Neuronal Disorders Research Articles

Exploring novel and potent glycogen synthase kinase-3β inhibitors through systematic drug designing approach

Significant implications of glycogen synthase kinase-3β (GSK-3β) have been reported in various neuronal disorders and malignant cancers. GSK-3β modulates diverse protein targets through phosphorylation, and its aberrant activity leads to neurological complications as well as tumour onset. Therefore, inhibiting GSK-3β activity through active-site fitting molecules may offer a favourable strategy for intercepting these disorders. This comprehensive study used multiple assays in tandem in order to explore the most potent GSK-3β inhibitor. Following structural similarity screening, 135 molecular docking and 135 standard MM-GBSA experiments were performed using AZD1080, a known inhibitor as standard. Among the 32 molecules demonstrating a stronger binding affinity than reference, only the two most potent molecules were chosen and their binding free energy was compared to AZD1080 using the Desmond trajectory clustering and eventual MM-GBSA. Additionally, the interaction status of these molecules and AZD1080 with GSK-3β was explored post-molecular dynamics. The stability of the strongest molecule (most potent) was evaluated in the active site of the above-mentioned kinase keeping its apo-form as reference. Notably, the e-Pharmacophores mapping was performed to address the level of complementarity of the most potent molecule and AZD1080 with the functional site of GSK-3β. Using various techniques, we identified the molecule with PubChem CID: 11167509 as the strongest molecule for obstructing GSK-3β, which may serve as a promising therapeutic after the meticulous evaluation on diverse models.

Congenital Bilateral Perisylvian Syndrome: A Rare Case.

Congenital bilateral perisylvian syndrome (CBPS) is a rare neuronal migration disorder of cortical development characterized by polymicrogyria on magnetic resonance imaging. Features include pseudobulbar palsy, language and speech difficulties, epilepsy, and cognitive deficits. We discuss the management of the case of a five-year-old male with classical features of CBPS.

Mesial Temporal Lobe Epilepsy as a Common but Elusive Case: A Case Report

Epilepsy is a common neuronal disorder that could include partial or generalized seizures due to abnormal brain electrical activity. A 32-year-old female patient was presented to the emergency room with a chief complaint of seizure. The seizure semiology started with epigastric pain, which then progressed into sudden speech arrest. Afterward, the patient experienced left-sided head movement followed by jerkings on the left hand. The patient then became unconscious and experienced full body rigidity. Physical examinations, vital signs, and laboratory results showed no abnormalities. Diagnostic assessments only showed unspecific signs of diffuse cerebral edema through a CT Scan and an atrophy of the right hippocampus with a slight increase in FLAIR signal intensity and dilatation of the right lateral ventricle pericornu through MRI. The patient was given phenytoin and folic acid twice daily. The presence of right mesial temporal sclerosis served as a possible cause of epilepsy in this patient despite having several obscurities. The patient showed atypical signs of generalized tonic seizure progression, adult-onset seizures, and increased MRI FLAIR signal intensity. More detailed examinations and constant reports of epilepsy cases are highly needed among physicians to provide more specific methods and tools to diagnose, classify, and treat epilepsy in the future.

Transcriptome-wide alternative mRNA splicing analysis reveals post-transcriptional regulation of neuronal differentiation.

Alternative splicing (AS) plays an important role in neuronal development, function, and disease. Efforts to analyze the transcriptome of AS inneurons on a wide scale are currently limited. We characterized the transcriptome-wide AS changes in SH-SY5Y neuronal differentiation model, which is widely used to study neuronal function and disorders. Our analysis revealed global changes in five AS programs that drive neuronal differentiation. Motif analysis revealed the contribution of RNA-binding proteins (RBPs) to the regulation of AS during neuronal development. We concentrated on the primary alternative splicing program that occurs during differentiation, specifically on events involving exon skipping (SE). Motif analysis revealed motifs for polypyrimidine tract-binding protein 1 (PTB) and ELAV-like RNA binding protein 1 (HuR/ELAVL1) to be the top enriched in SE events, and their protein levels were downregulated after differentiation. shRNA knockdown of either PTB and HuR was associated with enhanced neuronal differentiation and transcriptome-wide exon skipping events that drive the process of differentiation. At the level of gene expression, we observed only modest changes, indicating predominant post-transcriptional effects of PTB and HuR. We also observed that both RBPs altered cellular responses to oxidative stress, in line with the differentiated phenotype observed after either gene knockdown. Our work characterizes the AS changes in a widely used and important model of neuronal development and neuroscience research and reveals intricate post-transcriptional regulation of neuronal differentiation.

The Impact of Mitochondria on Neurodegenerative Diseases

Neurodegenerative diseases (NDDs) include Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), which are defined by the progressive deterioration of neurons in the central nervous system and functional decline. The pathogenesis of these diseases is complex and there is currently no effective treatment. For example, the failure rate of clinical trials for AD treatment strategies is as high as 99.5%. Research indicates that elements such mitochondrial malfunction, oxidative stress, excitotoxicity, inflammation, and apoptosis are closely related to the onset of NDDs, especially mitochondrial dysfunction, which is considered to be one of the core mechanisms of NDDs. Mitochondria are not only the main production site of ATP, but also participate in key processes such as metabolite synthesis and reactive oxygen generation. Due to the high energy demand of brain neurons and their high dependence on mitochondrial function, abnormal mitochondrial function may lead to serious neuronal structural and functional disorders. In addition, neurons also need to maintain local activities such as synaptic transmission and axonal transport through the precise transport and distribution of mitochondria. Therefore, abnormalities in mitochondrial dynamics and function may become early characteristics and potential pathogenic factors of NDDs. By reviewing the mechanism of mitochondrial abnormalities in AD, PD, and HD and their potential therapeutic strategies.This article seeks to investigate mitochondria as a prospective target for the prevention, early detection, and treatment of NDD

Unraveling the genetic mysteries of spinal muscular atrophy in Chinese families

ObjectiveSpinal muscular atrophy (SMA) is a motor neuron disorder encompassing 5q and non-5q forms, causing muscle weakness and atrophy due to spinal cord cell degeneration. Understanding its genetic basis is crucial for genetic counseling and personalized treatment options.MethodsThis study retrospectively analyzed families of patients suspected of SMA at our institution from February 2006 to March 2024. Various molecular techniques, including multiplex ligation-dependent probe amplification analysis, long-range polymerase chain reaction (PCR) combined with nested PCR, Sanger sequencing, and whole-exome sequencing were employed to establish a thorough genetic variant profile in 680 Chinese pedigrees with clinically suspected SMA.ResultsOut of 680 families suspected of having SMA, 675 exhibited mutations in the SMN1 gene, while three families were linked to mutations in the IGHMBP2 gene. One family exhibited a genetic variation in the NEB gene, and another family exhibited a variation in the SCO2 gene. Among the families with mutations in the SMN1 gene, 645 families exhibited either E7‒E8 or E7 homozygous deletion. Some families displayed E7‒8 heterozygous deletions along with other mutations, such as E1 or E1‒6 heterozygote deletion and point mutations. Furthermore, one family demonstrated a compound-heterozygous double mutation, while another carried a type “2 + 0” mutation alongside a point mutation.ConclusionsThis study comprehensively analyzed the genetics of suspected familial SMA cases in the Chinese population, providing insights into the molecular genetic mechanisms of SMA and the utility of various detection techniques. The findings revealed important implications for genetic counseling, prenatal diagnosis, and targeted therapies in clinical practice.

The Primary Cilia are Associated with the Axon Initial Segment in Neurons.

The primary cilia serve as pivotal mediators of environmental signals and play crucial roles in neuronal responses. Disruption of ciliary function has been implicated in neuronal circuit disorders and aberrant neuronal excitability. However, the precise mechanisms remain elusive. To study the link between the primary cilia and neuronal excitability, manipulation of somatostatin receptor 3 (SSTR3) is investigated, as an example of how alterations in ciliary signaling may affect neuronal activity. It is found that aberrant SSTR3 expression perturbed not only ciliary morphology but also disrupted ciliary signaling cascades. Genetic deletion of SSTR3 resulted in perturbed spatial memory and synaptic plasticity. The axon initial segment (AIS) is a specialized region in the axon where action potentials are initiated. Interestingly, loss of ciliary SSTR3 led to decrease of Akt-dependent cyclic AMP-response element binding protein (CREB)-mediated transcription at the AIS, specifically downregulating AIS master organizer adaptor protein ankyrin G (AnkG) expression. In addition, alterations of other ciliary proteins serotonin 6 receptor (5-HT6R)and intraflagellar transport protein 88 (IFT88) also induced length changes of the AIS. The findings elucidate a specific interaction between the primary cilia and AIS, providing insight into the impact of the primary cilia on neuronal excitability and circuit integrity.

Respiratory surveillance and inward rectifier potassium channel expression in lung tissue within an experimental epilepsy model.

Epilepsy is characterized by neuronal discharges that occur as a result of disruption of the excitatory and inhibitory balance of the brain due to functional and structural changes. It has been shown in the literature that this neurological disorder may be related to the expression of ion channels. Any defect in the function or expression mechanism of these channels can lead to various neuronal disorders such as epilepsy. Epileptic seizures occur as a result of the accumulation of biological disorders in the circulatory, respiratory and nervous systems. In this study, we aimed to examine the changes in the expression of inward-directing potassium channels (Kir 3.1 and 6.2) in lung tissue and respiratory functions, considering that it will contribute to the elucidation of the mechanisms of sudden deaths thought to be caused by cardiorespiratory complications in epilepsy. In the study, 48 adult male Wistar albino rats weighing 250-300g were used in the study. During the research process, respiratory function tests were performed on epileptic rats induced with pentylenetetrazol (PTZ) firing model, and then histopathological changes in lung and hippocampus tissues, and expression levels of the Kir (3.1 and 6.2) channels were evaluated by immunohistochemistry, qRT-PCR and Western blot analysis. Memantine and tertiapin-Q have been shown to protect epileptic groups from histopathological harm induced by PTZ application and also reduce HIF-1α, Kir 3.1 and Kir 6.2 expression. The findings imply that memantine and tertiapin-Q would be suitable options for treating epilepsy patients.

Cilostazol Counteracts Mitochondrial Dysfunction in Hepatic Encephalopathy Rat Model: Insights into the role of cAMP/AMPK/SIRT1/ PINK-1/Parkin hub and p-CREB /BDNF/ TrkB neuroprotective trajectory.

A devasting stage of chronic hepatic dysfunction is strictly correlated with neurological impairment, signifying hepatic encephalopathy (HE). HE is a multifactorial condition; therefore, hyperammonemia, oxidative stress, neuroinflammation, and mitochondrial dysfunction interplay in HE's progressive development. Cilostazol (Clio) has shown promising neuroprotective and hepatoprotective effectiveness in different neuronal and hepatic disorders; however, its efficiency against HE hasn't yet been explored. This study aimed to investigate the protective role of Cilo against thioacetamide (TAA)-induced HE in rats targeting mitochondrial dysfunction via modulation of Adenosine monophosphate-activated protein kinase (AMPK)/ Silent information regulator 1 (SIRT1) dependent pathways. Rats were allocated into three groups: the normal control group, the TAA group received (100 mg/kg, three times per week, for six weeks) to induce HE, and the Cilo group received (Cilo 100 mg/kg/day for six weeks, oral gavage) concurrently with TAA. Cilo counteracted HE indicated in the enhancement of cognitive impairment and the motor performance of rats (P<0.0001), modulation AMPK/SIRT1signaling pathway causing reduction of NF-kB p65 (P<0.0001) evoked inflammation along with histopathological alterations and glial fibrillary acidic protein (GFAP) immunoreactivity (P<0.0001), restoration nuclear factor E2-related factor 2 ( Nrf2 ) (P<0.0001) antioxidant effects, reduction of Bax and elevation of Bcl2 immunoreactivity (P<0.0001) in addition to boosting mitochondrial biogenesis by upregulation of PTEN-induced kinase-1 (PINK-1)/Parkin (P<0.0001)and restoration of Brain-derived neurotrophic factor (BDNF) (P=0.0002)/ tropomyosin-related kinase B (TrkB) (P<0.0001)/ cAMP response element-binding (CREB) (P<0.0001) neuroprotective axis. Collectively, Cilo activates the SIRT1 trajectory to abridge mitochondrial dysfunction invigorated in the HE rat model via restoration of mitochondrial hemostasis.

Are oligodendrocytes bystanders or drivers of Parkinson's disease pathology?

The major pathological feature of Parkinson 's disease (PD), the second most common neurodegenerative disease and most common movement disorder, is the predominant degeneration of dopaminergic neurons in the substantia nigra, a part of the midbrain. Despite decades of research, the molecular mechanisms of the origin of the disease remain unknown. While the disease was initially viewed as a purely neuronal disorder, results from single-cell transcriptomics have suggested that oligodendrocytes may play an important role in the early stages of Parkinson's. Although these findings are of high relevance, particularly to the search for effective disease-modifying therapies, the actual functional role of oligodendrocytes in Parkinson's disease remains highly speculative and requires a concerted scientific effort to be better understood. This Unsolved Mystery discusses the limited understanding of oligodendrocytes in PD, highlighting unresolved questions regarding functional changes in oligodendroglia, the role of myelin in nigral dopaminergic neurons, the impact of the toxic environment, and the aggregation of alpha-synuclein within oligodendrocytes.

Current Updates on Nanotechnology-based Drug Delivery Platforms for Treating Alzheimer’s with Herbal Drugs

Abstract: Alzheimer's disease (AD) is an irreversible brain disorder that led to memory loss and disrupts daily life. Earlier strategies to treat AD such as acetylcholinesterase inhibitor (AChEI) drugs are not showing effectiveness due to the inability to cross the blood-brain barrier. Moreover, traditional AChEI provides limited efficacy in terms of bioavailability and solubility for treating AD treatment. Many of the current drugs such as donepezil taken to treat the disease exhibited harmful side effects. Hence, researchers are keen to find the alternative effective therapeutic agents for treating AD. This review summarizes the recent advancement in nanotechnology-based drug delivery systems of herbal drugs such as Curcumin, Ginkgo biloba, Salvia officinalis, etc for the prevention and cure of AD. Herbal drugs proved useful in treating neuronal disorders such as AD but exhibited some limitations like low bioavailability via oral drug delivery. Such limitations were overcome by tagging these drugs by nanoparticles which enables them to cross the blood-brain barrier and offer the delivery of greater concentration of herbal drugs to the brain. Inorganic nanoparticle-based drugdelivery systems such as gold nanoparticles and magnetic nanoparticles, organic nanoparticulate systems like polymeric micelles and dendrimers, and solid polymeric nanoparticles were some of the effective methods that have earlier shown potential for enhancing the delivery of herbal drugs to the brain. Long-term repeated injection of drugs loaded on nanomaterials can lead to the accumulation of nanomaterials in the body without timely and effective degradation which can cause serious issues to the brain. Hence, nanotechnology-based strategies should involve the formulation of nontoxic nanoparticles in such a way that they can significantly transport the drugs across the BBB followed by effective degradation of nanoparticles.

Stereoelectroencephalographic thermocoagulation in FLNA-positive heterotopia: Is it an effective treatment?

Periventricular nodular heterotopia (PVNH) is a neuronal migration disorder often associated with drug-resistant epilepsy. The epileptogenic zone network (EZN) in PVNH is generally large, contraindicating surgery. Stereoelectroencephalography (SEEG) can be proposed to map the EZN and perform radiofrequency thermocoagulation (THC) with an efficacy rate of approximately 65%. There are genetic forms of PVNH, particularly with mutations in the filamin A gene (FLNA). However, data on SEEG-guided THC in these patients still have not been described. We report four patients with FLNA-positive PVNH who underwent SEEG-guided THC. All were women with several types of seizures and psychiatric comorbidities. EZN was extensive and often bilateral, including a part of the heterotopias. The outcomes of SEEG-guided THC varied; two patients experienced significant seizure reduction and improvement in psychiatric symptoms (Engel class I-II), one showed partial improvement (Engel class III), and one had no significant benefit (Engel class IV). Psychiatric comorbidities, including posttraumatic stress disorder, depression, and anxiety, were present in all cases, with some patients showing symptom improvement alongside seizure reduction. Despite genetic origin, SEEG-guided THC can be proposed in FLNA-positive PVNH-related epilepsy, although outcomes vary. The presence of FLNA mutations should not contraindicate surgical intervention but may influence the therapeutic response. Further research is needed to understand the impact of genetic variants on epilepsy outcome.

Unlocking the Stratum Corneum Barrier to Skin Penetration for the Transdermal Delivery of Cyclovirobuxine D.

Background/Objectives: Cyclovirobuxine D, a natural compound derived from the medicinal plant Buxus sinica, demonstrates a diverse array of therapeutic benefits, encompassing anti-arrhythmic properties, blood pressure regulation, neuronal protection, and anti-ischemic activity. However, its limited solubility hinders the bioavailability of current oral and injectable formulations, causing considerable adverse reactions and toxicity. Methods: In this investigation, we embarked on an unprecedented exploration of the skin penetration potential of cyclovirobuxine D utilizing chemical penetration enhancers and niosomes as innovative strategies to enhance its dermal absorption. These strategies were rigorously tested and optimized. Results: Among the tested chemical penetration enhancers, azone emerged as the most potent, achieving a 4.55-fold increase in skin penetration compared to the untreated group. Additionally, when encapsulated within niosomes, primarily composed of Span60 and cholesterol, the skin penetration of cyclovirobuxine D was notably enhanced by 1.50-fold. Furthermore, when both cyclovirobuxine D and azone were co-encapsulated within the niosomes, the skin penetration of cyclovirobuxine D was remarkably elevated by 8.10-fold compared to the solvent-dispersed group. This enhancement was corroborated through rigorous in vitro and in vivo experiments. Notably, the combination of other chemical penetration enhancers with niosome encapsulation also exhibited synergistic effects in enhancing the skin penetration of cyclovirobuxine D. Conclusions: These findings provide a compelling rationale for the administration of cyclovirobuxine D via skin-mediated transdermal delivery, offering superior safety, efficacy, and convenience. The innovative combination of niosomes and chemical penetration enhancers represents a novel system for the transdermal delivery of cyclovirobuxine D, holding immense promise for clinical applications in the treatment of brain, neuronal, and cardiovascular disorders.

Impact of Visual Kinesthetic Illusions on Reciprocal Inhibition and Motor Function

Reciprocal inhibition is often diminished in elderly individuals and those with upper motor neuron disorders. This reduction in reciprocal inhibition can hinder smooth joint movement. For subjects who have increased muscle tone and a limited range of motion in the joints, we focused on visual kinesthetic illusions as an intervention to increase reciprocal inhibition. We aimed to investigate the effects of visual kinesthetic illusions on reciprocal inhibition and motor function in the ankle joint. Participants participated in two experiments measuring reciprocal inhibition, namely reciprocal Ia inhibition and D1 inhibition, as well as motor functions related to ankle dorsiflexion and plantar flexion. Visual kinesthetic illusion was induced by displaying an image of each subject’s foot on a monitor. Our results showed that the visual kinesthetic illusion enhanced D1 inhibition and improved motor function in the ankle joint by prioritizing agonist muscle activity. We also observed a correlation between reciprocal inhibition and the muscle activity ratio. These findings suggest that visual kinesthetic illusions may improve motor function by increasing reciprocal inhibition. This study is the first to demonstrate the effects of visual kinesthetic illusion on reciprocal inhibition, and we believe that these findings can be applied in rehabilitation.

Neuroglia in Neurodegeneration: Exploring Glial Dynamics in Brain Disorders

Neurodegenerative diseases represent a significant global health burden, characterized by progressive loss of neuronal function and structure. While traditionally viewed as primarily neuronal disorders, recent research has highlighted the crucial roles of neuroglia-astrocytes, microglia, and oligodendrocytes in the pathogenesis and progression of these diseases. This review explores the dual nature of glial cells in neurodegenerative processes, focusing on their protective and potentially harmful functions in Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and other neurodegenerative disorders. We examine the complex interactions between different glial cell types and neurons, highlighting recent discoveries in glial-neuronal metabolic coupling, neuroinflammation, and protein aggregation. Advanced technologies, such as single-cell RNA sequencing and spatial transcriptomics, have revealed unprecedented glial heterogeneity and disease-specific glial states, reshaping our understanding of these cells’ roles in health and disease. The review also discusses emerging concepts in neuroglial research, including the role of extracellular vesicles in disease propagation, epigenetic regulation of glial function, and the application of artificial intelligence in glial biology. Finally, we explore the therapeutic implications of targeting glia in neurodegenerative diseases, addressing both the promising avenues and challenges in developing glial-focused interventions. By integrating recent advances in neuroglial research, this review provides a comprehensive overview of the field and highlights future directions for research and therapeutic development. Understanding the complex roles of neuroglia in neurodegenerative diseases is crucial for developing more effective treatments and ultimately improving patient outcomes.

Action potentials of the superior cervical ganglion neurons in the rats in diabetes mellitus

It’s well known that sympathetic and sensory neurons are affected in the early stages of diabetes mellitus (DM). However, the functional disorders that occur in neurons of the superior cervical ganglion (SCG) under the conditions of DM remain insufficiently studied. Therefore, the aim of this study was to evaluate the effect of streptozotocin-induced diabetes mellitus (DM) of the rats on action potentials (AP) recorded in the superior cervical ganglion`s (SCG) neurons. Rats with blood sugar level more than 30 mM were taken into experiment. The SCG of healthy control rats (n=12), rats at week 4 (n=9), and rats at week 12 after streptozotocin injection (n=9) were studied in vitro. AP of the SCG neurons were registered by the microelectrode technique. Neurons of the SCG were stimulated directly with 150 ms depolarizing current in pulse of 100 pA. The AP parameters of 36 SCG neurons of control rats were alternately compared with the corresponding AP parameters of 22 neurons of rats at week 4 and 30 SCG neurons of rats at week 12 after streptozotocin injection. The data obtained demonstrate that the AP amplitude and overshoot of AP, maximum rise and fall rates, and afterhyperpolarization amplitude significantly decreased at 12 weeks after DM induction. At the same time, the rheobase value significantly increased, this may indicates decreasing of the neurons plasma membrane excitability. Only the AP maximum rate of fall decreased statistically significant at week 4, the maximum rate of rise had an insignificant tendency to decrease at that time. However, the resting membrane potential and excitation threshold didn’t change even at 12 weeks after the injection. Thus, functional disorders of rat SCG neurons were appeared at a quite late stage of DM. The differences in AP parameters may result from neurons’ membrane ionic conductivity alterations, decreasing of its excitability and reducing ion channels efficiency in later stages of DM. This suggests that SCG is an important target of pathophysiological disorders caused by DM.

Exploring Tractography: An Analysis of Brain Connectivity Patterns in Men.

White matter tracts that connect different parts of the brain comprise the structural connectome, which is essential to its operation. Assessing behavioral changes and brain health requires an understanding of these tracts. Diffusion tensor imaging (DTI), in particular, allows for the thorough viewing and characterization of these routes in tractography. In order to assess the impact of aging on white matter integrity, this study examines the 10 main white matter tracts in men, paying particular attention to volume, fractional anisotropy (FA), and mean diffusivity (MD). A cohort of 49 menaged 18-50 years was examined using a Philips Multiva 1.5T MRI. DTI scans were performed after obtaining informed consent. Participants with neuronal disorders were excluded. Ten tracts were assessed: inferior fronto-occipital fasciculus (IFOF), superior fronto-occipital fasciculus (SFOF), inferior longitudinal fasciculus (ILF), superior longitudinal fasciculus (SLF), cingulum, corticospinal tract (CST), forceps major, forceps minor, uncinate fasciculus, and anterior thalamic radiation (ATR). Statistical analysis employed Kruskal-Wallis tests to compare age groups. Significant age-related differences were observed in the IFOF, which exhibited notable changes in both volume and MD. Specifically, the IFOF's volume peaked in the 31-40 age group (14.42 ± 6.05) and declined in the 41-50 age group (8.71 ± 5.07), with a statistically significant p-value of 0.019. In parallel, MD increased significantly with age, moving from 0.86 ± 0.08 in the 18-30 group to 1.09 ± 0.13 in the 31-40 group and stabilizing at 0.96 ± 0.12 in the 41-50 group (p < 0.001). Notably, while the FA values remained relatively stable across age groups (p = 0.063), the increase in MD suggests a decline in neural efficiency or potential myelin degradation. Other tracts, including the SFOF and SLF, displayed stability in volume, FA, and MD across age groups, indicating a degree of resilience in certain neural pathways. This study highlights the utility of tractography in understanding age-related changes in white matter, such as in Alzheimer's disease, age- and sex-related abnormalities, and dementia, particularly emphasizing the IFOF's sensitivity. Findings offer insights into brain connectivity and neurological health, indicating a need for further contribution to inform interventions aimed at cognitive preservation.

Advances in drug screening and toxicity testing: A review on Parkinson's disease using brain-on-a-chip

Abstract. Neurodegenerative diseases like Parkinson's disease (PD) pose substantial challenges to health and well-being. PD is characterized by the progressive degeneration of dopamine-producing neurons in the substantia nigra of the brain, leading to motor dysfunction, cognitive decline, and various non-motor symptoms. Advances in drug screening and toxicity testing have transformed the study of neurodegenerative diseases. Traditional methods often fall short in replicating the intricate environment of the human brain, highlighting the necessity for alternative pre-clinical models. Brain-on-a-chip technology, an innovative in vitro platform, offers a promising solution by simulating the intricate architecture and microenvironment of brain tissue. This microfluidic device incorporates living brain cells within a controlled setting, enabling the examination of neuronal behavior, disorder mechanisms, and pharmacological responses in a physiologically relevant context. This review examines recent advancements in brain-on-a-chip systems for PD research, emphasizes their potential to advance drug discovery and toxicity testing, also discusses the difficulty and limitations of current brain-on-a-chip technologies, for examples, challenges of specific neuron cell selection and incubation, and also restriction of organ-organ connection. By comparing in vitro and in vivo studies, brain-on-a-chip technology shows great promise for accelerating the development of effective therapies for PD, ultimately contributing to improved patient outcomes and a deeper understanding of the disease.

Copper homeostasis and neurodegenerative diseases.

Copper, one of the most prolific transition metals in the body, is required for normal brain physiological activity and allows various functions to work normally through its range of concentrations. Copper homeostasis is meticulously maintained through a complex network of copper-dependent proteins, including copper transporters (CTR1 and CTR2), the two copper ion transporters the Cu -transporting ATPase 1 (ATP7A) and Cu-transporting beta (ATP7B), and the three copper chaperones ATOX1, CCS, and COX17. Disruptions in copper homeostasis can lead to either the deficiency or accumulation of copper in brain tissue. Emerging evidence suggests that abnormal copper metabolism or copper binding to various proteins, including ceruloplasmin and metallothionein, is involved in the pathogenesis of neurodegenerative disorders. However, the exact mechanisms underlying these processes are not known. Copper is a potent oxidant that increases reactive oxygen species production and promotes oxidative stress. Elevated reactive oxygen species levels may further compromise mitochondrial integrity and cause mitochondrial dysfunction. Reactive oxygen species serve as key signaling molecules in copper-induced neuroinflammation, with elevated levels activating several critical inflammatory pathways. Additionally, copper can bind aberrantly to several neuronal proteins, including alpha-synuclein, tau, superoxide dismutase 1, and huntingtin, thereby inducing neurotoxicity and ultimately cell death. This study focuses on the latest literature evaluating the role of copper in neurodegenerative diseases, with a particular focus on copper-containing metalloenzymes and copper-binding proteins in the regulation of copper homeostasis and their involvement in neurodegenerative disease pathogenesis. By synthesizing the current findings on the functions of copper in oxidative stress, neuroinflammation, mitochondrial dysfunction, and protein misfolding, we aim to elucidate the mechanisms by which copper contributes to a wide range of hereditary and neuronal disorders, such as Wilson's disease, Menkes' disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. Potential clinically significant therapeutic targets, including superoxide dismutase 1, D-penicillamine, and 5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline, along with their associated therapeutic agents, are further discussed. Ultimately, we collate evidence that copper homeostasis may function in the underlying etiology of several neurodegenerative diseases and offer novel insights into the potential prevention and treatment of these diseases based on copper homeostasis.

Drosophila glial system: an approach towards understanding molecular complexity of neurodegenerative diseases.

Glia is pivotal in regulating neuronal stem cell proliferation, functioning, and nervous system homeostasis, significantly influencing neuronal health and disorders. Dysfunction in glial activity is a key factor in the development and progression of brain pathology. However, a deeper understanding of the intricate nature of glial cells and their diverse role in neurological disorders is still required. To this end, we conducted data mining to retrieve literature from PubMed and Google Scholar using the keywords: glia, Drosophila, neurodegeneration, and mammals. The retrieved literature was manually screened and used to comprehensively understand and present the different glial types in Drosophila, i.e., perineurial, subperineurial, cortex, astrocyte-like and ensheathing glia, their relevance with mammalian counterparts, mainly microglia and astrocytes, and their potential to reveal complex neuron-glial molecular networks in managing neurodegenerative processes.