Motor Dysfunction Research Articles

Gold nanoparticles exhibit anti-osteoarthritic effects via modulating interaction of the “microbiota-gut-joint” axis

Osteoarthritis (OA) is a common degenerative joint disease that can cause severe pain, motor dysfunction, and even disability. A growing body of research indicates that gut microbiota and their associated metabolites are key players in maintaining bone health and in the progression of OA. Short-chain fatty acids (SCFAs) are a series of active metabolites that widely participate in bone homeostasis. Gold nanoparticles (GNPs) with outstanding anti-bacterial and anti-inflammatory properties, have been demonstrated to ameliorate excessive bone loss during the progression of osteoporosis (OP) and rheumatoid arthritis (RA). However, the protective effects of GNPs on OA progression are not clear. Here, we observed that GNPs significantly alleviated anterior cruciate ligament transection (ACLT)-induced OA in a gut microbiota-dependent manner. 16S rDNA gene sequencing showed that GNPs changed gut microbial diversity and structure, which manifested as an increase in the abundance of Akkermansia and Lactobacillus. Additionally, GNPs increased levels of SCFAs (such as butyric acid), which could have improved bone destruction by reducing the inflammatory response. Notably, GNPs modulated the dynamic balance of M1/M2 macrophages, and increased the serum levels of anti-inflammatory cytokines such as IL-10. To sum up, our study indicated that GNPs exhibited anti-osteoarthritis effects via modulating the interaction of “microbiota-gut-joint” axis, which might provide promising therapeutic strategies for OA.

Thrombomodulin reduces α-synuclein generation and ameliorates neuropathology in a mouse model of Parkinson’s disease

The neurotoxic α-synuclein (α-syn) oligomers play an important role in the occurrence and development of Parkinson’s disease (PD), but the factors affecting α-syn generation and neurotoxicity remain unclear. We here first found that thrombomodulin (TM) significantly decreased in the plasma of PD patients and brains of A53T α-syn mice, and the increased TM in primary neurons reduced α-syn generation by inhibiting transcription factor p-c-jun production through Erk1/2 signaling pathway. Moreover, TM decreased α-syn neurotoxicity by reducing the levels of oxidative stress and inhibiting PAR1-p53-Bax signaling pathway. In contrast, TM downregulation increased the expression and neurotoxicity of α-syn in primary neurons. When TM plasmids were specifically delivered to neurons in the brains of A53T α-syn mice by adeno-associated virus (AAV), TM significantly reduced α-syn expression and deposition, and ameliorated the neuronal apoptosis, oxidative stress, gliosis and motor deficits in the mouse models, whereas TM knockdown exacerbated these neuropathology and motor dysfunction. Our present findings demonstrate that TM plays a neuroprotective role in PD pathology and symptoms, and it could be a novel therapeutic target in efforts to combat PD.Schematic representation of signaling pathways of TM involved in the expression and neurotoxicity of α-syn. A TM decreased RAGE, and resulting in the lowered production of p-Erk1/2 and p-c-Jun, and finally reduce α-syn generation. α-syn oligomers which formed from monomers increase the expression of p-p38, p53, C-caspase9, C-caspase3 and Bax, decrease the level of Bcl-2, cause mitochondrial damage and lead to oxidative stress, thus inducing neuronal apoptosis. TM can reduce intracellular oxidative stress and inhibit p53-Bax signaling by activating APC and PAR-1. B The binding of α-syn oligomers to TLR4 may induce the expression of IL-1β, which is subsequently secreted into the extracellular space. This secreted IL-1β then binds to its receptor, prompting p65 to translocate from the cytoplasm into the nucleus. This translocation downregulates the expression of KLF2, ultimately leading to the suppression of TM expression. By Figdraw.

Cognitive reserve in ALS: the role of occupational skills and requirements

Objective Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous neurodegenerative condition featuring variable degrees of motor and cognitive impairment. We assessed the impact of specific, empirically derived occupational skills and requirements on cognitive and motor functioning in ALS. Methods Individuals with ALS (n = 150) were recruited from the University of Pennsylvania’s Comprehensive ALS Clinic. The Edinburgh Cognitive and Behavioral ALS Screen (ECAS) measured cognition, and the Penn Upper Motor Neuron (PUMNS) and ALS Functional Rating Scales (ALSFRS-R) measured motor symptoms. We derived 17 factors representing distinct occupational skills and requirements from the Occupational Information Network (O*NET), which were related to cognitive and motor scores using multiple linear regression. Results Occupational roles involving greater reasoning ability (β = 2.12, p < .05), social ability (β = 1.73, p < .05), analytic skills, (β = 3.12, p < .01) and humanities knowledge (β = 1.83, p<.01) were associated with better performance on the ECAS, while jobs involving more exposure to environmental hazards (β=−2.57, p < .01) and technical skills (β=−2.16, p<.01) were associated with lower ECAS scores. Jobs requiring more precision skills (β = 1.91, p < .05) were associated with greater motor dysfunction on the PUMNS. Conclusions Occupational histories involving more cognitively complex skills and activities were related to preserved cognitive functioning in ALS consistent with the cognitive reserve hypothesis, while jobs with greater exposure to environmental hazards and technical demands were linked to poorer cognitive functioning. Jobs involving more repetitive movements were associated with worse motor functioning, possibly due to overuse. Occupational history provides insight into protective and risk factors for variable degrees of cognitive and motor dysfunction in ALS.

Implicit motor learning in children with autism spectrum disorder: current approaches and future directions.

Motor dysfunction is increasingly being viewed as a core characteristic of autism spectrum disorder (ASD) in children. In particular, children with ASD have difficulty in learning new motor skills and there is a need to develop effective methods to improve this. Previous research has found that children with ASD may retain the ability to implicitly learn motor skills in comparison to their explicit learning of motor skills, which is typically impaired. This literature mini review focuses on summarizing the study of implicit learning in the acquisition of motor skills in children with ASD. First, we briefly introduce several common implicit learning methods in children's motor skill learning. Second, we focus on the role of two important implicit learning approaches in motor skill learning, namely, an external focus of attention and analogy learning. Finally, based on our review of the existing studies, we present an outlook for future research and the areas that need to be improved in the practical teaching of implicit learning in the acquisition of motor skills in children with ASD.

Multi-layer CNN-LSTM network with self-attention mechanism for robust estimation of nonlinear uncertain systems.

With the help of robot technology, intelligent rehabilitation of patients with lower limb motor dysfunction caused by stroke can be realized. A key factor constraining the clinical application of rehabilitation robots is how to realize pattern recognition of human movement intentions by using the surface electromyography (sEMG) sensors to ensure unhindered human-robot interaction. A multilayer CNN-LSTM prediction network incorporating the self-attention mechanism (SAM) is proposed, in this paper, which can extract and learn the periodic and trend characteristics of the sEMG signals, and realize the accurate autoregressive prediction of the human motion information. Firstly, the multilayer CNN-LSTM network utilizes the CNN layer for initial feature extraction of data, and the LSTM network is used to improve the enhancement of the historical time-series features. Then, the SAM is used to improve the global feature extraction performance and parallel computation speed of the network. In comparison with existing test is carried out using actual data from five healthy subjects as well as a clinical hemiplegic patient to verify the superiority and practicality of the proposed algorithm. The results show that most of the model's prediction R > 0.9 for different motion states of healthy subjects; in the experiments oriented to the motion characteristics of patient subjects, the angle prediction results of R > 0.99 for the untrained data on the affected side, which proves that our proposed model also has a better effect on the angle prediction of the affected side. The main contribution of this paper is to realize continuous motion estimation of ankle joint for healthy and hemiplegic individuals under non-ideal conditions (weak sEMG signals, muscle fatigue, high muscle tension, etc.), which improves the pattern recognition accuracy and robustness of the sEMG sensor-based system.

Association of lipid levels with motor and cognitive function and decline in Parkinson's disease.

Most studies have focused on comparing blood lipid biomarkers between Parkinson's disease (PD) and normal controls (NC). However, further research is necessary to explore the impact of blood lipid levels on motor and cognitive function, as well as the progression of motor dysfunction and cognitive decline over time. Thus, the aim of this study is to investigate the relationship between blood lipid biomarkers and these indicators in individuals with PD. The cohort study enrolled 157 PD patients and 146 NC from the Tianjin Huanhu Hospital from September 2017 to September 2019. Serum lipid fractions were detected in fasting serum samples. PD patients were followed up at 2 ± 0.6 years for clinical assessment. PD patients exhibited lower serum triglyceride (TG) levels as compared to NC (P = 0.008). PD male patients exhibited lower serum lipoprotein cholesterol(LDL-C) and total cholesterol (TC) levels than female patients (LDL-C: P = 0.034; TC: P = 0.019). Serum TG levels correlated significantly with Unified PD Rating Scale III, Hoehn and Yahr stage and Montreal Cognitive Assessment scores in PD patients. Additionally, serum TG levels were associated with follow-up motor function decline and cognitive decline in adjusted regression models in PD patients. To summarise, the study findings suggest that decreased serum TG levels are significantly associated with greater motor dysfunction, cognitive dysfunction and the greater deterioration of the two indicators.

Impact of motor dysfunction on neuropsychiatric symptom profile in patients with autopsy-confirmed Alzheimer’s disease

Motor dysfunction, which includes changes in gait, balance, and/or functional mobility, is a lesser-known feature of Alzheimer’s Disease (AD), especially as it relates to the development of neuropsychiatric symptoms (NPS). This study (1) compared rates of NPS between autopsy-confirmed AD patients with and without early-onset motor dysfunction and (2) compared rates of non-AD dementia autopsy pathology (Lewy Body disease, Frontotemporal Lobar degeneration) between these groups. This retrospective longitudinal cohort study utilized National Alzheimer’s Coordinating Center (NACC) data. Participants (N = 856) were required to have moderate-to-severe autopsy-confirmed AD, Clinical Dementia Rating-Global scores of ≤1 at their index visit, and NPS and clinician-rated motor data. Early motor dysfunction was associated with significantly higher NPI-Q total scores (T = 4.48, p < .001) and higher odds of delusions (OR [95%CI]: 1.73 [1.02–2.96]), hallucinations (2.45 [1.35–4.56]), depression (1.51 [1.11–2.06]), irritability (1.50 [1.09–2.08]), apathy (1.70 [1.24–2.36]), anxiety (1.38 [1.01–1.90]), nighttime behaviors (1.98 [1.40–2.81]), and appetite/eating problems (1.56 [1.09–2.25]). Early motor dysfunction was also associated with higher Lewy Body disease pathology (1.41 [1.03–1.93]), but not Frontotemporal Lobar degeneration (1.10 [0.71–1.69]), on autopsy. Our results suggest that motor symptoms in early AD are associated with a higher number and severity of NPS, which may be partially explained by comorbid non-AD neuropathology.

Exploring promising minor natural phenolic compounds in neuroprotection-related preclinical models.

Neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, are characterised by the progressive loss of specific neuronal cell populations due to multifactorial factors, including neurochemical and immunological disturbances. Consequently, patients can develop cognitive, motor and behavioural dysfunctions, which lead to impairments in their quality of life. Over the years, studies have reported on the neuroprotective properties inherent in phenolic compounds. Therefore, this review highlights the most recent scientific findings regarding phenolic compounds as promising neuroprotective molecules against neurodegenerative diseases.

Targeting NKAα1 to treat Parkinson's disease through inhibition of mitophagy-dependent ferroptosis

Dysfunction of the Na+/K+-ATPase (NKA) has been documented in various neurodegenerative diseases, yet the specific role of NKAα1 in Parkinson's disease (PD) remains incompletely understood. In this investigation, we utilized NKAα1 haploinsufficiency (NKAα1+/−) mice to probe the influence of NKAα1 on dopaminergic (DA) neurodegeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our findings reveal that NKAα1+/− mice displayed a heightened loss of DA neurons and more pronounced motor dysfunction compared to the control group when exposed to MPTP. Intriguingly, this phenomenon coincided with the activation of ferroptosis and impaired mitophagy both in vivo and in vitro. To scrutinize the role and underlying mechanism of NKAα1 in PD, we employed DR-Ab, an antibody targeting the DR-region of the NKA α subunit. Our study demonstrates that the administration of DR-Ab effectively reinstated the membrane abundance of NKAα1, thereby mitigating MPTP-induced DA neuron loss and subsequent improvement in behavioral deficit. Mechanistically, DR-Ab heightened the formation of the surface NKAα1/SLC7A11 complex, inhibiting SLC7A11-dependent ferroptosis. Moreover, DR-Ab disrupted the cytosolic interaction between NKAα1 and Parkin, facilitating the translocation of Parkin to mitochondria and enhancing the process of mitophagy. In conclusion, this study establishes NKAα1 as a key regulator of ferroptosis and mitophagy, identifying its DR-region as a promising therapeutic target for PD.

Effects of Crocin on Brain Neurotrophins, Cognition, Balance and Pain in Toxic-Induced Demyelination Model

Objective: The purpose of this study was to investigate the effects of Crocin on brain neuroterophins, cognition, sensory and motor dysfunction and compare to fingolimod effects in toxic-induced demyelination with Ethidium Bromide (EB) in female Wistar rats. Methods: Animals were assigned in to 8 groups; Sham, Sham operated (ShOp), Experimental Autoimmune Encephalomyelitis (EAE), crocin treated (Cr5,10,20 mg/kg), Vehicle, Fingolompd (Fing) and fingolimod + crocin (Cr+Fing). Demyelination was induced by single dose injection of 10 μl of EB 0.1% into the fourth ventricle of the brain. Crocin and fingolimod were administered for 21 days, daily, oral gavage. BDNF, NGF1, tail flake latency, balance and behavioral variables were sampled and analyzed by paired t-test and ANOVA test with repeated post hoc measurements. Results: The results showed that crocin improves all studied factors, but remarkable improvements were observed in dosage of 10 mg/kg. Crocin (10mg/kg) and fingolimod (1mg/kg) significantly improved cognition variables in open field test, sensory and motor nerve conduction velocity, tail flick latency and clinical scores (p&lt;005). In addition, applying of crocin co-administered with fingolimod led to significant increases in all assessed factors, greater than crocin or fingolimod intervention alone (α≤0.001). Conclusion: Based on the current findings, crocin can improve the level of brain neurotrophins, exploratory behavior, balance and pain after toxin-demyelination as close as fingolimod results.

The SLC6A1 Mutation Schizophrenia case — A Comprehensive Case Study With iPSC Generation

IntroductionThe main finding of a large-scale collaborative study (Rees et al. Nat Neurosci 2020;23(2) 179-184), which focused on de novo mutations in schizophrenia, was the discovery of an enrichment of these mutations in the SLC6A1 gene. This gene encodes the gamma-aminobutyric acid (GABA) transporter GAT1, thereby encouraging further research into novel schizophrenia targets within the GABA pathway. However, the gene was not highlighted in recent schizophrenia genetic studies, while typically pathogenic SLC6A1 mutations result in epilepsy, motor dysfunction, autistic spectrum disorder (ASD) and developmental delay. The absence of genetic replication for SLC6A1’s involvement in schizophrenia and the differing clinical spectrum for SLC6A1 mutations led us to study in depth one of the only three original probands from the Rees et al. 2020 study.ObjectivesIn our comprehensive case study, we delved deep into the relationship between the SLC6A1 mutation and schizophrenia.MethodsOur subject, a patient who first presented with acute mania symptoms at age 15 and was later diagnosed with schizophrenia, carried the SLC6A1 Arg211Cys mutation. Over a detailed 25-year follow-up, we conducted an array of assessments and tests, including cognitive testing, personality assessments, EEG, and 1H-MRS.ResultsNotably, we discovered abnormal GABA levels, potentially indicating a dysfunction in GABA reuptake, adding a new layer of complexity to our understanding. Further analysis revealed a significant correlation between the patient’s clinical picture and a polygenic background, rather than the SLC6A1 mutation. Despite having a high polygenic risk score for bipolar disorder, the dominant features of his condition were more representative of schizophrenia. Interestingly, neither the patient nor his father, who also showed a higher BP PRS, had a diagnosis of bipolar disorder. The pathogenic significance of the mutation warrants investigation in cells of neuronal origin. We generated induced pluripotent stem cells (iPSC) from the patient and his parents. This approach provides us with a platform for future investigations into the pathogenic significance of the mutation in neuronal cells. The Human Pluripotent Stem Cell Registry accession numbers of those cells are MHRCCGi001-A (patient), MHRCCGi005-A (mother) and MHRCCGi004-A (father).ConclusionsIn the presented case the clinical picture is rather explained by the polygenic background than by the SLC6A1 Arg211Cys mutation. The study is supported by Russian Science Foundation, grant 21-15-00124 (https://rscf.ru/project/21-15-00124)Disclosure of InterestNone Declared

The application value and improved warning criterion of D-wave monitoring in intramedullary spinal cord tumor surgery

BACKGROUND CONTEXTThe primary treatment method for intramedullary spinal cord tumor (IMSCT) is surgical resection, but this procedure carries a significant risk of neurological damage. Intraoperative neurophysiological monitoring (IONM) has become a necessary adjunctive tool for IMSCT resection. PURPOSEThe current study aimed to explore the application value of D-wave monitoring in IMSCT surgery, and tried to investigate a tailored criterion for its early warning. STUDY DESIGNA retrospective clinical study. PATIENT SAMPLEA retrospective analysis was conducted based on the data of patients who underwent IMSCT surgeries performed by the same neurosurgical team at our hospital. IONM was applied in all surgeries. According to inclusion and exclusion criteria, ultimately 90 patients were enrolled in the study. OUTCOME MEASURESThe McCormick Scale (MMS) was applied to assess the functional outcome through outpatient visits or telephone follow-up at one month and six months postoperatively. Patients with an MMS grade over II one month after surgery were considered to have newly developed postoperative motor dysfunction (PMD). If the MMS grade could be restored to I or II six months after surgery, it was defined as a short-term PMD. Otherwise, it was defined as a long-term PMD. METHODSThe predictive value of different IONM modalities, including somatosensory evoked potential (SEP), muscle motor evoked potential (MEP), and D-wave for PMD, was assessed with sensitivity, specificity, positive predictive value, negative predictive value, and subsequent logistic regression analysis. At last, the cut-off value of the D-wave amplitude reduction ratio for predicting PMD was obtained through the receiver operating characteristic (ROC) curve analysis. RESULTSSEP showed the worst performance in predicting short-term and long-term PMD. Significant MEP changes were indicated as an independent predictive factor for short-term PMD (OR 5.062, 95% CI 1.947–13.166, p=.001), while D-wave changes were demonstrated as an independent predictor for long-term PMD (OR 339.433, 95% CI 11.337–10770.311, p=.001). The optimum cut-off value of the D-wave amplitude reduction ratio for predicting long-term PMD was 42.18%, with a sensitivity of 100% and a specificity of 93.8% (AUC=0.981, p<.001). CONCLUSIONSD-wave monitoring showed extremely high specificity in predicting PMD compared to SEP and MEP monitoring. Moreover, the authors suggested that a D-wave amplitude reduction of over 40% during IMSCT surgery generally indicates long-term PMD for patients.

376 Pathophysiology of voluntary motor commands in patients with multiple sclerosis identified using reverse engineering of motor unit population discharge.

OBJECTIVES/GOALS: Our objective is to characterize excitatory, inhibitory, and neuromodulatory components of the voluntary motor command at the level of the spinal motoneuron in people with multiple sclerosis (MS). This information will provide insight into neural mechanisms of motor dysfunction and their heterogeneity among patients with MS. METHODS/STUDY POPULATION: Due to advances in high-density surface EMG (HDsEMG) decomposition and the recent development of a paradigm for reverse engineering of motor unit population discharge, we can feasibly estimate aspects of excitatory, inhibitory, and neuromodulatory components of the voluntary motor command in humans on a person-specific basis. We tested 11 ambulatory patients with MS and mild-moderate disability. We recorded HDsEMG from tibialis anterior (TA) and soleus (SOL) during isometric plantarflexion and dorsiflexion, performed as slow triangle contractions. EMG was decomposed into motor unit spike trains using blind source separation. We calculated a number of motor unit variables, most notably delta-F, which estimates motoneuron excitability and the balance of neuromodulatory and inhibitory inputs. RESULTS/ANTICIPATED RESULTS: There were consistent differences in MS patients vs. controls. For TA, values were decreased for delta-F (3.9 vs. 5.9 pps), initial firing rate acceleration (5.8 vs. 7.1 pps), firing rate range (9.3 vs. 11.9 pps), and max firing rate (12.3 vs. 15.0 pps). SOL had more modest decreases in delta-F (3.0 vs. 3.8 pps) and firing rate range (4.8 vs. 5.6 pps). Self-sustained firing was longer for MS patients. Within a patient, abnormalities in motor unit variables were not consistent across muscles and legs. Interestingly, there were several abnormalities in the patients with a normal clinical motor exam, indicating that perhaps our measures are sensitive to subclinical changes in processing of voluntary motor commands. DISCUSSION/SIGNIFICANCE: Excitatory, inhibitory, and neuromodulatory components of the voluntary motor command must be appropriately balanced for skilled motor output. This study is the first to characterize how they are disrupted in MS, providing foundational information to inform the development of mechanistically-based rehabilitation interventions.

Totally laparoscopic management of a giant sigmoid colon diverticulum: Case report and review of literature

The giant diverticulum of the sigmoid colon is a rare clinical condition characterized by a high risk of complications. Its etiology is multifactorial, with longstanding diverticular disease and motor dysfunction of the colon as risk factors. Even though its diagnosis could be challenging, clinicians can rely on barium enemas revealing the characteristic findings of a large, air-filled sac adjacent to the colon on a computed tomography scan and colonoscopy. The use of these tools aids in ruling out alternative diagnoses and confirming the presence of a diverticulum. Timely surgical management is essential, also in asymptomatic fit-for-surgery patients, to prevent potential complications.

Small nucleolar RNA host gene 1 silence inhibits the lipopolysaccharide-induced microglial apoptosis and inflammation.

Microglia activation is an early mediator of neuroinflammation and a major contributor to spinal damage and motor dysfunction. This study was designed to investigate the role of small nucleolar RNA host gene 1 (SNHG1) on the apoptosis and inflammatory response of microglial cell BV-2 and its underlying molecular mechanism. The C5 lamina contusion-induced mouse model of spinal cord injury (SCI) was constructed. Mouse microglia BV2 was stimulated by lipopolysaccharide (LPS) to establish the in vitro model of SCI. The quantitative reverse transcription polymerase chain reaction method was used to quantify RNA expression levels. Enzyme-linked immunosorbent assays were used to quantify concentrations of inflammatory cytokines. Protein levels were assessed by western blotting, and apoptosis was assessed by flow cytometry. Dual luciferase reporter gene assay and RNA pull-down assay were conducted to investigate the binding relationships between molecules. Upregulation of SNHG1 and downregulation of miR-195-5p were observed in the spinal cords of SCI mouse model. LPS treatment led to elevation of SNHG1 expression in BV2 cells, as well as accelerated apoptosis and inflammation. Evident mitigation of LPS-induced BV2 cell damage was observed after SNHG1 knockdown. MiR-195-5p was identified as a target of SNHG1. Inhibition of miR-195-5p restored the impact of SNHG1 knockdown on cell damage of LPS-treated BV2 cells. Furthermore, miR-195-5p can target activating transcription factor-6 (ATF6). In summary, SNHG1 knockdown ameliorates LPS-induced microglial apoptosis and inflammatory response via the miR-195-5p/ATF6 axis, providing a novel direction for SCI treatment.

Deep Learning-Enhanced Hand Grip and Release Test for Degenerative Cervical Myelopathy: Shortening Assessment Duration to 6 Seconds.

Hand clumsiness and reduced hand dexterity can signal early signs of degenerative cervical myelopathy (DCM). While the 10-second grip and release (10-s G&R) test is a common clinical tool for evaluating hand function, a more accessible method is warranted. This study explores the use of deep learning-enhanced hand grip and release test (DL-HGRT) for predicting DCM and evaluates its capability to reduce the duration of the 10-s G&R test. The retrospective study included 508 DCM patients and 1,194 control subjects. Propensity score matching (PSM) was utilized to minimize the confounding effects related to age and sex. Videos of the 10-s G&R test were captured using a smartphone application. The 3D-MobileNetV2 was utilized for analysis, generating a series of parameters. Additionally, receiver operating characteristic curves were employed to assess the performance of the 10-s G&R test in predicting DCM and to evaluate the effectiveness of a shortened testing duration. Patients with DCM exhibited impairments in most 10-s G&R test parameters. Before PSM, the number of cycles achieved the best diagnostic performance (area under the curve [AUC], 0.85; sensitivity, 80.12%; specificity, 74.29% at 20 cycles), followed by average grip time. Following PSM for age and gender, the AUC remained above 0.80. The average grip time achieved the highest AUC of 0.83 after 6 seconds, plateauing with no significant improvement in extending the duration to 10 seconds, indicating that 6 seconds is an adequate timeframe to efficiently evaluate hand motor dysfunction in DCM based on DL-HGRT. DL-HGRT demonstrates potential as a promising supplementary tool for predicting DCM. Notably, a testing duration of 6 seconds appears to be sufficient for accurate assessment, enhancing the test more feasible and practical without compromising diagnostic performance.

Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-Induced Huntington's Disease-Like Symptoms in Rats.

Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric dysfunction caused by a mutant huntingtin protein. Compromised metabolic activity resulting from systemic administration of the mitochondrial toxin, 3-nitropropionic acid (3-NP), is known to mimic the pathology of HD and induce HD-like symptoms in rats. N-hexanoic-Tyr-Ile-(6)-amino hexanoic amide (PNB-0408), also known as Dihexa, has been shown to have neuroprotective and procognitive properties in animal models of Alzheimer's and Parkinson's diseases. Given the mechanism of action and success in other neurodegenerative diseases, we felt it an appropriate compound to investigate further for HD. The present study was designed to test if PNB-0408, an angiotensin IV analog, could attenuate 3-NP-induced HD-like symptoms in rats and serve as a potential therapeutic agent. Forty male Wistar rats were randomized into three groups consisting of a "vehicle" group, a "3-NP" group, and a "3-NP + PNB-0408" group. PNB-0408 was administered along with chronic exposure to 3-NP. Animal body weight, motor function, and cognitive abilities were measured for five weeks, before euthanasia and histopathological analysis. Exposure to 3-NP decreased the amount of weight rats gained, impaired spatial learning and memory consolidation, and led to marked motor dysfunction. From our observations and analysis, PNB-0408 did not protect rats from the deficits induced by 3-NP neurotoxicity. Our findings suggest that PNB-0408 may not be an efficacious treatment strategy for preventing 3-NP-induced HD-like symptoms in a preclinical model. These data highlight the need for further research of this compound in alternate models and/or alternative approaches to managing this disorder.

Protopanaxadiols Eliminate Behavioral Impairments and Mitochondrial Dysfunction in Parkinson’s Disease Mice Model

Currently, there are no effective therapies to cure Parkinson’s disease (PD), which is the second most common neurodegenerative disease primarily characterized by motor dysfunction and degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Protopanaxadiols (PPDs), including 20 (R)- protopanaxadiol (R-PPD) and 20 (S)- protopanaxadiol (S-PPD), are main metabolites of ginsenosides. The role of ginsenosides in neurodegenerative diseases has been thoroughly studied, however, it is unknown whether PPDs can attenuate behavioral deficits and dopaminergic neuron injury in PD model mice to date. Here, we administered PPDs to MPTP-induced PD model mice and monitored the effects on behavior and dopaminergic neurons to investigate the effects of R-PPD and S-PPD against PD. Our results showed that R-PPD and S-PPD (at a dose of 20 mg/kg, i.g.) treatment alleviated MPTP (30 mg/kg, i.p.) induced behavioral deficits. Besides, R-PPD and S-PPD protected MPP+-induced neuron injury and mitochondrial dysfunction, and reduced the abnormal expression of Cyt C, Bax, caspase-3 and Bcl-2. These findings demonstrate that R-PPD and S-PPD were potentially useful to ameliorate PD.

Petunidin-3-glucoside supplementation causes sex-specific effects on the lifespan and motor function in \(\textit{Drosophila melanogaster}\)

Petunidin-3-glucoside (P3G), an anthocyanin prevalent in vegetables, fruits, and wine, possesses noteworthy antioxidant properties attributed to its capacity to scavenge free radicals. This property has sparked interest in the potential for anthocyanins to confer benefits on longevity and age-related motor dysfunctions. In this study, the impact of petunidin-3-glucoside (P3G) on the lifespan and motor function in Drosophila melanogaster was examined, both in the presence and absence of neurotoxic substances, such as glyphosate or ethanol. Varying concentrations of P3G were incorporated into the flies' diet immediately after hatching. Subsequently, distinct sets of flies were subjected to diverse conditions, including a stress-free environment, ethanol exposure, and glyphosate exposure. The survival rate of the flies was monitored daily, and their motor function was assessed using a negative geotaxis assay on days 1, 5, 10, and 15 post-eclosion. Only male flies exhibited an extended lifespan under normal and ethanol-exposed conditions. While P3G did not induce significant alterations in overall motor function for male and female flies across various conditions, intriguing variations were observed at different time points. In female flies, low concentrations of P3G seemed to exacerbate motor function decline during mid to late adulthood, particularly in the presence of glyphosate. Conversely, middle P3G concentration improved motor function in male flies during early to mid-adulthood, a trend consistent regardless of neurotoxic exposures. Taken together, the findings underscore the potential sex-specific effects of P3G on both lifespan and motor function, with observed benefits predominantly applicable to male flies. Nonetheless, while suggestive, a more in-depth investigation is imperative to comprehensively determine whether the advantageous impact of P3G on motor function is exclusive to the early to mid-adult stage. As such, this study presents a foundation that warrants further investigation.

Compensatory upregulation of MT2A alleviates neurogenic intermittent claudication through inhibiting activated p38 MAPK-mediated neuronal apoptosis.

Neurogenic intermittent claudication (NIC), a classic symptom of lumbar spinal stenosis (LSS), is associated with neuronal apoptosis. To explore the novel therapeutic target of NIC treatment, we constructed the rat model of NIC by cauda equina compression (CEC) method and collected dorsal root ganglion (DRG) tissues, a region responsible for sensory and motor function, for mRNA sequencing. Bioinformatic analysis of mRNA sequencing indicated that upregulated metallothionein 2A (MT2A), an apoptosis-regulating gene belonging to the metallothionein family, might participate in NIC progression. Activated p38 MAPK mediated motor dysfunction following LSS and it was also found in DRG tissues of rats with NIC. Therefore, we supposed that MT2A might affect NIC progression by regulating p38 MAPK pathway. Then the rat model of NIC was used to explore the exact role of MT2A. Rats at day 7 post-CEC exhibited poorer motor function and had two-fold MT2A expression in DRG tissues compared with rats with sham operation. Co-localization analysis showed that MT2A was highly expressed in neurons, but not in microglia or astrocytes. Subsequently, neurons isolated from DRG tissues of rats were exposed to hypoxia condition (3% O2, 92% N2, 5% CO2) to induce cell damage. Gain of MT2A function in neurons was performed by lentivirus-mediated overexpression. MT2A overexpression inhibited apoptosis by inactivating p38 MAPK in hypoxia-exposed neurons. Our findings indicated that high MT2A expression was related to NIC progression, and MT2A overexpression protected against NIC through inhibiting activated p38 MAPK-mediated neuronal apoptosis in DRG tissues.