

Results: 78 patients were found, among whom the maximum percentage with glioblastoma had blood group O+ (53.8%). The second highest frequency had blood group A+ (20.4%), followed by B+ (9.0%) and A- (5.1%), and the least with O-. Liquid biopsy biomarkers included Alanine Aminotransferase (ALT), Lactate Dehydrogenase (LDH), lymphocytes, Urea, Alkaline phosphatase (AST), Neutrophils, and C-Reactive Protein (CRP). The levels of all the components increased significantly with the severity of the glioma, with maximum levels seen in glioblastoma (grade IV), followed by grade III and grade II, respectively.

Conclusion: Gliomas have significant clinical challenges due to their progression with heterogeneous nature and aggressive behavior. A liquid biopsy is a non-invasive approach that aids in setting up the status of the patient and figuring out the tumor grade; therefore, it may show diagnostic and prognostic utility. Additionally, our study provides evidence to prove the role of ABO blood group antigens in the development of glioma. However, future clinical research on liquid biopsy will improve the sensitivity and specificity of these tests and confirm their clinical usefulness to guide treatment approaches.

Background and objective: The brain α7 nicotinic acetylcholine receptor (α7 nAChR) has a critical role in the pathophysiology of Major Depressive Disorder (MDD) involving neuroinflammation. The α7 nAChR stimulation has been shown to modulate the anti-inflammatory effects of nuclear peroxisome proliferator-activated receptor-α (PPAR-α) via its endogenous ligands in the brain. The present study determined the effects of α7 nAChR modulator PNU120596 on PPAR-α, an inhibitor of κB (IκB) and nuclear factor-κB (NF-κB) expression and interleukin-1β (IL-1β) level in the hippocampus and prefrontal cortex (PFC) in an inflammatory mouse model of MDD induced by lipopolysaccharide (LPS). We also evaluated the combined effects of PNU120596 and GW6471, a PPAR-α antagonist, on depressive-like and cognitive deficit-like behaviors in mice.

Materials and methods: Male C57BL/6J mice were treated with PNU120596, followed by systemic LPS (1 mg/kg, i.p.) administration. The effects of PNU120596 on the mRNA expression of PPAR-α and IκB were assessed in the hippocampus and PFC using qRT-PCR following LPS administration. Similarly, the effects of PNU120596 on the immunoreactivity of PPAR-α and NF-κB were measured in the hippocampus and PFC using an immunofluorescence assay. Furthermore, the effects of PNU120596 on pro-inflammatory cytokine IL-1β levels were measured in the hippocampus and PFC using ELISA. The combined effects of PNU120596 and GW6471 were also assessed against LPS-induced depressive-like and cognitive deficit-like behaviors using the Tail Suspension Test (TST), Forced Swim Test (FST), and Y-maze test.

Results: PNU120596 (4 mg/kg) significantly prevented LPS-induced dysregulation of PPAR-α, IκB, p-NF-κB p⁶⁵, and IL-1β in the hippocampus and PFC. Pretreatment with PNU120596 showed significant antidepressant-like effects by reducing immobility time in the TST and FST. Similarly, pretreatment with PNU120596 significantly reduced cognitive deficit-like behavior in the Y-maze test. The antidepressant and pro-cognitive-like effects of PNU120596 were reversed by PPAR-α antagonist GW6471 (2 mg/kg).

Conclusion: These results suggest that PNU120596 prevented LPS-induced MDD and cognitivelike behavior by regulating α7 nAChR/PPAR-α signaling pathway in the hippocampus and PFC.

Introduction: Ischemic injury to the brain can result in a variety of life-threatening conditions, mortality, or varying degrees of disability. Hypoxia-inducible factor 1α (HIF 1α), an oxygen- sensitive transcription factor that controls the adaptive metabolic response to hypoxia, is a critical constituent of cerebral ischemia. It participates in numerous processes, such as metabolism, proliferation, and angiogenesis, and plays a major role in cerebral ischemia.

Methods: Through the use of a number of different search engines like Scopus, PubMed, Bentham, and Elsevier databases, a literature review was carried out for investigating the pharmacological modulation of HIF-1α pathways for the treatment of cerebral ischemia.

Results: Various signalling pathways, such as Mitogen-activated protein kinase (MAPK), Janus kinase/ signal transducers and activators (JAK/STAT), Phosphoinositide-3-kinase (PI3-K), and cAMPresponse element binding protein (CREB) play a vital role in modulation of HIF-1α pathway, which helps in preventing the pathogenesis of cerebral ischemia.

Conclusion: The pharmacological modulation of the HIF-1α pathway via various molecular signalling pathways, such as PI3-K, MAPK, CREB, and JAK/STAT activators, offer a promising prospect for future interventions and treatment for cerebral ischemia.

Background: Parkinson's Disease (PD) is frequently associated with a spectrum of sleep-related disorders, including insomnia, Excessive Daytime Sleepiness (EDS), REM sleep Behaviour Disorder (RBD), Restless Legs Syndrome (RLS), and Sleep-related Breathing Disorders (SBDs). These disorders significantly impact PD patients' Quality of Life (QoL) and present unique diagnostic and therapeutic challenges.

Methods: This review has explored the intricate relationship between PD and sleep-related disorders, emphasizing their distinctive features and underlying neurobiological mechanisms. It aimed to consolidate current knowledge to optimize clinical management and improve patient care. The profound impact of these disorders on QoL has been evaluated, along with precise diagnostic methodologies. Additionally, various therapeutic strategies, including pharmacological treatments, nonpharmacological interventions, and device-aided therapies, have been examined.

Results: Sleep-related disorders are prevalent among PD patients. Specifically, RBD exhibits a prevalence of 40-50%, often preceding the onset of motor symptoms, indicating its potential as an early marker of PD. Despite their significant impact on QoL, these non-motor symptoms are frequently under-recognized and inadequately managed in clinical practice. Pharmacological treatments, along with nonpharmacological interventions, like cognitive-behavioral therapy for insomnia and lifestyle modifications, have shown varied efficacy. Device-aided therapies have also demonstrated the potential to improve sleep-related disorders and overall non-motor symptom burden.

Conclusion: Effective management of sleep-related disorders in PD calls for personalized, comprehensive, and multimodal therapeutic approaches. This requires the collaborative efforts of neurologists, sleep specialists, psychiatrists, and other healthcare professionals. Future research should focus on the intricate relationship between PD and sleep disorders, aiming to develop innovative treatments and significantly improve patient outcomes.

Parkinson's Disease (PD) is a progressive neurodegenerative disorder marked by the deterioration of dopamine-producing neurons, resulting in motor impairments like tremors and rigidity. While the precise cause remains elusive, genetic and environmental factors are implicated. Mitochondrial dysfunction, oxidative stress, and protein misfolding contribute to the disease's pathology. Current therapeutics primarily aim at symptom alleviation, employing dopamine replacement and deep brain stimulation. However, the quest for disease-modifying treatments persists. Ongoing clinical trials explore novel approaches, such as neuroprotective agents and gene therapies, reflecting the evolving PD research landscape. This review provides a comprehensive overview of PD, covering its basics, causal factors, major pathways, existing treatments, and a nuanced exploration of ongoing clinical trials. As the scientific community strives to unravel PD's complexities, this review offers insights into the multifaceted strategies pursued for a better understanding and enhanced management of this debilitating condition.

The prevalence of neurodegenerative diseases has increased with longer life expectancies, necessitating the exploration of novel neuroprotective agents. Tangeretin, a polymethoxylated flavone derived from citrus fruits, has gathered attention for its potential therapeutic effects. This review highlights the neuroprotective properties of tangeretin via its antioxidant and anti-inflammatory mechanisms. Tangeretin demonstrates efficacy in mitigating oxidative stress, neuroinflammation, and neuronal damage across various neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, cerebral ischemia, and epilepsy. It shows promise in ameliorating cognitive deficits and memory impairments associated with these diseases. Moreover, tangeretin modulates multiple signalling pathways and protects against neuronal apoptosis, underscoring its potential as a therapeutic agent.

Alzheimer's disease is an ailment that is linked with the degeneration of the brain cells, and this illness is the main cause of dementia. Metabolic stress affects the activity of the brain in AD via FOXO signaling. The occurrence of AD will significantly surge as the world's population ages, along with lifestyle changes perceived in current decades, indicating a main contributor to such augmented prevalence. Similarly, metabolic disorders of current adulthood, such as obesity, stroke, and diabetes mellitus, have been observed as the risk-causing factors of AD. Environmental influences induce genetic mutations that result in the development of several diseases. Metabolic disorders develop when individuals are exposed to an environment where food is easily accessible and requires minimal energy expenditure. Obesity and diabetes are among the most significant worldwide health concerns. Obesity arises because of an imbalance between the amount of energy consumed and the amount of energy expended, which is caused by both behavioral and physiological factors. Obesity, insulin resistance syndrome, hypertension, and inflammation are factors that contribute to the worldwide risk of developing diabetes mellitus and neurodegenerative diseases. FOXO transcription factors are preserved molecules that play an important part in assorted biological progressions, precisely in aging as well as metabolism. Apoptosis, cell division and differentiation, oxidative stress, metabolism, and lifespan are among the physiological processes that the FOXO proteins are adept at controlling. In this review, we explored the correlation between signaling pathways and the cellular functions of FOXO proteins. We have also summarized the intricate role of FOXO in AD, with a focus on metabolic stress, and discussed the prospect of FOXO as a molecular link between AD and metabolic disorders.

Alzheimer's Disease (AD) is a neurodegenerative disorder mainly characterized by dementia and cognitive decline. AD is essentially associated with the presence of aggregates of the amyloid-β peptide and the hyperphosphorylated microtubule-associated protein tau. The available AD therapies can only alleviate the symptoms; therefore, the development of natural treatments that exhibit neuroprotective effects and correct the behavioral impairment is a critical requirement. The present review aims to collect the natural substances that have been evaluated for their neuroprotective profile against AD-like behaviors induced in zebrafish (Danio rerio) by scopolamine. We focused on articles retrieved from the PubMed database via preset searching strings from 2010 to 2023. Our review assembled 21 studies that elucidated the activities of 28 various natural substances, including bioactive compounds, extracts, fractions, commercial compounds, and essential oils. The listed compounds enhanced cognition and showed several mechanisms of action, namely antioxidant potential, acetylcholinesterase's inhibition, and reduction of lipid peroxidation. Additional studies should be achieved to demonstrate their preventive and therapeutic activities in cellular and rodent models. Further clinical trials would be extremely solicited to support more insight into the neuroprotective effects of the most promising drugs in an AD context.