Dopamine D2 Receptor Modulates Exercise Related Effect on Cortical Excitation/Inhibition and Motor Skill Acquisition.

Exercise is known to benefit motor skill learning in health and neurological disease. Evidence from brain stimulation, genotyping, and Parkinson's disease studies converge to suggest that the dopamine D2 receptor, and shifts in the cortical excitation and inhibition (E:I) balance, are prime candidates for the drivers of exercise-enhanced motor learning. However, causal evidence using experimental pharmacological challenge is lacking. We hypothesized that the modulatory effect of the dopamine D2 receptor on exercise-induced changes in the E:I balance would determine the magnitude of motor skill acquisition. To test this, we measured exercise-induced changes in excitation and inhibition using paired-pulse transcranial magnetic stimulation (TMS) in 22 healthy female and male humans, and then had participants learn a novel motor skill-the sequential visual isometric pinch task (SVIPT). We examined the effect of D2 receptor blockade (800 mg sulpiride) on these measures within a randomized, double-blind, placebo-controlled design. Our key result was that motor skill acquisition was driven by an interaction between the D2 receptor and E:I balance. Specifically, poorer skill learning was related to an attenuated shift in the E:I balance in the sulpiride condition, whereas this interaction was not evident in placebo. Our results demonstrate that exercise-primed motor skill acquisition is causally influenced by D2 receptor activity on motor cortical circuits.

Children had increased risks of impaired motor and visual-motor skills after prenatal exposure to opioid maintenance therapy.

AIM: Preschool children prenatally exposed to opioid maintenance therapy (OMT) have an increased risk of neurodevelopmental impairments. We aimed to investigate long-term motor and visual-motor integration outcome in children aged 5-13 Years, born to mothers in OMT. METHODS: From January 2018 to June 2021, 63 children prenatally exposed to OMT and 63 comparison children matched for age and gender, were examined at two Norwegian hospitals. Motor skills were assessed by the Movement-ABC test and visual-motor integration by the Beery VMI test. A motor function neurological assessment test was used to examine neuromotor soft signs. RESULTS: In the OMT-exposed group, 16% had motor impairment, 35% had motor problems and 19% had visual-motor integration problems. Forty-three percent of the exposed children had neuromotor soft signs. Strabismus had some influence on motor and visual-motor outcomes but could not explain the group differences. CONCLUSION: Children prenatally exposed to opioid maintenance therapy have an increased risk of long-term motor impairment and visual-motor problems. In addition, they exhibit significantly more neuromotor soft signs, which may affect general well-being, leisure activities and school performance.

Longitudinal assessment of cognitive function in young children undergoing general anaesthesia.

BACKGROUND: Exposure to general anaesthesia in children may be related to deficits in certain areas of cognition. It is unclear if these deficits could be measured in the immediate postoperative period in young children. The goal of the current study was to evaluate the trajectory of cognitive function in the domains of processing speed, working memory, and fine motor skills amongst children aged 2.5-6 yr who underwent general anaesthesia for elective surgery. METHODS: Children who were scheduled to receive general anaesthesia for surgery were recruited for assessment of cognitive function at three times: preoperatively, 1-2 weeks postoperatively, and 3 months postoperatively. Assessments included processing speed, working memory, and fine motor skills. To assess longitudinal changes in the cognitive outcomes, linear mixed models were built with visit number included as a categorical variable and subject-specific random intercepts. RESULTS: Sixty-one children (33 girls [54%]) enrolled in the study. Twenty-three children (38%) had received general anaesthesia previously. Significant improvements in picture memory, cancellation, and the processing speed composite were found at Visit 2. The improvement in cancellation and processing speed composite remained significant at Visit 3. Statistically significant improvement in Mullen fine motor score was noticed at Visit 3 compared with Visit 1. The pattern of results did not depend upon prior anaesthesia exposure. CONCLUSIONS: General anaesthesia for elective surgery in young children was not associated with declines in working memory, processing speed, and fine motor skills in the first 3 months postoperatively, including in children with prior exposure to anaesthesia.

Visuospatial processing and fine motor function among 7-years old Guadeloupe children pre- and postnatally exposed to the organochlorine pesticide chlordecone.

BACKGROUND: Chlordecone is an organochlorine that was largely used as an insecticide to control a species of root borers, the Banana weevil (Cosmopolites sordidus), in the French West Indies, Guadeloupe and Martinique. Its molecules have been shown to be very persistent in the environment as pollution in soils leading to contamination of water sources and foodstuff will last for several decades. Our team previously reported associations between prenatal chlordecone exposure and poorer fine motor development at two points in time during infancy. OBJECTIVE: To document whether effects of prenatal exposure to chlordecone previously reported persists until middle-childhood, and whether deleterious effects are observed in domain of visual processing. Associations with postnatal exposure and sex-specific vulnerabilities were also investigated. METHODS: We examined 410 children from the TIMOUN mother-child cohort in Guadeloupe at 7 years of age. Concentrations of chlordecone and other environmental contaminants were measured in cord- and children's blood at age 7 years. Fine motor function was assessed using the Bruininks Oseretsky Test of Motor Proficiency Second Edition (BOT-2). The Computerized Adaptive Testing System (CATSYS) was used to evaluated postural hand tremor, while non-verbal visuospatial processing was measured using the Stanford Binet copying (S-B copying) test. We used adjusted multiple linear regressions to test the relationship between children's scores and both continuous and categorical blood chlordecone concentrations, adding child sex as a moderator in continuous models. RESULTS: Cord chlordecone concentrations are associated with a regular frequency pattern of subtle hand tremors in both hands, and not related to visual processing and fine motor precision. Chlordecone concentrations in blood sample collected at testing time are associated with poorer visual processing when copying geometric figures, but not significantly related to poorer fine movement precision in tasks requiring pencil, scissors and paper. No sex-specific vulnerability was reported in any of the outcomes. CONCLUSIONS: These results at school aged expand those previously reported in the same cohort during infancy at age 7- and 18 months, and corroborate the negative effects of chlordecone exposure on fine motor function in absence of intoxication. Our results support the need to continue public health efforts aimed at reducing exposure especially among women of child bearing age and young children.

CAG repeat-binding small molecule improves motor coordination impairment in a mouse model of Dentatorubral-pallidoluysian atrophy.

Dentatorubral-pallidoluysian atrophy (DRPLA) is a devastating genetic disease presenting myoclonus, epilepsy, ataxia, and dementia. DRPLA is caused by the expansion of a CAG repeat in the ATN1 gene. Aggregation of the polyglutamine-expanded ATN1 protein causes neuro-degeneration of the dentatorubral and pallidoluysian systems. The expanded CAG repeats are unstable, and ongoing repeat expansions contribute to disease onset, progression, and severity. Inducing contractions of expanded repeats can be a means to treat DRPLA, for which no disease-modifying or curative therapies exist at present. Previously, we characterized a small molecule, naphthyridine-azaquinolone (NA), which binds to CAG slip-out structures and induces repeat contraction in Huntington's disease mice. Here, we demonstrate that long-term intracerebroventricular infusion of NA leads to repeat contraction, reductions in mutant ATN1 aggregation, and improved motor phenotype in a murine model of DRPLA. Furthermore, NA-induced contraction resulted in the modification of repeat-length-dependent dysregulation of gene expression profiles in DRPLA mice. Our study reveals the therapeutic potential of repeat contracting small molecules for repeat expansion disorders, such as DRPLA.

The association of bone and blood manganese with motor function in Chinese workers.

Manganese (Mn) is an essential element. However, Mn overexposure is associated with motor dysfunction. This cross-sectional study assessed the association between bone Mn (BnMn) and whole blood Mn (BMn) with motor function in 59 Chinese workers. BnMn and BMn were measured using a transportable in vivo neutron activation analysis system and inductively coupled plasma mass spectrometry, respectively. Motor function (manual coordination, postural sway, postural hand tremor, and fine motor function) was assessed using the Coordination Ability Test System (CATSYS) and the Purdue Pegboard. Relationships between Mn biomarkers and motor test scores were analyzed with linear regression models adjusted for age, education, current employment, and current alcohol consumption. BMn was significantly inversely associated with hand tremor intensity (dominant hand (ß=-0.04, 95 % confidence interval (CI):-0.07, -0.01; non-dominant hand ß=-0.05, 95 % CI:-0.08, -0.01) hand tremor center frequency (non-dominant hand ß=-1.61, 95 % CI:-3.03, -0.19) and positively associated with the Purdue Pegboard Assembly Score (ß = 4.58, 95 % CI:1.08, 8.07). BnMn was significantly inversely associated with finger-tapping performance (non-dominant hand ß=-0.02, 95 % CI:-0.04,-0.004), mean sway (eyes closed and foam ß=-0.68, 95 % CI:-1.31,-0.04), and positively associated with hand tremor center frequency (dominant hand, ß = 0.40, 95 % CI:0.002, 0.80). These results suggest BMn is related to better postural hand tremor and fine motor control and BnMn is related to worse motor coordination and postural hand tremor but better (i.e., less) postural sway. The unexpected positive results might be explained by choice of biomarker or confounding by work-related motor activities. Larger, longitudinal studies in this area are recommended.

Unilateral Intrastriatal 6-Hydroxydopamine Lesion in Mice: A Closer Look into Non-Motor Phenotype and Glial Response.

Parkinson's disease (PD) is a prevalent movement disorder characterized by the progressive loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). The 6-hydroxydopamine (6-OHDA) lesion is still one of the most widely used techniques for modeling Parkinson's disease (PD) in rodents. Despite commonly used in rats, it can be challenging to reproduce a similar lesion in mice. Moreover, there is a lack of characterization of the extent of behavioral deficits and of the neuronal loss/neurotransmitter system in unilateral lesion mouse models. In this study, we present an extensive behavioral and histological characterization of a unilateral intrastriatal 6-OHDA mouse model. Our results indicate significant alterations in balance and fine motor coordination, voluntary locomotion, and in the asymmetry's degree of forelimb use in 6-OHDA lesioned animals, accompanied by a decrease in self-care and motivational behavior, common features of depressive-like symptomatology. These results were accompanied by a decrease in tyrosine hydroxylase (TH)-labelling and dopamine levels within the nigrostriatal pathway. Additionally, we also identify a marked astrocytic reaction, as well as proliferative and reactive microglia in lesioned areas. These results confirm the use of unilateral intrastriatal 6-OHDA mice for the generation of a mild model of nigrostriatal degeneration and further evidences the recapitulation of key aspects of PD, thereby being suitable for future studies beholding new therapeutical interventions for this disease.

Disruption of mitochondrial complex I induces progressive parkinsonism.

Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson's disease1. Yet, whether this change contributes to Parkinson's disease pathogenesis is unclear2. Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism-which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson's disease paradigm3,4.

Biomonitoring and bioaccessibility of environmental airborne manganese in relation to motor function in a healthy adult population.

BACKGROUND/AIM: Santander, the capital of Cantabria, Spain (172,000 inhabitants) is 7 km from an industrial emission source (IES) of Mn located in a 10,000 inhabitants town (Maliaño) (annual air Mn arithmetic mean = 231.8 ng/m3; reference WHO guideline = 150 ng/m3). Our objective was to compare the motor function of adult healthy volunteers living in both places. METHODS: Cross-sectional study analyzing 130 consecutive participants. Exposure to Mn was assessed in terms of source distance from the IES, by Personal Environmental Monitors (PEMs) carried for 24 h by participants consisting of a portable impactor connected to a personal pump, and by biomarkers (blood, hair and fingernails). The impactor allowed the separation of fine (PM2.5) and coarse (PM10-2.5) particles and for each particle size in-vitro bioaccessibility tests with biologically active fluids were performed to separate the soluble (bioaccessible) from the insoluble (non-bioaccessible) fraction. Mean Differences (MDs) adjusted for age, sex, and study level, were obtained for motor function tests results. RESULTS: Regarding Grooved Pegboard, overall mean time to complete the test was 59.31 and 65.27 seconds (Standard Deviation = 10.11 and 11.69) for dominant and nondominant hands respectively. Statistically significant higher times (indicating worse function) were observed when living near the IES in both hands but MDs of only 1.22 and 2.05 seconds were obtained after adjusting for the predefined confounders (p = 0.373 and 0.221 respectively). Regarding Mn levels in their PEMs (in both bioaccessible and non-bioaccessible coarse&fine fractions) higher times were computed in participants with higher levels for the bioaccessible-fine fraction, with a MD that diminished but still yielded statistical significance after controlling for confounding: adjusted MD = 3.01 more seconds; 95%CI (0.44-5.38), p = 0.022. Poorer results were also observed for fingernails levels. Regarding Finger Tapping Test, no statistically significant differences were found with the exception of Mn fingernails levels. CONCLUSIONS: Our results suggest poorer motor function as assessed by Grooved Pegboard test in relation to "proximity to IES", "bioaccessible-fine fraction as determined by PEMs and "Mn fingernails levels". However, our findings were affected by confounding, and only the adjusted MD for the Mn bioaccessible-fine fraction remained of sufficient magnitude to maintain statistical significance.

Iduronate-2-sulfatase transport vehicle rescues behavioral and skeletal phenotypes in a mouse model of Hunter syndrome.

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by deficiency of the iduronate-2-sulfatase (IDS) enzyme, resulting in cellular accumulation of glycosaminoglycans (GAGs) throughout the body. Treatment of MPS II remains a considerable challenge as current enzyme replacement therapies do not adequately control many aspects of the disease, including skeletal and neurological manifestations. We developed an IDS transport vehicle (ETV:IDS) that is engineered to bind to the transferrin receptor; this design facilitates receptor-mediated transcytosis of IDS across the blood-brain barrier and improves its distribution into the brain while maintaining distribution to peripheral tissues. Here we show that chronic systemic administration of ETV:IDS in a mouse model of MPS II reduced levels of peripheral and central nervous system GAGs, microgliosis, and neurofilament light chain, a biomarker of neuronal injury. Additionally, ETV:IDS rescued auricular and skeletal abnormalities when introduced in adult MPS II mice. These effects were accompanied by improvements in several neurobehavioral domains, including motor skills, sensorimotor gating, and learning and memory. Together, these results highlight the therapeutic potential of ETV:IDS for treating peripheral and central abnormalities in MPS II. DNL310, an investigational ETV:IDS molecule, is currently in clinical trials as a potential treatment for patients with MPS II.

Prenatal exposure to phthalates and its effects upon cognitive and motor functions: A systematic review.

Phthalates are chemicals widely used in packaging and consumer products, which have been shown to interfere with normal hormonal function and development in some human and animal studies. In recent decades, pregnant women's exposure to phthalates has been shown to alter the cognitive outcomes of their babies, and some studies have found delays in motor development. METHODS: electronic databases including PubMed/MEDLINE and Scopus were searched from their inception to March 2021, using the keywords "phthalate", "cognitive" and "motor". RESULTS: most studies find statistically significant inverse relationships between maternal urinary phthalate concentration during pregnancy and subsequent outcomes in children's cognitive and motor scales, especially in boys rather than girls. However, many associations are not significant, and there were even positive associations, especially in the third trimester. CONCLUSION: the relationship between exposure to phthalates during pregnancy and low results on neurocognitive scales is sufficiently clear to adopt policies to reduce exposure. Further studies are needed to analyze sex differences, coordination and motor scales, and phthalate levels during breastfeeding.

Classical complement pathway inhibition reduces brain damage in a hypoxic ischemic encephalopathy animal model.

Perinatal hypoxic ischemic encephalopathy (HIE) remains a major contributor of infant death and long-term disability worldwide. The role played by the complement system in this ischemia-reperfusion injury remains poorly understood. In order to better understand the role of complement activation and other modifiable mechanisms of injury in HIE, we tested the dual-targeting anti-inflammatory peptide, RLS-0071 in an animal model of HIE. Using the well-established HIE rat pup model we measured the effects of RLS-0071 during the acute stages of the brain injury and on long-term neurocognitive outcomes. Rat pups subject to hypoxia-ischemia insult received one of 4 interventions including normothermia, hypothermia and RLS-0071 with and without hypothermia. We measured histopathological effects, brain C1q levels and neuroimaging at day 1 and 21 after the injury. A subset of animals was followed into adolescence and evaluated for neurocognitive function. On histological evaluation, RLS-0071 showed neuronal protection in combination with hypothermia (P = 0.048) in addition to reducing C1q levels in the brain at 1hr (P = 0.01) and at 8 hr in combination with hypothermia (P = 0.005). MRI neuroimaging demonstrated that RLS-0071 in combination with hypothermia reduced lesion volume at 24 hours (P<0.05) as well as decreased T2 signal at day 21 in combination with hypothermia (P<0.01). RLS-0071 alone or in combination with hypothermia improved both short-term and long-term memory. These findings suggest that modulation by RLS-0071 can potentially decrease brain damage resulting from HIE.

Manganese body burden in children is associated with reduced visual motor and attention skills.

Manganese (Mn) is an essential element, however, children with moderate to high Mn exposure can exhibit neurobehavioral impairments. One way Mn appears to affect brain function is through altering dopaminergic systems involved with motor and cognitive control including frontal - striatal brain systems. Based on the risk for motor and attention problems, we evaluated neurobehavioral function in 255 children at risk for Mn exposure due to living in proximity to coal ash storage sites. Proton Induced X-ray Emissions (PIXE) analysis was conducted on finger and toenails samples. Multiple neuropsychological tests were completed with the children. Fifty-five children had Mn concentrations above the limit of detection (LOD) (median concentration = 3.95 ppm). Children with detectable Mn concentrations had reduced visual motor skills (ß = -5.62, CI: -9.11, -2.12, p = 0.008) and more problems with sustained attention, based on incorrect responses on a computerized attention test, (ß = 0.40, CI: 0.21, 0.59, p < 0.001) compared with children who had Mn concentrations below the LOD. Findings suggest that Mn exposure impacts attention and motor control possibly due to neurotoxicity involving basal ganglia and forebrain regions. Visual-motor and attention tests may provide a sensitive measure of Mn neurotoxicity, useful for evaluating the effects of exposure in children and leading to better treatment options.

Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls.

BACKGROUND: Type 1 spinal muscular atrophy (SMA) is a progressive neuromuscular disease characterized by an onset at 6 months of age or younger, an inability to sit without support, and deficient levels of survival of motor neuron (SMN) protein. Risdiplam is an orally administered small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein in blood. METHODS: We conducted an open-label study of risdiplam in infants with type 1 SMA who were 1 to 7 months of age at enrollment. Part 1 of the study (published previously) determined the dose to be used in part 2 (reported here), which assessed the efficacy and safety of daily risdiplam as compared with no treatment in historical controls. The primary end point was the ability to sit without support for at least 5 seconds after 12 months of treatment. Key secondary end points were a score of 40 or higher on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND; range, 0 to 64, with higher scores indicating better motor function), an increase of at least 4 points from baseline in the CHOP-INTEND score, a motor-milestone response as measured by Section 2 of the Hammersmith Infant Neurological Examination (HINE-2), and survival without permanent ventilation. For the secondary end points, comparisons were made with the upper boundary of 90% confidence intervals for natural-history data from 40 infants with type 1 SMA. RESULTS: A total of 41 infants were enrolled. After 12 months of treatment, 12 infants (29%) were able to sit without support for at least 5 seconds, a milestone not attained in this disorder. The percentages of infants in whom the key secondary end points were met as compared with the upper boundary of confidence intervals from historical controls were 56% as compared with 17% for a CHOP-INTEND score of 40 or higher, 90% as compared with 17% for an increase of at least 4 points from baseline in the CHOP-INTEND score, 78% as compared with 12% for a HINE-2 motor-milestone response, and 85% as compared with 42% for survival without permanent ventilation (P<0.001 for all comparisons). The most common serious adverse events were pneumonia, bronchiolitis, hypotonia, and respiratory failure. CONCLUSIONS: In this study involving infants with type 1 SMA, risdiplam resulted in higher percentages of infants who met motor milestones and who showed improvements in motor function than the percentages observed in historical cohorts. Longer and larger trials are required to determine the long-term safety and efficacy of risdiplam in infants with type 1 SMA. (Funded by F. Hoffmann-La Roche; FIREFISH ClinicalTrials.gov number, NCT02913482.).

Effect of lobeglitazone on motor function in rat model of Parkinson's disease with diabetes co-morbidity.

Parkinson's disease (PD) and diabetes mellitus share similar pathophysiological characteristics, genetic and environmental factors. It has been reported that people with diabetes mellitus appear to have a remarkable higher incidence of PD than age matched non diabetic individuals. Evidences suggest that use of antidiabetic glitazone is associated with a diminished risk of PD incidence in patients with diabetes. This study examined the effect of lobeglitazone, a member of thiazolidinedione class, in rat model of Parkinson's disease with diabetes co-morbidity. Rats received either rotenone and/or a combination of streptozocin and a high calorie diet for disease induction and they were treated with different doses of lobeglitazone or its vehicle. Behavioral tests comprising rotarod, bar test and rearing test were conducted to evaluate the motor function. Changes in the level tyrosine hydroxylase, TNF-α and NF-κB were analyzed using ELISA. In the same brain regions the possible changes in PPAR-γ receptor level were evaluated. Findings showed that although lobeglitazone tends to reverse the effect of rotenone in animals with diabetes, it was just able to prevent partly the motor defect in rearing test. Furthermore, lobeglitazone (1 mg/kg) reversed, in substantia nigra and striatum, the changes in tyrosine hydroxylase, TNF-α, NF-κB and PPAR-γ receptor content induced by rotenone in rats with diabetic condition. Although other preclinical studies are needed, these findings suggest that lobeglitazone is a promising neuroprotective candidate for clinical trials for PD patients with diabetes co-morbidity.

Protective effects of prucalopride in MPTP-induced Parkinson's disease mice: Neurochemistry, motor function and gut barrier.

Evidence suggests constipation precedes motor dysfunction and is the most common gastrointestinal symptom in Parkinson's disease (PD). 5-HT4 receptor (5-HT4R) agonist prucalopride has been approved to treat chronic constipation. Here, we reported intraperitoneal injection of prucalopride for 7 days increased dopamine and decreased dopamine turnover. Prucalopride administration improved motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-induced PD mouse models. Prucalopride treatment also ameliorated intestinal barrier impairment and increased IL-6 release in PD model mice. However, prucalopride treatment exerted no impact on JAK2/STAT3 pathway, suggesting that prucalopride may stimulate IL-6 via JAK2/STAT3-independent pathway. In conclusion, prucalopride exerted beneficial effects in MPTP-induced Parkinson's disease mice by attenuating the loss of dopamine, improving motor dysfunction and intestinal barrier.

A Novel Anti-Inflammatory d-Peptide Inhibits Disease Phenotype Progression in an ALS Mouse Model.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by selective neuronal death in the brain stem and spinal cord. The cause is unknown, but an increasing amount of evidence has firmly certified that neuroinflammation plays a key role in ALS pathogenesis. Neuroinflammation is a pathological hallmark of several neurodegenerative disorders and has been implicated as driver of disease progression. Here, we describe a treatment study demonstrating the therapeutic potential of a tandem version of the well-known all-d-peptide RD2 (RD2RD2) in a transgenic mouse model of ALS (SOD1*G93A). Mice were treated intraperitoneally for four weeks with RD2RD2 vs. placebo. SOD1*G93A mice were tested longitudinally during treatment in various behavioural and motor coordination tests. Brain and spinal cord samples were investigated immunohistochemically for gliosis and neurodegeneration. RD2RD2 treatment in SOD1*G93A mice resulted not only in a reduction of activated astrocytes and microglia in both the brain stem and lumbar spinal cord, but also in a rescue of neurons in the motor cortex. RD2RD2 treatment was able to slow progression of the disease phenotype, especially the motor deficits, to an extent that during the four weeks treatment duration, no significant progression was observed in any of the motor experiments. Based on the presented results, we conclude that RD2RD2 is a potential therapeutic candidate against ALS.

Adverse health effects of PCBs on fine motor performance - Analysis of a neurophysiological pathway in the HELPcB surveillance program.

Since research literature indicates neurotoxic health effects of polychlorinated biphenyls (PCBs), it is necessary to identify by which mechanism PCBs might affect the human central nervous system and human behavior. In the present study, a neurophysiological pathway is assumed to explain the negative association of PCB exposure and performance in fine motor tasks mediated by the level of the dopamine (DA) metabolite homovanillic acid (HVA). A total of 113 occupationally PCB exposed workers and their relatives from an occupational health monitoring program were examined (89.4 % men). PCBs were analyzed in plasma via human biomonitoring and HVA was assessed in urine. The motor performance series was used to measure two dimensions of fine motor skills with 5 subgroups (accuracy: steadiness, line tracking accuracy; speed: line tracking speed, aiming, tapping). The direct effects of PCBs on fine motor performance and the indirect effects of PCBs on fine motor performance via DA metabolite HVA were tested with multiple regressions. We found significant effects for the accuracy dimension, namely a negative direct effect of PCBs on line tracking accuracy mediated by HVA. Further, an indirect effect could be found for PCBs with steadiness accuracy through HVA. There were no significant effects related to fine motor performances in the speed dimension. These results provide first indications for an underlying neurochemical pathomechanism involving the dopamine system of PCB-related deterioration of fine motor performance regarding accuracy.

Promotion of corticospinal tract growth by KLF6 requires an injury stimulus and occurs within four weeks of treatment.

Axons in the corticospinal tract (CST) display a limited capacity for compensatory sprouting after partial spinal injuries, potentially limiting functional recovery. Forced expression of a developmentally expressed transcription factor, Krüppel-like factor 6 (KLF6), enhances axon sprouting by adult CST neurons. Here, using a pyramidotomy model of injury in adult mice, we confirm KLF6's pro-sprouting properties in spared corticospinal tract neurons and show that this effect depends on an injury stimulus. In addition, we probed the time course of KLF6-triggered sprouting of CST axons and demonstrate a significant enhancement of growth within four weeks of treatment. Finally, we tested whether KLF6-induced sprouting was accompanied by improvements in forelimb function, either singly or when combined with intensive rehabilitation. We found that regardless of rehabilitative training, and despite robust cross-midline sprouting by corticospinal tract axons, treatment with KLF6 produced no significant improvement in forelimb function on either a modified ladder-crossing task or a pellet-retrieval task. These data clarify important details of KLF6's pro-growth properties and indicate that additional interventions or further optimization will be needed to translate this improvement in axon growth into functional gains.

Therapeutics effects of [Pyr1] apelin-13 on rat contusion model of spinal cord injury: An experimental study.

Spinal cord injury (SCI) can cause various symptoms, including pain, complete or incomplete loss of autonomic, sensory, motor and functions inferior to the site of the damage. Despite wondrous advances in medicine, treating spinal cord injuries remains a thorny issue yet. Recently, the control of inflammatory processes after damage to the nervous system has been noticed as a promising therapeutic target. The goal of the present experiment was to identify the effects of apelin-13 on the histological outcome, inflammatory factors, and functional recovery in the animal contusion model of SCI were analyzed. 40 Female Wistar rats were randomly but equally assigned in laminectomy, contusion, PBS (1 mL PBS, i.p), control group which received apelin-13 (control + apelin, 100 µg/kg, i.p), and apelin-13 treatment groups. In the treatment group, apelin-13 (100 µg/kg) was injected intraperitoneally 30 min after injury. The weight-dropping contusion model was used for inducing SCI. The Basso, Beattie, and Bresnahan scale (BBB), narrow beam test (NBT), rotarod test, and the open-field test was applied to evaluate locomotor and behavioral activity. Real-time polymerase chain reaction (PCR) and ELISA technique was accomplished eight weeks after inducing SCI to measure the level of fibroblast growth factor FGF-1, FGFR1 and the inflammatory factors including interleukin (IL)-1ß, tumor necrosis factor-α (TNF-α), IL-6, and IL-10. Furthermore, histological change was estimated by H&E staining. Our results showed that apelin-13 treatment after SCI led to a significant increase in functional recovery and behavioral tests. Stereological estimation illustrated that apelin-13 could reduce significantly central cavity volume and number of glial cells, and also increase significantly spinal cord volume and number of neural cells. PCR and ELISA evaluation shows a significant increase in IL-10 level and decrease in levels of FGF-1, FGF-R1, and pro-inflammatory cytokines (PIC). This study suggested that apelin-13 has neuroprotective effects by regulating the inflammatory process after SCI.