Motor Neuron Damage Research Articles

Effects of low-intensity exercise on contractile property of skeletal muscle and the number of motor neurons in diabetic rats.

The mode of diabetes-induced muscle and motor neuron damage depends on the type of muscle and motor neuron. One of the purposes of exercise therapy for diabetes is to improve blood glucose levels; however, information on the effects of low-intensity exercise on muscle and motor neuron disorders remain unknown. Therefore, this study aimed to examine the effects of low-intensity exercise on diabetes-induced muscle and motor neuron damage in a rat model of type 1 diabetes mellitus. We subjected adult male Wistar rats treated with streptozotocin to develop type 1 diabetes and age-matched rats to low-intensity treadmill exercise for 12weeks. We recorded electrically evoked maximum twitch tension in leg muscles, and examined the number of motor neurons and cell body sizes. Low-intensity exercise ameliorated the prolonged half-relaxation time and the decreased numbers of the retrograde-labeled motor neurons observed in the soleus muscle of type 1 diabetic rats. However, no effect was observed in the diabetic group, as atrophy was not improved and the twitch force in the medial gastrocnemius muscle was decreased in the diabetic group. In addition, there was no improvement in the blood glucose levels after exercise. These data indicate that low-intensity exercise may relieve the onset of muscle and motor neuron damage in the soleus muscle of type 1 diabetic rats.

Training in Walking with Aids – Risks and Safety for the Patient

Impaired locomotor activity changes the dynamic stereotype of each person, and this leads to significant changes in daily life related to maintaining personal hygiene, performing household activities, social contacts and skills and habits at work. Building a new motor habit carries the main characteristics of a pedagogical process with in-depth knowledge of the basic principles and methods of training, knowledge and practical skills for performing a given motor act, but it also has its own specifics of motor training. The new motor habit for walking with aids must guarantee the safety of the patient, consistent with his individual functional capabilities for its formation. The purpose of this article is to formulate methodological guidelines for overcoming the risk factors in learning to walk with aids, guaranteeing the safety of the patient with impaired locomotion. Material and methods. Patients who have impaired or difficult locomotion, which can be a result of hip or knee arthroplasty; post-fracture conditions; soft tissue damage; central or peripheral motor neuron damage; femoral or lower leg amputation. Results and discussion. The emphasis in the development of a methodology for training patients in walking with aids is the formulation of methodological guidelines from the point of view of the safety for the patient and the reduction of the risk of trauma during training (fall), considering the peculiarities of the characteristic of the main phases for building a new motor habit (generalization, concentration, automation). Conclusion. Compliance with the methodical instructions in training in walking with aids ensures the cyclical construction of a new motor habit and minimizes the influence of risk factors.

Surgical reconstruction of arm and hand functions in tetraplegia : Current concepts

The reconstruction of arm and hand functions is of enormous importance for tetraplegic patients as it enables at least some degree of independence. Depending on the level of the spinal cord injury, certain residual functions are present in the arms which can be used for surgical reconstruction of upper extremity functions. By utilizing tendon and nerve transfers missing functions can at least be partially reconstructed. Tendon transfers are aproven technique with reliable results that can be performed at any time regardless of the type of accident. Due to the frequent presence of lower motor neuron damage, it is essential to consider the optimal time window for nerve transfer interventions. From the multitude of surgical options, an individual reconstruction plan must be created for each patient, which considers multiple factors. The combination of nerve transfers and later completing the functional reconstruction by tendon transfers is the preferred concept of the authors of this article.

Chronic carbon disulfide exposure induces parkinsonian pathology via α-synuclein aggregation and necrosome complex interaction

Exposure to carbon disulfide (CS2) has been associated with an increased incidence of parkinsonism in workers, but the mechanism underlying this association remains unclear. Using a rat model, we investigated the effects of chronic CS2 exposure on parkinsonian pathology. Our results showed that CS2 exposure leads to significant motor impairment and neuronal damage, including loss of dopaminergic neurons and degeneration of the substantia nigra pars compacta (SNpc). The immunoassays revealed that exposure to CS2 induces aggregation of α-synuclein and phosphorylated α-synuclein, as well as activation of necroptosis in the SNpc. Furthermore, invitro and invivo experiments demonstrated that the interaction between α-synuclein and the necrosome complex (RIP1, RIP3, and MLKL) is responsible for the loss of neuronal cells after CS2 exposure. Taken together, our results demonstrate that CS2-mediated α-synuclein aggregation can induce dopaminergic neuron damage and parkinsonian behavior through interaction with the necrosome complex.

Analysis on the effect of genes on amyotrophic lateral sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a progressive weakness and atrophy of the muscles including the bulb (the part of the muscles innervated by the medulla oblongata), limbs, trunk, chest, and abdomen following injury to upper and lower motor neurons. However, the reasons for developing ALS are still not very clear. Both genetic defects and environmental factors may damage motor neurons. At present, ALS is a difficult disease to cure. For environmental factors, people can change their lifestyles to reduce or avoid the effects of the environment. However, inherited genetic defects are hard to avoid. Therefore, in this paper, the author explores the treatment of ALS by analyzing and summarizing a large number of papers and experimental studies learning the relationship between genes and ALS. In conclusion, the gene TARDBP and the gene C9ORF72 were found in a large number of disease-causing genes. Mutations in these genes can lead to changes in the encoded proteins that cause the development of ALS disease.

Motor outcomes in patients with infantile and juvenile Pompe disease: Lessons from neurophysiological findings.

In Infantile Onset Pompe Disease (IOPD), enzyme replacement therapy (ERT) may improve survival, cardiac function, and motor development. However, even with early enzyme replacement therapy, some patients experienced poor response to ERT and abnormal motor milestones that could be due to motor neuron involvement. In this long-term retrospective study, we analyzed concomitant clinical motor outcomes and electroneuromyography (ENMG) findings in patients with IOPD and Juvenile Onset Pompe Disease (JOPD). Twenty-nine pediatric patients were included and 20 surviving were analyzed for neuromotor studies: 12 had IOPD (group 1), 4 had JOPD (group 2) and 4 (group 3) received ERT in the first month of age. Motor nerve conduction studies were mostly normal. Needle EMG performed at diagnosis always indicated the existence of myopathy that responded to ERT. Two IOPD patients (group 1) presenting with mixed motor neuropathy and myopathy displayed a poor outcome and never walked. Two patients became non-walkers (one IOPD patient and one patient of group 3) at respectively 9 and 3years of age. One JOPD patient is about to lose walking ability. This motor deterioration was associated with the development of a motor neuropathy. Patients older than 10years of age develop a motor neuropathy. Initial or secondary motor neuron involvement seems to be associated with a poor motor outcome showing that ERT may fail to prevent the accumulation of glycogen in motor neuron. Neurophysiological findings are important to assess severity of motor neuron damage in all Pompe pediatric patients and should be systematically performed.

Electrical stimulation in lower motoneuron lesions, from scientific evidence to clinical practice: a successful transition.

Long pulse stimulation in its application in everyday clinical practice still represents a challenge for many therapists and clinicians. It is often unclear how the intervention setup, in particular the parameters pulse width, frequency and amplitude, can influence muscle morphology. In addition, the cause of damage to the lower motoneuron can have multiple reasons and is not anatomically located at the same site. Given the large heterogeneity, it is essential to know the current options and limitations in order to carry out a targeted treatment. A retrospective data analysis of n=128 patients, seen at the Swiss Paraplegic Centre (SPC) in 2022, shows a broad variability in manifestation of lower motoneuron damage. Treatment examples based on different causes of lower motoneuron damage are shown and corresponding stimulation programmes are assigned, as well as the expected results in terms of stimulation duration, volume and configuration.

THE AMYOTROPIC LATERAL SCLEROSIS AND FUNCTIONAL RATING SCALE (ALSFRS)

Research material and methods: During the last five years, 60 patients from different parts of Georgia, including Samegrolo, Kartli, Adjara, Abkhazia, Guria, Kakheti regions have been studied, searched and examined by us. The Georgian Neurologists Corps participated and helped us in finding patients. With the consent of the individual patient, which is confirmed in writing, the study was conducted in accordance with the modern requirements of research. We studied patient's anamnesis, physical data, evaluated their mental, cognitive functions and neurological status. We have also interviewed family members, as it was often difficult for the patient to accurately describe the symptoms. Brain MRI and electromyography were also performed. 60 patients with different forms of ALS participated in the study, including 34 (56.66%) men and 26 (43.33%) women. Their age ranges from 30 to 81 years. Patients were included in the study according to the El Escorial criteria. Among those examined by us, the disease began mainly with muscle numbness, weakness of the limbs, fasciculations, in 36 (60%) patients with speech difficulties. According to our research, the diagnosis of ALS is difficult until muscle atrophy and tremors are detected. There are relatively less cases of ALS (23 (38.33%) patients) with symptoms of one or both legs. At this time, the patients felt uncomfortable while walking, the ankle lost its flexibility, its range of motion was limited. muscle weakness is expressed; muscle spasms; increase of deep reflexes or expansion of the reflexogenic zone; pathological reflexes; pronounced muscle atrophy; increased spasticity; At this time, the upper limbs were less damaged, although the flexibility of the fingers in the upper limbs is limited. ALS with bulbar events was detected in 24 (40%) patients with difficulty speaking, the patient spoke "through the nose", later had difficulty swallowing. Disturbance of speech (dysarthria, anarthria), voice production disorder (dysphonia, aphonia). Disappearance of soft palate and throat reflexes, salivation, breathing disorders were soon added to the symptoms; While in the 11 (18.33%) patients with ALS confirmed by us, the symptoms included signs of both lower and upper motor neuron damage, the upper motor neuron showed: muscle hypertonia, hyperreflexia, pathological Babinski reflex; and in case of damage to the lower motoneurons: muscle weakness and atrophy, involuntary fasciculations. Thus, for the first time in Georgia, we determined the structure and characteristics of the most common syndromes of amyotrophic lateral sclerosis in over the last 5 years, and the prevalence of patients with this disease, taking into account age, sex, disease anamnesis, and other symptoms.

Influence of noise on perception of different types of dysarthric speech

Disturbances in the central nervous system may lead to changes in the speech muscle system, which impact muscle strength, tone, and coordination as well as movement speed, resulting in different types of dysarthria, each impacting respiration, phonation, articulation, resonance, and prosody differentially. Bilateral upper motor neuron damage leads to spastic dysarthria, cerebellar damage ataxic dysarthria, and damage to basal ganglia hypokinetic dysarthria. In estimating the severity of speech impairment, and measuring speech intelligibility, both reading and spontaneous speech samples are routinely used by speech-language pathologists. However, noise levels in acute and rehabilitation hospitals often exceed the World Health Organization guidelines (Busch-Vishniac et al., 2005) which may impact the clinical outcomes. In this study, 100 graduate student clinicians in Speech-Language Pathology measured speech intelligibility and estimated the severity of speech impairment of speech samples produced by three types of dysarthric speakers: spastic, ataxic, and hypokinetic, in two different noise conditions (quiet, and hospital noise). The differential impact of noise on different types of dysarthria is examined, and its implication on clinical outcomes is discussed.

Motor neuron damage in late-onset Pompe disease: a case report and literature review

庞贝病（Pompe disease）亦称糖原贮积病Ⅱ型（GSDⅡ），传统认为它是一种遗传性肌肉病，特征是编码酸性α-葡萄糖苷酶（GAA）的基因突变，其糖原贮积主要在肌肉。但有文献报道庞贝病可见脑血管内皮细胞受损、自主神经功能障碍、周围神经系统和小纤维神经病变。罕见运动神经元受累表现。本文报道1例庞贝病合并运动神经元受损病例，提示庞贝病是一种神经肌肉疾病并文献回顾，以提高临床诊断效率。.

Sporadic Spinal-Onset Amyotrophic Lateral Sclerosis Associated with Myopathy in Three Unrelated Portuguese Patients

Amyotrophic lateral sclerosis (ALS) and myopathy have been already described as part of a common genetic syndrome called multisystem proteinopathy. They may occur together or not, and can be associated with other clinical features such as frontotemporal dementia and Paget's bone disease. In addition, primary skeletal muscle involvement has been also reported in inherited forms of lower motor neuron disease, in spinal-bulbar muscular atrophy and in spinal muscular atrophy. We aim to characterize three sporadic, spinal-onset ALS patients, one with a concurrent non-specific myopathy, and two with a previous diagnosis of myopathy before upper and lower motor neuron signs emerged. Perhaps our sporadic ALS cases associated with myopathy share a common, but still unknown, pathogenic background. These cases raise the paradigm of a possible interplay between skeletal muscle degeneration and motor neuron damage.

Therapeutic Hypothermia after Cardiac Arrest Attenuates Hindlimb Paralysis and Damage of Spinal Motor Neurons and Astrocytes through Modulating Nrf2/HO-1 Signaling Pathway in Rats.

Cardiac arrest (CA) and return of spontaneous circulation (ROSC), a global ischemia and reperfusion event, lead to neuronal damage and/or death in the spinal cord as well as the brain. Hypothermic therapy is reported to protect neurons from damage and improve hindlimb paralysis after resuscitation in a rat model of CA induced by asphyxia. In this study, we investigated roles of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in the lumbar spinal cord protected by therapeutic hypothermia in a rat model of asphyxial CA. Male Sprague-Dawley rats were subjected to seven minutes of asphyxial CA (induced by injection of 2 mg/kg vecuronium bromide) and hypothermia (four hours of cooling, 33 ± 0.5 °C). Survival rate, hindlimb motor function, histopathology, western blotting, and immunohistochemistry were examined at 12, 24, and 48 h after CA/ROSC. The rats of the CA/ROSC and hypothermia-treated groups had an increased survival rate and showed an attenuated hindlimb paralysis and a mild damage/death of motor neurons located in the anterior horn of the lumbar spinal cord compared with those of the CA/ROSC and normothermia-treated groups. In the CA/ROSC and hypothermia-treated groups, expressions of cytoplasmic and nuclear Nrf2 and HO-1 were significantly higher in the anterior horn compared with those of the CA/ROSC and normothermia-treated groups, showing that cytoplasmic and nuclear Nrf2 was expressed in both motor neurons and astrocytes. Moreover, in the CA/ROSC and hypothermia-treated group, interleukin-1β (IL-1β, a pro-inflammatory cytokine) expressed in the motor neurons was significantly reduced, and astrocyte damage was apparently attenuated compared with those found in the CA/ROSC and normothermia group. Taken together, our results indicate that hypothermic therapy after CA/ROSC attenuates CA-induced hindlimb paralysis by protecting motor neurons in the lumbar spinal cord via activating the Nrf2/HO-1 signaling pathway and attenuating pro-inflammation and astrocyte damage (reactive astrogliosis).

Dietary Transfer of Zinc Oxide Nanoparticles Induces Locomotive Defects Associated with GABAergic Motor Neuron Damage in Caenorhabditis elegans.

The widespread use of zinc oxide nanoparticles (ZnO-NPs) and their release into the environment have raised concerns about the potential toxicity caused by dietary transfer. However, the toxic effects and the mechanisms of dietary transfer of ZnO-NPs have rarely been investigated. We employed the bacteria-feeding nematode Caenorhabditis elegans as the model organism to investigate the neurotoxicity induced by exposure to ZnO-NPs via trophic transfer. Our results showed that ZnO-NPs accumulated in the intestine of C. elegans and also in Escherichia coli OP50 that they ingested. Additionally, impairment of locomotive behaviors, including decreased body bending and head thrashing frequencies, were observed in C. elegans that were fed E. coli pre-treated with ZnO-NPs, which might have occurred because of damage to the D-type GABAergic motor neurons. However, these toxic effects were not apparent in C. elegans that were fed E. coli pre-treated with zinc chloride (ZnCl2). Therefore, ZnO-NPs particulates, rather than released Zn ions, damage the D-type GABAergic motor neurons and adversely affect the locomotive behaviors of C. elegans via dietary transfer.

Overview of amyotrophic lateral sclerosis and medications for disease progression

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects the nerve cells responsible for controlling voluntary muscle movement. The progression of ALS varies, but generally follows a predictable pattern. There is no cure for ALS, and treatment is focused on managing symptoms and maximizing quality of life. Medications such as riluzole and edaravone are commonly prescribed to manage symptoms and slow the disease progression. Riluzole works by reducing the release of glutamate, a neurotransmitter that can damage motor neurons, modulating voltage-gated sodium channels, and stabilizing intracellular calcium levels. Clinical trials have demonstrated that riluzole can help slow the progression of ALS, though it does not cure the disease. It is important to note that riluzole is not effective for all patients with ALS, and its benefits are modest. Therefore, it is important to discuss the potential benefits and risks of riluzole with a health-care provider before starting treatment.

Oxidative stress disrupts the cytoskeleton of spinal motor neurons.

Traumatic spinal cord injury (SCI) is a common and devastating central nervous disease, the treatment of which faces many challenges to the medical community and society as a whole. Treatment measures based on oxidative stress of spinal motor neurons during SCI are expected to help restore biological functions of neurons under injury conditions. However, to date, there are no systematic reports regarding oxidative stress on spinal motor neuron injury. Our aim is to better understand and explain the influences and mechanisms of oxidative stress on spinal motor neurons during SCI. We first exposed VSC4.1 motor neurons to hydrogen peroxide (H2 O2 ) and evaluated the effects on cell viability, morphology, cycling, and apoptosis, with an emphasis on the changes to the cytoskeleton and the effect of N-acetyl-l-cysteine (NAC) on these changes. Then, we investigated the effects of NAC on these cytoskeletal changes in vitro and in vivo. We found that H2 O2 caused severe damage to the normal cytoskeleton, leading to a reduction in neurite length and number, rearrangement of the actin cytoskeleton, and disorder of the microtubules and neurofilaments in VSC4.1. Importantly, NAC attenuated the oxidative damage of spinal motor neurons in vitro and in vivo, promoting the recovery of hindlimb motor ability in mice with SCI at the early stage of injury. This study shows that oxidative stress plays an important role in the cytoskeleton destruction of spinal motor neurons in SCI, and treatment of SCI on this basis is a promising strategy. These findings will help to elucidate the role of oxidative stress in spinal motor neuron injury in SCI and provide references for further research into the study of the pathology and underlying mechanism of SCI.

Neural recovery after cortical injury: Effects of MSC derived extracellular vesicles on motor circuit remodeling in rhesus monkeys.

Reorganization of motor circuits in the cortex and corticospinal tract are thought to underlie functional recovery after cortical injury, but the mechanisms of neural plasticity that could be therapeutic targets remain unclear. Recent work from our group have shown that systemic treatment with mesenchymal stem cell derived (MSCd) extracellular vesicles (EVs) administered after cortical damage to the primary motor cortex (M1) of rhesus monkeys resulted in a robust recovery of fine motor function and reduced chronic inflammation. Here, we used immunohistochemistry for cfos, an activity-dependent intermediate early gene, to label task-related neurons in the surviving primary motor and premotor cortices, and markers of axonal and synaptic plasticity in the spinal cord. Compared to vehicle, EV treatment was associated with a greater density of cfos+ pyramidal neurons in the deep layers of M1, greater density of cfos+ inhibitory interneurons in premotor areas, and lower density of synapses on MAP2+lower motor neurons in the cervical spinal cord. These data suggest that the anti-inflammatory effects of EVs may reduce injury-related upper motor neuron damage and hyperexcitability, as well as aberrant compensatory re-organization in the cervical spinal cord to improve motor function.

Mitochondrial dysfunction from malathion and chlorpyrifos exposure is associated with degeneration of GABAergic neurons in Caenorhabditis elegans

Toxicity resulting from off-target effects, beyond acetylcholine esterase inhibition, for the commonly used organophosphate (OP) insecticides chlorpyrifos (CPS) and malathion (MA) was investigated using Saccharomyces cerevisiae and Caenorhabditis elegans model systems. Mitochondrial damage and dysfunction were observed in yeast following exposure to CPS and MA, suggesting this organelle is a major target. In the C. elegans model, the mitochondrial unfolded protein response pathway showed the most robust induction from CPS and MA treatment among stress responses examined. GABAergic neurodegeneration was observed with CPS and MA exposure. Impaired movement observed in C. elegans exposed to CPS and MA may be the result of motor neuron damage. Our analysis suggests that stress from CPS and MA results in mitochondrial dysfunction, with GABAergic neurons sensitized to these effects. These findings may aid in the understanding of toxicity from CPS and MA from high concentration exposure leading to insecticide poisoning.

Impaired disassembly of the axon initial segment restricts mitochondrial entry into damaged axons

The proteasome is essential for cellular responses to various physiological stressors. However, how proteasome function impacts the stress resilience of regenerative damaged motor neurons remains unclear. Here, we develop a unique mouse model using a regulatory element of the activating transcription factor (Atf3) gene to label mitochondria in a damage‐induced manner while simultaneously genetically disrupting the proteasome. Using this model, we observed that in injury‐induced proteasome‐deficient mouse motor neurons, the increase of mitochondrial influx from soma into axons is inhibited because neurons fail to disassemble ankyrin G, an organizer of the axon initial segment (AIS), in a proteasome‐dependent manner. Further, these motor neurons exhibit amyotrophic lateral sclerosis (ALS)‐like degeneration despite having regenerative potential. Selectively vulnerable motor neurons in SOD1G93A ALS mice, which induce ATF3 in response to pathological damage, also fail to disrupt the AIS, limiting the number of axonal mitochondria at a pre‐symptomatic stage. Thus, damage‐induced proteasome‐sensitive AIS disassembly could be a critical post‐translational response for damaged motor neurons to temporarily transit to an immature state and meet energy demands for axon regeneration or preservation.

Antioxidant and Neuroprotective Effects of Paeonol against Oxidative Stress and Altered Carrier-Mediated Transport System on NSC-34 Cell Lines.

Paeonol is a naturally occurring phenolic agent that attenuates neurotoxicity in neurodegenerative diseases. We aimed to investigate the antioxidant and protective effects of paeonol and determine its transport mechanism in wild-type (WT; NSC-34/hSOD1WT) and mutant-type (MT; NSC-34/hSOD1G93A) motor neuron-like amyotrophic lateral sclerosis (ALS) cell lines. Cytotoxicity induced by glutamate, lipopolysaccharides, and H2O2 reduced viability of cell; however, the addition of paeonol improved cell viability against neurotoxicity. The [3H]paeonol uptake was increased in the presence of H2O2 in both cell lines. Paeonol recovered ALS model cell lines by reducing mitochondrial oxidative stress induced by glutamate. The transport of paeonol was time-, concentration-, and pH-dependent in both NSC-34 cell lines. Kinetic parameters showed two transport sites with altered affinity and capacity in the MT cell line compared to the WT cell line. [3H]Paeonol uptake increased in the MT cell line transfected with organic anion transporter1 (Oat1)/Slc22a6 small interfering RNA compared to that in the control. Plasma membrane monoamine transporter (Pmat) was also involved in the uptake of paeonol by ALS model cell lines. Overall, paeonol exhibits neuroprotective activity via a carrier-mediated transport system and may be a beneficial therapy for preventing motor neuronal damage under ALS-like conditions.

Spinal Muscular Atrophy - Is Newborn Screening Too Late for Children with Two SMN2 Copies?

Prompt treatment after genetic NBS for SMA substantially improves outcome in infantile SMA. However, deficiency of SMN-protein can cause damage of motor neurons even prior to birth. To describe the neurological status at the time of NBS and the reversibility of neurological deficits in a cohort of patients with only two copies of the SMN2 gene. We present motor, respiratory, and bulbar outcomes of 21 SMA patients identified in newborn screening projects in Germany. Inclusion criteria was initiation of SMN targeted medication at less than 6 weeks of age and a minimum age of 9 months at last examination. Twelve patients (57%) developed completely normally, reaching motor milestones in time and having no bulbar or respiratory problems. Three children (14.5%) caught up after initial delay in motor development. Six patients (29%) developed proximal weakness despite early treatment: Three of them (14.5%) achieved the ability to walk with assistance and the other three (14.5%) showed an SMA type 2 phenotype at the age of 16-30 months. One patient (4.8%) had respiratory problems. Three children (14.5%) had mild chewing problems and two individuals (9.5%) needed feeding via gastrotube. Initial CHOP-INTEND values below 30 could be indicative of a less favourable outcome, whereas values above 50 could indicate a good outcome, however in-depth statistic due to the small case number is not predictive. More than 70% of SMA patients with two SMN2 copies can achieve independent ambulation with immediate initiation of therapy. However, caregivers and paediatricians must be informed about the possibility of less favourable outcomes when discussing therapeutic strategies.