Neuronal Loss Research Articles

Progress in the mechanisms of pain associated with neurodegenerative diseases.

Neurodegenerative diseases (NDDs) represent a class of neurological disorders characterized by the progressive degeneration or loss of neurons, impacting millions of individuals globally. In addition to the typical manifestations, pain is a prevalent symptom associated with NDDs, seriously impacting the quality of life for patients. The pathogenesis of pain associated with NDDs is intricate and multifaceted. Currently, the clinical management of NDDs-related pain symptoms predominantly relies on conventional pharmacological agents or physical therapy. However, these approaches often fail to produce satisfactory outcomes. This article summarizes the underlying mechanisms of major NDDs-associated pain: Neuroinflammation, Brain and spinal cord dysfunctions, Mitochondrial dysfunction, Risk gene and pathological protein, as well as Receptor, channel, and neurotransmitter. While numerous studies have investigated the downstream pathological processes associated with these mechanisms, there remains a significant gap in identifying the key initiating factors. Specifically, there is insufficient evidence for the upstream elements that activate microglia and astrocytes in neuroinflammation leading to pain in NDDs. Likewise, there is an absence of upstream factors elucidating how dysfunctions in the brain and spinal cord, as well as mitochondrial impairments, contribute to the development of pain. Furthermore, the specific mechanisms through which hallmark pathological proteins related to NDDs contribute to these pathological processes remain inadequately understood. The objective of this article is to synthesize the existing mechanisms underlying pain associated with NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, Schizophrenia, Amyotrophic lateral sclerosis, and Multiple sclerosis, while also identifying gaps and deficiencies in these mechanisms. This paper offers insights for future research trajectories. Given the intricate pathogenesis of NDDs-related pain, it emphasizes that a promising short-term strategy is combination therapy-intervening concurrently in multiple pathological processes-akin to the cocktail approach utilized in treating acquired immunodeficiency syndrome (AIDS). For long-term advancements, achieving breakthroughs in the treatment of the NDDs themselves will remain essential for alleviating accompanying pain symptoms.

A Review on Tau Targeting Biomimetics Nano Formulations: Novel Approach for Targeting Alzheimer's Diseases.

Central nervous system disorders are prevalent, profoundly debilitating, and poorly managed. Developing innovative treatments for these conditions, including Alzheimer's disease, could significantly improve patients' quality of life and reduce the future economic burden on healthcare systems. However, groundbreaking drugs for central nervous system disorders have been scarce in recent years, highlighting the pressing need for advancements in this field. One significant challenge in the realm of nanotherapeutics is ensuring the precise delivery of drugs to their intended targets due to the complex nature of Alzheimer's disease. Although numerous therapeutic approaches for Alzheimer's have been explored, most drug candidates targeting amyloid-β have failed in clinical trials. Recent research has revealed that tau pathology can occur independently of amyloid-β and is closely correlated with the clinical progression of Alzheimer's symptoms. This discovery suggests that tau could be a promising therapeutic target. One viable approach to managing central nervous system disorders is the administration of nanoparticles to neurons, intending to inhibit tau aggregation by directly targeting p-tau. In Alzheimer's disease, beta-amyloid plaques and neurofibrillary tau tangles hinder neuron transmission and function. The disease also triggers persistent inflammation, compromises the blood-brain barrier, leads to brain shrinkage, and causes neuronal loss. While current medications primarily manage symptoms and slow cognitive decline, there is no cure for Alzheimer's.

Rotating magnetic field improved cognitive and memory impairments in a sporadic ad model of mice by regulating microglial polarization.

Neuroinflammation, triggered by aberrantly activated microglia, is widely recognized as a key contributor to the initiation and progression of Alzheimer's disease (AD). Microglial activation in the central nervous system (CNS) can be classified into two distinct phenotypes: the pro-inflammatory M1 phenotype and the anti-inflammatory M2 phenotype. In this study, we investigated the effects of a non-invasive rotating magnetic field (RMF) (0.2T, 4Hz) on cognitive and memory impairments in a sporadic AD model of female Kunming mice induced by AlCl3 and D-gal. Our findings revealed significant improvements in cognitive and memory impairments following RMF treatment. Furthermore, RMF treatment led to reduced amyloid-beta (Aβ) deposition, mitigated damage to hippocampal morphology, prevented synaptic and neuronal loss, and alleviated cell apoptosis in the hippocampus and cortex of AD mice. Notably, RMF treatment ameliorated neuroinflammation, facilitated the transition of microglial polarization from M1 to M2, and inhibited the NF-кB/MAPK pathway. Additionally, RMF treatment resulted in reduced aluminum deposition in the brains of AD mice. In cellular experiments, RMF promoted the M1-M2 polarization transition and enhanced amyloid phagocytosis in cultured BV2 cells while inhibiting the TLR4/NF-кB/MAPK pathway. Collectively, these results demonstrate that RMF improves memory and cognitive impairments in a sporadic AD model, potentially by promoting the M1 to M2 transition of microglial polarization through inhibition of the NF-кB/MAPK signaling pathway. These findings suggest the promising therapeutic applications of RMF in the clinical treatment of AD.

The Role of Ocimene in Decreasing α-Synuclein Aggregation using Rotenone-induced Rat Model.

Parkinson's disease is defined by the loss of dopaminergic neurons in the midbrain of substantia nigra associated with Lewy bodies. The precise mechanism is not yet entirely understood. The study aims to determine whether ocimene has antiparkinsonian activity by reducing α-Synuclein aggregation levels in the brains of rotenone-induced rat models. 36 male rats were used for six groups, with six animals in each group. Vehicle, control (rotenone, 2.5 mg/kg, i.p), standard (L-Dopa, 10 mg/kg, i.p), Test drug of low dose (66.66 mg/kg, i.p), medium dose (100 mg/kg, i.p), and high dose (200 mg/kg, i.p) were administered to the rats. The open field, actophotometer, hanging wire, and catalepsy tests were used to assess the rat's motor performance. The expressions of biomarkers such as AchE, D2 Receptor, and α- Synuclein were evaluated, and their level of expression in the brain samples was checked using ELISA. Histopathological analysis was also carried out to determine the degree of neuron degeneration in the brain samples. The open field test showed significant anxiety levels, whereas test groups showed fewer anxiety levels but increased motor activity. The biochemical tests revealed that rotenonetreated rats had higher levels of AchE, but ocimene-treated rats had a significant decrease in AchE levels. The test drug-treated rats also expressed high levels of D2 receptors. In ocimenetreated rats, α-Synuclein aggregation was reduced, however, in rotenone-treated rats' brain samples, higher clumps of α-Synuclein were observed. Ocimene has neuroprotective properties. As a result, this essential oil might be helpful as a therapeutic treatment for Parkinson's disease.

Neuroprotective and anti-inflammatory effects of the RIPK3 inhibitor GSK872 in an MPTP-induced mouse model of Parkinson’s disease

Parkinson's disease (PD) is a neurodegenerative disorder triggered by the loss of dopaminergic neurons in the substantia nigra (SN). Recent studies have demonstrated that necroptosis is involved in dopaminergic neuronal cell death and the resulting neuroinflammation. During the process of necroptosis, a necrosome complex is formed consisting of the proteins receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL). Although the neuroprotective effects of the RIPK1-specific inhibitor necrostatin-1, as well as RIPK3 and MLKL knockout in mice, have been described, the effects of RIPK3 pharmacological inhibitors have not yet been reported in animal models of PD. In the present study, we investigated the neuroprotective effects of GSK872, a specific RIPK3 inhibitor, in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. GSK872 rescued MPTP-induced motor impairment and inhibited tyrosine hydroxylase-positive dopaminergic cell death in the SN and striatum. Additionally, GSK872 inhibited the MPTP-induced increase in the expression of p-RIPK3 and p-MLKL in both the dopaminergic neurons and microglia, as assessed by biochemical and histological analyses. GSK872 further inhibited microglial activation and the expression of inflammatory mediators including NLRP3, interleukin (IL)-1β, IL-6, tumor necrosis factor-alpha, and inducible nitric oxide synthase in the SN region of MPTP mice. Using in vitro experiments, we validated the effects of GSK872 on necroptosis in SH-SY5Y neuronal and BV2 microglial cells. Overall, our results suggest that GSK872 exerts neuroprotective and anti-inflammatory effects, and may thus have therapeutic potential for PD.

A special focus on polyadenylation and alternative polyadenylation in neurodegenerative diseases: A systematic review

AbstractNeurodegenerative diseases (NDDs) are one of the prevailing conditions characterized by progressive neuronal loss. Polyadenylation (PA) and alternative polyadenylation (APA) are the two main post‐transcriptional events that regulate neuronal gene expression and protein production. This systematic review analyzed the available literature on the role of PA and APA in NDDs, with an emphasis on their contributions to disease development. A comprehensive literature search was performed using the PubMed, Scopus, Cochrane, Google Scholar, Embase, Web of Science, and ProQuest databases. The search strategy was developed based on the framework introduced by Arksey and O'Malley and supplemented by the inclusion and exclusion criteria. The study selection was performed by two independent reviewers. Extraction and data organization were performed in accordance with the predefined variables. Subsequently, quantitative and qualitative analyses were performed. Forty‐seven studies were included, related to a variety of NDDs, namely Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Disease induction was performed using different models, including human tissues, animal models, and cultured cells. Most investigations were related to PA, although some were related to APA or both. Amyloid precursor protein (APP), Tau, SNCA, and STMN2 were the major genes identified; most of the altered PA patterns were related to mRNA stability and translation efficiency. This review particularly underscores the key roles of PA and APA in the pathogenesis of NDDs through their mechanisms that contribute to gene expression dysregulation, protein aggregation, and neuronal dysfunction. Insights into these mechanisms may lead to new therapeutic strategies focused on the modulation of PA and APA activities. Further research is required to investigate the translational potential of targeting these pathways for NDD treatment. image

Elevated Cerebrospinal Fluid Ubiquitin Carboxyl-Terminal Hydrolase Isozyme L1 in Asymptomatic C9orf72 Hexanucleotide Repeat Expansion Carriers.

To identify biochemical changes in individuals at higher risk of developing amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD) via C9orf72 hexanucleotide repeat expansion (HRE) heterozygosity. Cross-sectional observational study of 48 asymptomatic C9orf72 HRE carriers, 39 asymptomatic non-carrier controls, 19 people with sporadic ALS, 10 with C9orf72 ALS, 14 with sporadic FTD, and 10 with C9orf72 FTD. Relative abundance of 30 pre-defined cerebrospinal fluid biomarkers of ALS and FTD were compared in asymptomatic C9orf72 HRE carriers and age-matched non-carrier controls. Differential abundance of these proteins was quantified using data independent acquisition mass spectrometry or electro chemiluminescent assay for neurofilament light chain. Unbiased analysis of the entire cerebrospinal fluid proteome was then carried out. Ubiquitin carboxyl-hydrolase isozyme L1 levels were higher in asymptomatic C9orf72 HRE carriers compared with age-matched non-carriers (log2fold change 0.20, FDR-adjusted p-value = 0.034), whereas neurofilament light chain levels did not significantly differ. Ubiquitin carboxyl-hydrolase isozyme L1 levels remained elevated after matching of groups by neurofilament levels (p = 0.011), and after adjusting for age, sex, and neurofilament levels. A significant difference was also observed when restricting analysis to younger participants (<37) matched by neurofilament level (p = 0.007). Elevated cerebrospinal fluid ubiquitin carboxyl-hydrolase isozyme L1 levels in C9orf72 HRE carriers can occur in the absence of increased neurofilament levels, potentially reflecting either compensatory or pathogenic mechanisms preceding rapid neuronal loss. This brings forward the window on changes associated with the C9orf72 HRE carrier state, with potential to inform understanding of penetrance and approaches to prevention. ANN NEUROL 2024.

Hesperetin attenuates neuroprotective effect against 3-Nitropropionic acid induced Huntington’s disease-like behavioral symptoms in rats

The disease Huntington’s (HD) is an autosomal neurologic disorder characterized by inexorable loss of nerve cells in the brain accompanied with cognitive, motor and psychiatric disorders. In the present study, 3-Nitropropionic acid (3-NP), an inhibitor of mitochondrial citric acid cycle results in symptoms like HD. Hesperetin(HSP) is a flavanone rich in citrus species which possess neuroprotective effects. The aim of the present study was to evaluate the protective role of HSP against 3-NP induced symptoms. Pre-treatment of animals with HSP/normal saline for 7 days and from 8th day, 3-NP (10mg/kg) was co-administered with HSP. It is continued for 21 days of the treatment schedule. At the end day of the study, the results showed that HSP improved all the cognitive, motor and psychiatric symptoms induced by 3-NP significantly. Hence, these findings show the protective effect of HSP against 3-NP induced neurological disorder. Keywords: Huntington’s disease, Hesperetin, 3-Nitropropionic acid,

Integration of Single-Cell and Spatial Transcriptomic Data Reveals Spatial Architecture and Potential Biomarkers in Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the gradual loss of neurons and the accumulation of amyloid plaques and neurofibrillary tangles. Despite advancements in the understanding of AD's pathophysiology, the cellular organization and interactions in the prefrontal cortex (PFC) remain elusive. Eight single-cell RNA sequencing (scRNA-seq) datasets from both normal controls and individuals with AD were harmonized. Stringent preprocessing protocols were implemented to uphold dataset integrity. Unsupervised clustering and annotation revealed 22 distinct cell clusters corresponding to 19 unique cell types. The spatial architecture of the PFC region was constructed using the CARD tool. Further analyses encompassed trajectory examination of Oligodendrocyte subtypes, evaluation of regulon activity scores, and spot clustering within white matter regions (WM). Differential expression analysis and functional enrichment assays unveiled molecular signatures linked to AD progression and were validated using microarray data sourced from neurodegenerative disorder patients. Our investigation employs scRNA-seq and spatial transcriptomics to uncover the cellular atlas and spatial architecture of the human PFC in AD. Moreover, our results indicate that Oligodendrocytes are more prevalent in AD patients, showcasing diverse subtypes and spatial organization within WM regions. Each subtype appears to be associated with distinct biological processes and transcriptional regulators, shedding light on their involvement in AD pathology. Notably, the Oligodendrocyte_C6 subtype is linked to neurological damage in AD patients, characterized by heightened expression of genes involved in cell-cell connections, cell membrane stability, and myelination. Additionally, 12 target genes regulated by NFIA were identified, which are upregulated in AD patients and associated with disease progression. Elevated PLXDC2 expression in peripheral blood was also identified, suggesting its potential as a non-invasive biomarker for early AD detection. Our study provides novel insights into the role of Oligodendrocytes in AD and highlights the potential of PLXDC2 as a blood biomarker for non-invasive diagnosis and monitoring of AD patients.

Reverse Split Hand as a Neurophysiological Hallmark of Spinal Muscular Atrophy

Objective: Motor unit number estimation (MUNE) methods are crucial for estimating lower motor neuron loss in motor neuron diseases. The MScanFit MUNE (MScanFit) is a novel method that estimates MUNE values from compound motor action potential (CMAP) scans, demonstrating high sensitivity and reproducibility in detecting motor unit loss in amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). In this study, we aimed to characterize the pattern of motor unit loss in the hand intrinsic muscles of SMA patients compared to ALS patients and healthy controls (HC) using MScanFit MUNE. Methods: Patients diagnosed with ALS, adult SMA patients, and HC were prospectively enrolled. MScanFit examinations were performed on the abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles. To focus on the different patterns of motor neuron degeneration in the intrinsic hand muscles, the ratio of CMAP amplitude of APB to ADM (CMAP ratio) and the ratio of MUNE values of APB to those of the ADM muscle (MUNE ratio) were calculated. Results: The study included 46 ALS patients, 16 SMA patients, and 23 HC. MScanFit MUNE revealed distinct patterns of motor unit degeneration in SMA patients, notably more severe in the ADM than in the APB muscle, indicating a “reverse” split-hand phenomenon. Both CMAP and MUNE ratios demonstrated high diagnostic accuracy in distinguishing ALS from SMA, with the MUNE ratio performing better. Conclusions: MScanFit MUNE is a valuable tool for exploring distinct patterns of motor neuron degeneration in patients with different types of motor neuron diseases.

Deletion of the Transient Receptor Potential Melastatin 2 Gene Mitigates the 6-Hydroxydopamine-Induced Parkinson's Disease-Like Pathology.

Pharmacological inhibition of the transient receptor potential melastatin 2 (TRPM2), an oxidative stress-activated calcium channel, was previously reported to be protective in Parkinson's disease (PD). However, the inhibitors used were not TRPM2 specific, so the involvement of this channel in PD remains unclear. Here, for the first time, Trpm2 partial (+ / -) and complete (- / -) knockout mice underwent stereotaxic surgery for PD induction. Six-hydroxydopamine was injected in the right striatum. On days 3 and 6, motor behavior tests (cylinder, apomorphine, and pole test) were performed. On day 7, brains were collected for dopaminergic neuron immunostaining. Our results showed that Trpm2 + / - male and female mice had reduced motor impairment and dopaminergic neuron death after PD induction. In addition, Trpm2 - / - male and female mice showed absent or lesser motor deficit and the dopaminergic neuronal loss was no longer observed. These findings suggest that TRPM2 is involved in the PD-like pathology and that targeting TRPM2 may possibly represent a potential neuroprotective strategy for PD.

Detection of Brain-Derived Cell-Free DNA in Plasma

Background: Neuronal loss is a major pathological feature of neurodegenerative diseases. The analysis of plasma cell-free DNA (cfDNA) is an emerging approach to track cell death events in a minimally invasive way and from inaccessible areas of the body, such as the brain. Previous studies showed that DNA methylation (DNAm) profiles can be used to map the tissue of origin of cfDNA and to identify molecules released from the brain upon cell death. The aim of the present study is to contribute to this research field, presenting the development and validation of an assay for the detection of brain-derived cfDNA (bcfDNA). Methods: To identify CpG sites with brain-specific DNAm, we compared brain and non-brain tissues for their chromatin state profiles and genome-wide DNAm data, available in public datasets. The selected target genomic regions were experimentally validated by bisulfite sequencing on DNA extracted from 44 different autoptic tissues, including multiple brain regions. Sequencing data were analysed to identify brain-specific epihaplotypes. The developed assay was tested in plasma cfDNA from patients with immune effector cell-associated neurotoxicity syndrome (ICANS) following chimeric antigen receptor T (CAR-T) therapy. Results: We validated five genomic regions with brain-specific DNAm (four hypomethylated and one hypermethylated in the brain). DNAm analysis of the selected genomic regions in plasma samples from CAR-T patients revealed higher levels of bcfDNA in participants with ongoing neurotoxicity syndrome. Conclusions: We developed an assay for the analysis of bcfDNA in plasma. The assay is a promising tool for the early detection of neuronal loss in neurodegenerative diseases.

BN SO30 - One hundred consecutive Laparoscopic Heller's Cardiomyotomy &amp; Fundoplication – a personal series

Abstract Background Oesophageal Achalasia (OA) is an uncommon primary oesophageal motility disorder, characterised by the loss of inhibitory neurons in the oesophageal myenteric plexus. The primary goal of treating OA is to alleviate dysphagia caused by the functional obstruction of the distal oesophagus due to the inability of the lower oesophageal sphincter (LOS) to relax appropriately after swallowing. Heller's cardiomyotomy (HCM) remains a standard treatment for OA. The aim of this study was to assess the symptomatic improvement and post-operative outcomes following HCM with fundoplication at our centre. Method All patients underwent HCM through laparoscopic blunt muscle separation technique, between January 2005 and March 2024, by a single surgeon. Retrospective review of electronic and compiled paper patient records were analysed to assess patient demographics, preoperative symptoms, operative details, length of stay (LOS), complications, post-operative symptoms, gastroscopy and pneumatic dilation (PD) as well as revisional surgery. Primary outcomes assessed were binary changes in key symptoms of weight loss, dysphagia, retrosternal pain and regurgitation. Comparison of pre and post-operative outcomes were performed using paired t-test. A p-value of &amp;lt;0.05 was considered statistically significant. Results 100 procedures involving 99 patients (average age 50 years, 43% female), 1 conversion to open and 1 revision at 3 years. ASA grades were 1 (27%), 2 (58%), and 3 (15%). Median LOS was one day, median follow-up 99 months. Post-operatively; weight loss persisted in 11% of patients from 48%, dysphagia reduced from 98% to 42%, retrosternal chest pain from 39% to 20% and regurgitation from 57% to 24% (all p&amp;lt;0.05). 2 patients required (PD) ≤30 days (CD≥3). 36 patients underwent PD at median of 13 months, 20 needed repeat PD. None of the patients developed cancer. Conclusion As demonstrated in this large series of 100 consecutive patients, HCM remains one of the best treatment modalities for OA. Key symptoms of OA significantly reduced following HCM. Our technique avoided the use of energy devices, ensured a short hospital stay and durable symptom improvement, lends support to its continued application in managing this condition.

Targeting Glucose Metabolism: A Novel Therapeutic Approach for Parkinson’s Disease

Glucose metabolism is essential for the maintenance and function of the central nervous system. Although the brain constitutes only 2% of the body weight, it consumes approximately 20% of the body’s total energy, predominantly derived from glucose. This high energy demand of the brain underscores its reliance on glucose to fuel various functions, including neuronal activity, synaptic transmission, and the maintenance of ion gradients necessary for nerve impulse transmission. Increasing evidence shows that many neurodegenerative diseases, including Parkinson’s disease (PD), are associated with abnormalities in glucose metabolism. PD is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, accompanied by the accumulation of α-synuclein protein aggregates. These pathological features are exacerbated by mitochondrial dysfunction, oxidative stress, and neuroinflammation, all of which are influenced by glucose metabolism disruptions. Emerging evidence suggests that targeting glucose metabolism could offer therapeutic benefits for PD. Several antidiabetic drugs have shown promise in animal models and clinical trials for mitigating the symptoms and progression of PD. This review explores the current understanding of the association between PD and glucose metabolism, emphasizing the potential of antidiabetic medications as a novel therapeutic approach. By improving glucose uptake and utilization, enhancing mitochondrial function, and reducing neuroinflammation, these drugs could address key pathophysiological mechanisms in PD, offering hope for more effective management of this debilitating disease.

Phytochemicals in Parkinson's Disease: a Pathway to Neuroprotection and Personalized Medicine.

Parkinson's disease (PD) is a complex neurodegenerative disorder marked by the progressive loss of dopaminergic neurons in the substantia nigra. While current treatments primarily manage symptoms, there is increasing interest in alternative approaches, particularly the use of phytochemicals from medicinal plants. These natural compounds have demonstrated promising neuroprotective potential in preclinical studies by targeting key pathological mechanisms such as oxidative stress, neuroinflammation, and protein aggregation. However, the clinical translation of these phytochemicals is limited due to a lack of robust clinical trials evaluating their safety, efficacy, and pharmacokinetics. This review provides a comprehensive overview of the neuroprotective potential of phytochemicals in PD management, examining the mechanisms underlying PD pathogenesis and emphasizing neuroprotection. It explores the historical and current research on medicinal plants like Mucuna pruriens, Curcuma longa, and Ginkgo biloba, and discusses the challenges in clinical translation, including ethical and practical considerations and the integration with conventional therapies. It further underscores the need for future research to elucidate mechanisms of action, optimize drug delivery, and conduct rigorous clinical trials to establish the safety and efficacy of phytochemicals, aiming to shape future neuroprotective strategies and develop more effective, personalized treatments for PD.

Periplaneta americana L. extract exerts neuroprotective effects by inhibiting endoplasmic reticulum stress via AKT-dependent pathway in experimental models of Parkinson's disease.

Parkinson's disease (PD) is a chronic neurodegenerative disorder that currently has no curable strategies. More and more evidence suggests that endoplasmic reticulum (ER) stress plays an essential role in PD pathogenesis. Periplaneta americana L. (P. americana) is a traditional Chinese medicine with diverse therapeutic properties. This study aims to investigate the neuroprotective effect and underlying mechanism of P. americana in in vitro and in vivo PD models. The exposure of SH-SY5Y cells to 1-methyl-4-phenyl-pyridinium (MPP+) was used as the in vitro PD model. MTT assay, Hoechst staining, Calcein AM-PI staining and flow cytometry were performed to measure the cell viability and apoptosis. DCFH-DA and JC-1 assay were used to measure the intracellular ROS and mitochondrial membrane potential (Δψm), respectively. Western-blot and immunostaining were conducted to detect the expression of key molecules related with ER stress. For the in vivo PD model induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydro-pyridine (MPTP), the motor function of mice was assessed by behavioral tests, the level of TH was examined by western-blot and immunostaining, the expression of key molecules related with ER stress was measured by western-blot. Periplaneta americana ethanol extract (PAE) concentration-dependently inhibited MPP+-induced cell loss and increased cell viability. PAE also remarkably attenuated ROS accumulation, the decline of Δψm as well as the excessive ER stress. The neuroprotective effects of PAE could be blocked by ROS inducer trimethylamine N-Oxide or ER stress activator tunicaymycin, while the antioxidant N-Acetyl-L-cysteine or ER stress inhibitor sodium 4-phenylbutyrate mimicked the effects of PAE. Furthermore, we found that PAE could activate AKT/GSK3β/β-catenin pathway. The effect of PAE on ROS production, Δψm and ER stress was blocked by AKT inhibitor MK-2206. In in vivo model, PAE significantly improved motor function, prevented dopaminergic neuronal loss and attenuated ER stress in substantia nigra and striatum of MPTP-treated mice. Similarly, the effects of PAE on MPTP-treated mice were also abolished by MK-2206. Our results suggest that P. americana exerts neuroprotective effects through inhibiting ER stress via AKT-dependent pathway. Periplaneta americana may represent a promising therapeutic agent for PD treatment and is worthy of further being exploited.

Opa1 and MT-Nd6 mutations induce early mitochondrial changes in the retina and prelaminar optic nerve of hereditary optic neuropathy mouse models

Abstract Hereditary optic neuropathies (HON), including dominant optic atrophy and Leber's hereditary optic neuropathy, are genetic disorders characterized by retinal ganglion cell (RGC) degeneration leading to vision loss, mainly associated with mitochondrial dysfunction. In this study, we analyzed mitochondrial distribution and ultrastructure in the retina and longitudinal optic nerve sections of presymptomatic HON mouse models with Opa1 and Nd6 deficiency to identify early mitochondrial changes. Our results show significant mitochondrial fragmentation and increased mitophagy in Opa1+/- mice, indicating early mitochondrial changes prior to neuronal loss. Conversely Nd6P25L mice exhibited mitochondrial hypertrophy, suggesting an adaptive response to compensate for altered energy metabolism. These pre-symptomatic mitochondrial changes were mainly observed in the unmyelinated portion of the RGC axons, where the transmission of the visual information requires high energy expenditure, constituting the specific point of vulnerability in HON. These findings highlight early focal mitochondrial changes prior to neuronal loss in HON and provide insight into presymptomatic therapeutic approaches.

Vibrotactile Gloves for Parkinson's Disease Patients

Parkinson’s Disease (PD) is a progressive neurodegenerative disorder marked by motor impairment due to the loss of dopamine-producing neurons. This paper presents the development of a vibrotactile glove designed to provide specific vibrational feedback through fingertip-based vibration motors, aimed at stimulating neuronal activity and potentially delaying PD symptoms. Constructed using an Arduino Nano, vibration motors, lithium-ion battery, slide switch, and a charging module, this glove prototype allows controlled vibrations at predefined frequencies and patterns. Preliminary testing suggests that this device may offer significant benefits in improving motor function and coordination, with potential implications as a preventive tool for those at risk of PD.

An Automated Diagnosis of Parkinson's Disease from MRI Scans Based on Enhanced Residual Dense Network with Attention Mechanism.

The increasing prevalence of neurodegenerative diseases has recently heightened interest in research on early diagnosis of these diseases. Parkinson's disease (PD), among the most prominent of these conditions, is a neurological disorder causing the loss of nerve cells and significantly affecting movement control. Detection of PD in early stages is of critical importance to prevent the progression of the disease and improve treatment processes. The aim of the current study is to develop a deep learning model that can perform accurate classification for early diagnosis of PD from MRI images. In this study, a densely connected feature fusion network with residual learning is designed to diagnose PD patients. The designed network consists of a serial dense block with skip connections and efficient attention mechanisms. In this architecture, squeeze-excitation (SE) blocks with ResNeXt (SE-ResNeXt block) modules are utilized to extract distinctive and high-level features. In the experiments, a publicly available T2-weighted MRI dataset is used, and an offline augmentation process is applied to limited data to increase the generalization ability and classification performance. The proposed method is evaluated and compared with current state-of-the-art deep learning methods. The obtained results show that the proposed model gives higher classification performance with an overall accuracy of 94.44%, precision of 91.67%, sensitivity of 91.67%, specificity of 95.83%, F1-score of 91.67%, and Matthew's correlation coefficient of 87.50% for the PD and healthy control subjects.

3D bioprinted in vitro epilepsy models for pharmacological evaluation in temporal lobe epilepsy

This study introduces a novelin vitromodel for intractable temporal lobe epilepsy (TLE) utilizing 3D bioprinting technology, aiming to replicate the complex neurobiological characteristics of TLE more accurately. Primary neural cell constructs were fabricated and subjected to epileptiform-inducing conditions, fostering synaptic proliferation and neuronal loss. Systematically electrophysiological and immunofluorescent analyses indicated that significant synaptic connectivity and sustained epileptiform activities within the constructs akin to those observed in human epilepsy models. Notably, the model responded to treatments with phenytoin and tetrodotoxin, illustrating its potential utility in drug response kinetics studies. Furthermore, we performed drug permeability simulations using COMSOL Multiphysics to analyze the diffusion characteristics of these drugs within the constructs. These results confirm that our 3D bioprinted neural model provides a physiologically relevant and ethically sustainable platform, which is beneficial for studying TLE mechanisms and developing therapeutic strategies with high accuracy and clinical relevance.