Altered Motor Function Research Articles

Hyperhomocysteinemia alters cytokine gene expression, cytochrome c oxidase activity and oxidative stress in striatum and cerebellum of rodents

AimsHomocysteine has been linked to neurodegeneration and motor function impairments. In the present study, we evaluate the effect of chronic mild hyperhomocysteinemia on the motor behavior (motor coordination, functional performance, and muscular force) and biochemical parameters (oxidative stress, energy metabolism, gene expression and/or protein abundance of cytokine related to the inflammatory pathways and acetylcholinesterase) in the striatum and cerebellum of Wistar male rats. Main methodsRodents were submitted to one injection of homocysteine (0.03 μmol Hcy/g of body weight) between 30th and 60th postnatal days twice a day. After hyperhomocysteinemia induction, rats were submitted to horizontal ladder walking, beam balance, suspension, and vertical pole tests and/or euthanized to brain dissection for biochemical and molecular assays. Key findingsChronic mild hyperhomocysteinemia did not alter motor function, but induced oxidative stress and impaired mitochondrial complex IV activity in both structures. In the striatum, hyperhomocysteinemia decreased TNF-α gene expression and increased IL-1β gene expression and acetylcholinesterase activity. In the cerebellum, hyperhomocysteinemia increased gene expression of TNF-α, IL-1β, IL-10, and TGF-β, while the acetylcholinesterase activity was decreased. In both structures, hyperhomocysteinemia decreased acetylcholinesterase protein abundance without altering total p-NF-κB, NF-κB, Nrf-2, and cleaved caspase-3. SignificanceChronic mild hyperhomocysteinemia compromises several biochemical/molecular parameters, signaling pathways, oxidative stress, and chronic inflammation in the striatum and cerebellum of rats without impairing motor function. These alterations may be related to the mechanisms in which hyperhomocysteinemia has been linked to movement disorders later in life and neurodegeneration.

Over three decades of natural history of limb girdle muscular dystrophy type R1/2A and R2/2B: Mathematical modelling of a multifactorial study

We aimed to describe the natural history of Limb Girdle Muscular Dystrophy type 2A and 2B over more than three decades by considering muscular strength, motor, cardiac and respiratory function. 428 visits of nineteen 2A and twenty 2B patients were retrospectively analysed through a regression model to create the curves of evolution with disease duration of muscle strength (through Medical Research Council grading), motor function measure scale (D1, D2 and D3 domains) and cardio-pulmonary function tests. Clinically relevant muscular and motor function alterations occurred after the first decade of disease, while mild respiratory function alterations started after the second, with preserved cardiac function. Although type 2A showed relatively stronger distal lower limb muscles, while type 2B started with relatively stronger upper limb muscles, the corresponding motor functions were similar, becoming severely compromised after 25 years of disease. This was the longest retrospective study in types 2A and 2B. It defined curves of disease evolution not only from a neuromuscular, but also from functional, cardiac, and respiratory points of view, to be used to evaluate how the natural progression is changed by therapies. Due to slow disease progression, it was not possible to identify time sensitive endpoints.

The effect of prucalopride on gastric sensorimotor function and satiation in healthy volunteers.

Gastric motor function alterations have been implicated in the pathogenesis of functional dyspepsia with postprandial distress syndrome (PDS). Prucalopride, a 5-TH4 agonist, is known to stimulate gastrointestinal motility. We aimed to evaluate the effect of prucalopride on gastric sensorimotor function in healthy subjects (HV). Barostat and intragastric pressure (IGP) measurements were performed in 17 HV (59% females, age 29.4±2.7y) after treatment with placebo or prucalopride (2mg) (single-blind cross-over). Isobaric stepwise distensions and gastric sensations were assessed to determine gastric compliance and sensitivity. Gastric accommodation (GA) with the barostat was quantified before and after ingestion of 200ml of a nutrient drink (ND). GA measured by IGP was quantified as the drop of IGP from baseline during the intragastric infusion of ND until maximal satiation (60ml/min). Prucalopride did not affect barostat assessed gastric compliance or sensitivity. No differences were observed in GA after prucalopride. During the barostat study, 10min after the meal, 7 HVs reported significantly higher ratings for nausea after prucalopride (p<0.001), and vomiting was induced in 4 of the HVs. A positive correlation was observed between the delta mean perception of nausea with the delta mean increase of intra-balloon volume before and after meal ingestion (r=0.37, p=0.03). During IGP measurements, no effect on nutrient tolerance was observed and increased cramp severity scores were observed which were associated with a significant increase of distal IGP (r=0.78, p<0.0001). Prucalopride does not enhances gastric accommodation but it might increase sensitivity to gastric distention. Furthermore, the increase in sensitivity seems to be related to an increase in nausea with distension. Clinicaltrials.gov: NCT04429802.

Predictors of Working Capacity Changes Related to Huntington's Disease: A Longitudinal Study.

Huntington's disease (HD) is an inherited neurodegenerative disorder that is characterized by motor, cognitive, and psychiatric symptoms. Although 65%of HD expanded gene carriers report changes in employment as the first functional loss, little is known about the predictors leading to changes of working capacity. Given the impact on quality of life, understanding of these factors is of great clinical value. This study evaluates disease specific characteristics and their predictive value in loss of working capacity in HD. Longitudinal data was collected through the worldwide observational study (Enroll-HD), with 15,301 participants in total and 2,791 HD and healthy control participants meeting the inclusion criteria. Changes in working capacity were analyzed by means of a survival analysis. Predictive values of demographic factors and clinical characteristics were assessed for premanifest and manifest HD through Cox regressions. HD expanded gene carriers, manifest and premanifest combined, had a 31%chance of experiencing changes in employment after three years, compared to 4%in healthy controls. Apathy was found to be the most crucial determinant of working capacity changes in premanifest HD, while executive and motor dysfunction play an important role in manifest HD. HD expanded gene carriers are more likely to lose working capacity compared to healthy controls. Disease progression, altered motor function, cognitive decline, and in an early stage of the disease apathetic symptoms are indicative of negative changes in working capacity. Clinicians should recognize that early disease related changes, especially apathy, can affect working capacity.

Microstructural alterations of the corticospinal tract are associated with poor motor function in patients with severe congenital heart disease

Congenital heart disease (CHD) patients are at risk for neurodevelopmental impairments, including altered motor function. However, little is known about the neuroanatomical correlates of persistent motor deficits in CHD. Thus, we examined the link between corticospinal tract (CST) microstructure and motor function in adolescent and adult CHD patients compared to healthy controls.This study investigated 89 CHD patients (N(adolescents) = 47, N(adults) = 42, mean age = 19.9 years) and 97 age-matched healthy controls (N(adolescents) = 44, N(adults) = 53, mean age = 20.6 years). Diffusion tensor imaging was conducted and fractional anisotropy (FA) of the left and right CST was extracted for each participant. Fine (pegboard) and pure motor (repeated finger, hand and foot movements) performance was evaluated with a standardized test battery. FA and motor performance were correlated and the effect of CHD complexity was tested using multivariate linear regression.Clinically relevant motor impairments (>2SD below normative mean) were evident in 24% of patients and 9% of controls. On average, motor performance was lower in CHD patients compared to controls, particularly in those with more complex CHD (fine motor: p = 0.023; pure motor: p < 0.001). FA CST was lower in patients compared to controls, particularly in those with more complex CHD (left: p < 0.001, right: p = 0.003). There was a significant interaction between CHD complexity and FA CST (left: p = 0.025, right: p = 0.025), indicating that FA correlates significantly with pure motor in patients with severe CHD, while there is only a weak association in moderate CHD and no association in patients with simple CHD and controls.Microstructure of the CST is altered in CHD patients, and is associated with pure motor impairments in patients with severe CHD. This indicates that persistent motor impairments may arise from atypical development of the primary motor pathway in the presence of a complex CHD. Early interventions promoting brain maturation in infancy may prevent persisting impairments across the lifetime.

Long-term persistence of infectious Zika virus: Inflammation and behavioral sequela in mice.

The neurodevelopmental defects associated with ZIKV infections early in pregnancy are well documented, however the potential defects and long-term consequences associated with milder infections in late pregnancy and perinatal period are less well understood. To model these, we challenged 1 day old (P1) immunocompetent C57BL/6 mice with ZIKV. The animals developed a transient neurological syndrome including unsteady gait, kinetic tremors, severe ataxia and seizures 10–15 days post-infection (dpi) but symptoms subsided after a week, and most animals survived. Despite apparent recovery, MRI of convalescent mice show reduced cerebellar volume that correlates with altered coordination and motor function as well as hyperactivity and impulsivity. Persistent mRNA levels of pro-inflammatory genes including Cd80, Il-1α, and Ifn-γ together with Cd3, Cd8 and perforin (PrfA), suggested persistence of low-grade inflammation. Surprisingly, the brain parenchyma of convalescent mice harbor multiple small discrete foci with viral antigen, active apoptotic processes in neurons, and cellular infiltrates, surrounded by activated astrocytes and microglia as late as 1-year post-infection. Detection of negative-sense strand viral RNA and isolation of infectious virus derived from these convalescent mice by blinded passage in Vero cells confirmed long-term persistence of replicating ZIKV in CNS of convalescent mice. Although the infection appears to persist in defined reservoirs within CNS, the resulting inflammation could increase the risk of neurodegenerative disorders. This raises concern regarding possible long-term effects in asymptomatic children exposed to the virus and suggests that long-term neurological and behavioral monitoring as well as anti-viral treatment to clear virus from the CNS may be useful in patients exposed to ZIKV at an early age.

Functional Neurological Symptom Disorder (Conversion Disorder) from an Interactional Approach: A Composite Case Study

Functional neurological symptom disorder, alternatively termed conversion disorder (FNSD‐CD) (Although the DSM‐5 utilises the term 'conversion disorder', practitioners and consumers consider this to be an outdated, unsubstantiated and often stigmatising term. In accordance with this, the current terminology used in the field is 'functional neurological symptom disorder'), involves symptoms of altered voluntary motor or sensory functions without identifiable nervous system disease or pathology. It is considered a psychiatric disorder and is, thus, listed in the Diagnostic and Statistical Manual of Mental Disorders (5th Ed.; DSM‐5). As per the nosology of the DSM‐5, the discrete behavioural or psychological syndrome or pattern observed in FNSD‐CD is assumed to be a function of a problem of, or a disorder within, the individual. Accordingly, the psychiatric approach to FNSD‐CD, as set out in the DSM‐5, invokes an assumption common to the medical model which is that of lineal (i.e., straight‐line) causality, namely, causal events are arranged in a lineal sequence. The interactional approach, however, which is a development of general system theory in the field of family therapy, offers an alternative approach to understanding psychiatric disorders. Specifically, this approach places the emphasis on the relationships between individuals and their reciprocal influences on – including their psychological and emotional wellbeing with – one another. It draws on the assumption of nonlineal (i.e., circular) causality, namely, causal events are arranged in a circular sequence. From an interactional approach, therefore, FNSD‐CD is thought to be a function of a problem of, or a deficit within, the individuals’ relationship/s, rather than within an individual, per se. This article utilises a composite case study to investigate FNSD‐CD from an interactional approach.

Neutrophil-to-Lymphocyte Ratio (NLR) and Platelet-to-Lymphocyte Ratio (PLR) at Admission Are Predictors for Worse Functional Outcome in Cerebral Venous Sinus Thrombosis

INTRODUCTION: Cerebral Venous Sinus Thrombosis (CVST) primarily affects children and young adults, especially young women of child-bearing age. Despite overall favorable outcome with systemic anticoagulation, it is still associated with up to 15% mortality and a high incidence of morbidity, resulting in a significant loss of productive life. Neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to monocyte ratio (LMR) and platelet-to-lymphocyte ratio (PLR) are inflammatory and immunologic serum biomarkers that have been described to be predictive of outcome in arterial and venous thromboembolism events including pulmonary embolism and ischemic stroke. Nonetheless, predictive values of these ratios in CVST are not well established. METHODS: This is a single-center, observational and retrospective study that included patients diagnosed with CVST from January 2004 to December 2016 in University of Iowa Hospitals and Clinics. Patients with age older than 18 years were included. Exclusion criteria were incomplete clinical or laboratory data and patients with active malignancy receiving chemotherapy at the time of CVST diagnosis. Patients' complete blood count obtained at admission was used for ratio calculation. Receiver Operating Characteristic (ROC) curve was used to determine cutoff value for the ratios. Predictive utility of each ratio was evaluated in separate multivariate logistic regression models, conditioned on variables that were already shown to have strong association with mRS outcome in univariate analyses. An Akaike information criterion (AIC)-based backward stepwise selection scheme was used for model selection. Functional outcome was assessed by using modified Rankin score (mRS) which was into good outcome (mRS score of 0 to 2) and poor outcome (mRS score of 3 to 6). A two-sided p-value of 0.05 was considered statistically significant. RESULTS: 134 patients were included; median age was 42 years (IQR = 26.75 years) and 90 (67%) were female. The overall mortality was 9% (N=13). After adjusting by demographic characteristics, presenting symptoms and comorbidities, NLR&amp;gt;6.24 (OR=4.57, 95% CI 1.85 - 11.29, p=0.001) and PLR&amp;gt;144 (OR=4.80, 95% CI 1.95 - 11.82, p=0.001) were statistically associated with poor mRS (mRS 3-6) at hospital discharge. Altered mental status on presentation was independently correlated with poor neurologic outcome and in-hospital mortality. While altered motor function and concomitant infection correlated with higher mRS and higher mortality, respectively. The present study did not observe significant prediction between ratios and in-hospital mortality, being NLR marginally significant (OR= 4.67, 95% CI 0.85 - 25.67, p=0.077). CONCLUSION: To the best of our knowledge, this is the first study that describes a statistically significant association between increased NLR and PLR at admission and poor functional outcome in CVST patients at discharge. Their predictive value could be potentially used in the early identification of high-risk patients who may benefit from more aggressive therapeutic approaches, such as endovascular treatment. Disclosures No relevant conflicts of interest to declare.

Function of a viral genome packaging motor from bacteriophage T4 is insensitive to DNA sequence.

Many viruses employ ATP-powered motors during assembly to translocate DNA into procapsid shells. Previous reports raise the question if motor function is modulated by substrate DNA sequence: (i) the phage T4 motor exhibits large translocation rate fluctuations and pauses and slips; (ii) evidence suggests that the phage phi29 motor contacts DNA bases during translocation; and (iii) one theoretical model, the ‘B-A scrunchworm’, predicts that ‘A-philic’ sequences that transition more easily to A-form would alter motor function. Here, we use single-molecule optical tweezers measurements to compare translocation of phage, plasmid, and synthetic A-philic, GC rich sequences by the T4 motor. We observed no significant differences in motor velocities, even with A-philic sequences predicted to show higher translocation rate at high applied force. We also observed no significant changes in motor pausing and only modest changes in slipping. To more generally test for sequence dependence, we conducted correlation analyses across pairs of packaging events. No significant correlations in packaging rate, pausing or slipping versus sequence position were detected across repeated measurements with several different DNA sequences. These studies suggest that viral genome packaging is insensitive to DNA sequence and fluctuations in packaging motor velocity, pausing and slipping are primarily stochastic temporal events.

Discovery of Novel Procaine‐Imidazole Derivative as Inhibitor of Monoamine Oxidase‐B for Potential Benefit in Parkinson's Disease

AbstractThe clinically utility of selective monoamine oxidase (MAO)‐B inhibitors in Parkinson disease is widely recognized due to significant improvement in altered motor function and long‐term benefit. Therefore, in the present study, a series of procaine‐imidazole was synthesized and subsequently evaluated for MAO‐A and MAO‐B inhibitory activity in an enzymatic assay. Comparative inhibitory activity suggest that, target compounds selectively inhibit MAO‐B, as compared to MAO‐A. Among the tested derivatives, compound 8 i (2‐(diethylamino)ethyl4‐(4‐(4‐fluorophenyl)‐2‐(4‐hydroxyphenyl)‐1H‐imidazol‐1‐yl)benzoate) selectively inhibited MAO‐B with IC50 of 0.032±0.002 (selectivity index over MAO‐A=475). The anti‐Parkinson effect of compound 8 i was further evaluated in MPTP (1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine) induced animal model of PD. It has been found that, compound 8 i causes significant improvement in motor function of mice as revealed by motor behavioral assessment using the footprint and horizontal wire test. Compound 8 i also improved the level of anti‐oxidant enzymes in the striatum of animal brains. Our study demonstrated the development of procaine‐imidazole derivatives as potent and selective MAO‐B inhibitor as potential agent against PD.

Motor Imagery Training During Arm Immobilization Prevents Corticomotor Idling: An EEG Resting-State Analysis.

Limb disuse causes overt, measurable alterations in motor functions. Motor imagery (MI) practice has been used as a behavioral strategy to prevent motor impairments due to limb disuse or immobilization. Yet, how MI operates at the neural level in the context of short-term limb immobilization remains understudied. We hypothesized that MI treatment applied during 12h of arm immobilization prevents immobilization-related changes in resting-state electroencephalographic (rsEEG) power and functional connectivity. Fourteen participants first underwent rsEEG after 12h of normal motor activity (without immobilization). Then, rsEEG recording was performed after 12h of arm immobilization either with MI treatment or without, each conditionseparated by 1week, according to a randomized within-subjects design. MI treatment consisted in performing varied visual and kinaesthetic MI exercises (5 sessions of 15min every two hours). The results showed that in the delta, theta, alpha and beta frequency bands, interhemispheric difference in sensors power over the motor cortex (i.e. C3 vs. C4) was reduced after arm immobilization, while it did not change when MI treatment was delivered during the immobilization period. Moreover, functional connectivity across the sensors-network in the delta (1-4Hz) and alpha (8-12Hz) frequency bands decreased after immobilization while it was restored by MI treatment. To conclude, MI counteracts functional neural changes within and between motor regions in the context of limb immobilization. Practical applications for motor rehabilitation strategies, particularly in stroke patients, are also discussed.

3D Movement Analysis using Deep Learning Algorithms Reveals Alterations in Motor Functions After Neurological Injuries in RAT Spasticity Model

3D Movement Analysis using Deep Learning Algorithms Reveals Alterations in Motor Functions After Neurological Injuries in RAT Spasticity Model

High GC Content DNA does not Affect Phage T4 DNA Packaging -- Test of a Scrunchworm Model for Packaging Motor Function

Many viruses use an ATP-powered DNA translocating molecular motor during assembly to package their genomes into preformed viral capsid shells. These powerful motors can generate >60 pN of force and translocate DNA at up to ∼2000 bp/s. One model for motor function, the “scrunchworm model”, proposed that the segment of DNA threaded through the motor-portal channel could be repeatedly induced to transition between longer and shorter structural forms. One version of the model hypothesized that transitions between the B- and A-form DNA might drive translocation and predicted that high GC content would alter motor function. We conducted single-molecule measurements of phage T4 packaging with optical tweezers and do not find any evidence that motor function is altered. Our results suggest that if the motor operates by a scrunchworm-type mechanism the DNA transitions are different than B-to-A form transitions.

Mutations in the Scn8a DIIS4 voltage sensor reveal new distinctions among hypomorphic and null Nav 1.6 sodium channels.

Mutations in the voltage-gated sodium channel gene SCN8A cause a broad range of human diseases, including epilepsy, intellectual disability, and ataxia. Here we describe three mouse lines on the C57BL/6J background with novel, overlapping mutations in the Scn8a DIIS4 voltage sensor: an in-frame 9 bp deletion (Δ9), an in-frame 3 bp insertion (∇3) and a 35 bp deletion that results in a frameshift and the generation of a null allele (Δ35). Scn8a Δ9/+ and Scn8a ∇3/+ heterozygous mutants display subtle motor deficits, reduced acoustic startle response, and are resistant to induced seizures, suggesting that these mutations reduce activity of the Scn8a channel protein, Nav 1.6. Heterozygous Scn8a Δ35/+ mutants show no alterations in motor function or acoustic startle response, but are resistant to induced seizures. Homozygous mutants from each line exhibit premature lethality and severe motor impairments, ranging from uncoordinated gait with tremor (Δ9 and ∇3) to loss of hindlimb control (Δ35). Scn8a Δ9/Δ9 and Scn8a ∇3/∇3 homozygous mutants also exhibit impaired nerve conduction velocity, while normal nerve conduction was observed in Scn8a Δ35/Δ35 homozygous mice. Our results suggest that hypomorphic mutations that reduce Nav 1.6 activity will likely result in different clinical phenotypes compared to null alleles. These three mouse lines represent a valuable opportunity to examine the phenotypic impacts of hypomorphic and null Scn8a mutations without the confound of strain-specific differences.

Laparoscopic Resection Technique of Sacral Roots Endometriosis

Video Objective To describe a surgical procedure, performed to completely resect an endometrioc lesion that tackles s2 sacral root. Setting A 34 years old patient, previously submitted to surgery for deep endometriosis, with recurrence, that led to a strong intensity burning pain, on the right medial buttock during the menstruation time, with no irradiation, alteration of motor function or bowel and urinary habits. Interventions It was performed laparoscopic surgery for the complete resection of the endometriotic lesion. Conclusion The complete resection of the endometriosis lesions of sacral nerves, through the appropriate technique, perfomed by an experienced surgeon, leads to the cure of the symptoms and preserves the nerve fuction.

P41. Intraoperative neurophysiologic monitoring and neurologic outcomes in orthopedic spine surgery patients without preoperative neurologic deficits

P41. Intraoperative neurophysiologic monitoring and neurologic outcomes in orthopedic spine surgery patients without preoperative neurologic deficits

The Regulation of the Small Heat Shock Protein B8 in Misfolding Protein Diseases Causing Motoneuronal and Muscle Cell Death.

Misfolding protein diseases are a wide class of disorders in which the aberrantly folded protein aggregates accumulate in affected cells. In the brain and in the skeletal muscle, misfolded protein accumulation induces a variety of cell dysfunctions that frequently lead to cell death. In motoneuron diseases (MNDs), misfolded proteins accumulate primarily in motoneurons, glial cells and/or skeletal muscle cells, altering motor function. The deleterious effects of misfolded proteins can be counteracted by the activity of the protein quality control (PQC) system, composed of chaperone proteins and degradative systems. Here, we focus on a PQC system component: heat shock protein family B (small) member 8 (HSPB8), a chaperone induced by harmful stressful events, including proteotoxicity. In motoneuron and muscle cells, misfolded proteins activate HSPB8 transcription and enhance HSPB8 levels, which contributes to prevent aggregate formation and their harmful effects. HSPB8 acts not only as a chaperone, but also facilitates the autophagy process, to enable the efficient clearance of the misfolded proteins. HSPB8 acts as a dimer bound to the HSP70 co-chaperone BAG3, a scaffold protein that is also capable of binding to HSP70 (associated with the E3-ligase CHIP) and dynein. When this complex is formed, it is transported by dynein to the microtubule organization center (MTOC), where aggresomes are formed. Here, misfolded proteins are engulfed into nascent autophagosomes to be degraded via the chaperone-assisted selective autophagy (CASA). When CASA is insufficient or impaired, HSP70 and CHIP associate with an alternative co-chaperone, BAG1, which routes misfolded proteins to the proteasome for degradation. The finely tuned equilibrium between proteasome and CASA activity is thought to be crucial for maintaining the functional cell homeostasis during proteotoxic stresses, which in turn is essential for cell survival. This fine equilibrium seems to be altered in MNDs, like Amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA), contributing to the onset and the progression of disease. Here, we will review how misfolded proteins may affect the PQC system and how the proper activity of this system can be restored by boosting or regulating HSPB8 activity, with the aim to ameliorate disease progression in these two fatal MNDs.

Phytochemical/Antioxidant Properties and Individual/Synergistic Actions of Salvia officinalis L. Aqueous Extract and Loperamide on Gastrointestinal Altering Motor Function.

Medicinal plants are known by pharmacological relevance and were used for long time to prevent/treat numerous gastrointestinal (GI) disorders. The current study focuses on the phytochemical/antioxidant characteristics of sage aqueous extract (SAE), as well as its pharmacological actions on altering motor function in the intestine and related disruptions. In vitro phytochemical/antioxidant properties were investigated by colorimetric/biochemical methods. Male rats were divided into seven groups of six animals in each: control (C), castor oil (CO), CO + loperamide (LOP, 10 mg/kg, b.w., p.o.), CO + various doses of SAE (50, 100, and 200 mg/kg, b.w., p.o.), and the mixture (MIX: SAE, 50 mg/kg, b.w., p.o. + LOP, 5 mg/kg, b.w., i.p.) group. In vivo GI/physiological/pharmacological actions of SAE were explored based on the watery/frequent stools, enteropooling, and GI transit time, as well as their associated disturbances. The aqueous extract of S. officinalis contains high tannins/flavonols/anthocyanin contents and a strong, free radical scavenging activity (EC50 = 48.56 ± 0.34 μg/mL). SAE/MIX significantly reduced CO-induced diarrhea in a dose-dependent manner. SAE/MIX decreased also the gastric and intestinal mucosal malondialdehyde/hydrogen peroxide levels and preserved the normal activities/levels of enzymatic/nonenzymatic antioxidants. Added to that, we showed that SAE/MIX pretreatment provided stability of lipid profile (cholesterol and triglycerides), hepatic transaminases, renal injury indicators, and C-reactive protein/alkaline phosphatase levels changed by CO intoxication. These findings suggested that SAE/MIX exerted benefic individual/synergistic effects confirming their use as a strategy in the treatment of GI physiological disorders.

Targeting MOR-mGluR5 heteromers reduces bone cancer pain by activating MOR and inhibiting mGluR5

Pain is among the most common symptoms in cancer and approximately 90% of patients experience end-stage cancer pain. The management of cancer pain is challenging due to the significant side effects associated with opioids, and novel therapeutic approaches are needed. MMG22 is a bivalent ligand containing MOR agonist and mGluR5 antagonist pharmacophores joined by a 22-atom spacer. MMG22 exhibited extraordinary analgesia following intrathecal administration in a mouse model of bone cancer pain. Here, we assessed the effectiveness of systemic administration of MMG22 in reducing cancer pain and evaluated whether MMG22 displays side effects associated with opioids. Fibrosarcoma cells were injected into and around the calcaneus bone in C3H mice. Mechanical hyperalgesia was defined as an increase in the paw withdrawal frequencies (PWFs) evoked by application of a von Frey monofilament (3.9 mN bending force) applied to the plantar surface of the hind pawSubcutaneous (s.c.), intramuscular (i.m.), and oral (p.o.) administration of MMG22 produced robust dose-dependent antihyperalgesia, whose ED50 was orders of magnitude lower than morphine. Moreover, the ED50 for MMG22 decreased with disease progression. Importantly, s.c. administration of MMG22 did not produce acute (24 h) or long-term (9 days) tolerance, was not rewarding (conditioned place preference test), and did not produce naloxone-induced precipitated withdrawal or alter motor function. A possible mechanism of action of MMG22 is discussed in terms of inhibition of spinal NMDAR via antagonism of its co-receptor, mGluR5, and concomitant activation of neuronal MOR. We suggest that MMG22 may be a powerful alternative to traditional opioids for managing cancer pain.This article is part of the Special Issue entitled ‘New Vistas in Opioid Pharmacology’.

Toward optical coherence tomography angiography-based biomarkers to assess the safety of peripheral nerve electrostimulation

Objective. Peripheral nerves serve as a link between the central nervous system and its targets. Altering peripheral nerve activity through targeted electrical stimulation is being investigated as a therapy for modulating end organ function. To support rapid advancement in the field, novel approaches to predict and prevent nerve injury resulting from electrical stimulation must be developed to overcome the limitations of traditional histological methods. The present study aims to develop an optical imaging-based approach for real-time assessment of peripheral nerve injury associated with electrical stimulation. Approach. We developed an optical coherence tomography (OCT) angiography system and a 3D printed stimulating nerve stabilizer (sNS) to assess the real-time microvascular and blood flow changes associated with electrical stimulation of peripheral nerves. We then compared the microvascular changes with established nerve function analysis and immunohistochemistry to correlate changes with nerve injury. Main results. Electrical stimulation of peripheral nerves has a direct influence on vessel diameter and capillary flow. The stimulation used in this study did not alter motor function significantly, but a delayed onset of mechanical allodynia at lower thresholds was observed using a sensory function test. Immunohistochemical analysis pointed to an increased number of macrophages within nerve fascicles and axon sprouting potentially related to nerve injury. Significance. This study is the first to demonstrate the ability to image peripheral nerve microvasculature changes during electrical stimulation. This expands the knowledge in the field and can be used to develop potential biomarkers to predict nerve injury resulting from electrical stimulation.