Acute motor deficit and subsequent remyelination-associated recovery following internal capsule demyelination in mice.

Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system (CNS), characterized by accumulated motor disability. However, whether remyelination promotes motor recovery following demyelinating injury remains unclear. Damage to the internal capsule (IC) is known to result in motor impairment in multiple sclerosis and stroke. Here, we induced focal IC demyelination in mice by lysophosphatidylcholine (LPC) injection, and examined its effect on motor behavior. We also compared the effect of LPC-induced IC damage to that produced by endothelin-1 (ET1), a potent vasoconstrictor used in experimental stroke lesions. We found that LPC or ET1 injections induced asymmetric motor deficit at 7 days post-lesion (dpl), and that both lesion types displayed increased microglia/macrophage density, myelin loss, and axonal dystrophy. The motor deficit and lesion pathology remained in ET1-injected mice at 28 dpl. In contrast, LPC-injected mice regained motor function by 28 dpl, with corresponding reduction in activated microglia/macrophage density, and recovery of myelin staining and axonal integrity in lesions. These results suggest that LPC-induced IC demyelination results in acute motor deficit and subsequent recovery through remyelination, and may be used to complement future drug screens to identify drugs for promoting remyelination.

Investigating fine motor deficits during maintenance therapy in children with acute lymphoblastic leukemia.

OBJECTIVES: Children diagnosed with acute lymphoblastic leukemia (ALL) in their early childhood are more susceptible to neuromuscular and musculoskeletal impairments. This cross-sectional study was designed to address different types of fine motor impairments in Egyptian children diagnosed with ALL. METHODS: Fifty-four children treated for ALL in maintenance phase aged from four to seven years were compared with an age- and sex-matched control group. Fine motor performance was assessed using the total fine motor form of the Bruininks-Oseretsky Test of Motor Proficiency-second edition (BOT-2). Sex- and age-specific norms of BOT-2 were used to calculate scale and standard scores in both groups. RESULTS: Children with ALL had significantly impaired fine motor skills in all subtests and composites of BOT-2 compared with the typically developing group (P < 0.00001). Cumulative doses of vincristine, methotrexate, and dexamethasone revealed no significant correlation with any BOT-2 measure. Males performed significantly better than females in all BOT-2 scores except for the fine motor integration subtest and the total fine motor control composite as no significant differences were observed. The protocol risk stratum, duration of maintenance treatment, and the age at assessment did not significantly affect the BOT-2 measures. CONCLUSION: About 67% of children with ALL on maintenance treatment experienced fine motor difficulties. Periodic evaluation along the course of chemotherapy could identify specific impaired fine motor domains providing the base for a successful rehabilitation program.

Extracellular Vesicles from Hyperammonemic Rats Induce Neuroinflammation and Motor Incoordination in Control Rats.

Minimal hepatic encephalopathy is associated with changes in the peripheral immune system which are transferred to the brain, leading to neuroinflammation and thus to cognitive and motor impairment. Mechanisms by which changes in the immune system induce cerebral alterations remain unclear. Extracellular vesicles (EVs) seem to play a role in this process in certain pathologies. The aim of this work was to assess whether EVs play a role in the induction of neuroinflammation in cerebellum and motor incoordination by chronic hyperammonemia. We characterized the differences in protein cargo of EVs from plasma of hyperammonemic and control rats by proteomics and Western blot. We assessed whether injection of EVs from hyperammonemic to normal rats induces changes in neuroinflammation in cerebellum and motor incoordination similar to those exhibited by hyperammonemic rats. We found that hyperammonemia increases EVs amount and alters their protein cargo. Differentially expressed proteins are mainly associated with immune system processes. Injected EVs enter Purkinje neurons and microglia. Injection of EVs from hyperammonemic, but not from control rats, induces motor incoordination, which is mediated by neuroinflammation, microglia and astrocytes activation and increased IL-1b, TNFα, its receptor TNFR1, NF-kB in microglia, glutaminase I, and GAT3 in cerebellum. Plasma EVs from hyperammonemic rats carry molecules necessary and sufficient to trigger neuroinflammation in cerebellum and the mechanisms leading to motor incoordination.

Prior exercise protects against oxidative stress and motor deficit in a rat model of Parkinson's disease.

This study investigated if a prior long-term physical exercise protocol protects the substantia nigra and the striatum against oxidative stress and motor deficits in a Parkinson Disease model induced by 6-hydroxydopamine. Three animal treatment groups were included in the study: sham; 6-hydroxydopamine and 6-hydroxydopamine/exercise. Previously to the intrastriatal lesion by 6-hydroxydopamine, rats in the exercise groups performed a swimming program for 18 weeks. The rats were submitted to behavioral tests before and after intrastriatal 6-hydroxydopamine injection. The oxidative stress was analyzed by Thiobarbituric Acid Reactive Substances and Glutathione reductase activity methods. The exercise decreased lipid peroxidation and increased glutathione reductase activity in the substantia nigra. In contrast, in the striatum, exercise increased lipid peroxidation and decreased glutathione reductase activity. Exercise increased contralateral rotations and reduces immobility levels at 14 days post lesion. The exercise prior to 6-OHDA lesion had protective action only in substantia nigra against oxidative stress.

Motor function in survivors of pediatric acute lymphoblastic leukemia treated with chemotherapy-only.

BACKGROUND: Up to 43% of survivors of pediatric acute lymphoblastic leukemia (ALL) may exhibit fine-motor problems. Information on manual dexterity in this cohort is still limited. OBJECTIVES: We tested survivors of childhood ALL treated with chemotherapy-only for fine-motor function in terms of drawing and handwriting abilities using a Digitizing Tablet (DT) with three tasks for drawing and handwriting of varying complexity, for ataxia using the International Cooperative Ataxia Rating Scale (ICARS), and for tremor and hand-eye coordination using the Nine Hole Steadiness Tester (NHST). RESULTS: We examined a cohort of non-irradiated survivors (n = 31) after a median time of 3.5 years after end of therapy. In all tasks of the DT the cohort demonstrated significant (p < 0.05) impairment of speed, automation, and variability in at least two tasks and significantly more pressure. Impaired speed (SPV) inversely correlated with lag time since end of therapy. Dexterity performance of six survivors (19%) lay below the 5th percentile. No survivor exhibited ataxia, tremor, or impaired hand-steadiness. CONCLUSION: Despite the absence of gross ataxia, tremor, and impaired hand-eye coordination, we nevertheless detected significant fine-motor impairment in a relevant number of survivors of childhood ALL. Prospective studies are needed to reveal the pathophysiological underpinnings and genetic risk factors for development of such deficits due to ALL and its treatment.

Hydroxysafflor Yellow A Improves Motor Dysfunction in the Rotenone-Induced Mice Model of Parkinson's Disease.

Dopamine D3 receptor (DRD3) is diminished in patients of Parkinson's disease (PD). Brain-derived neurotrophic factor (BDNF) is responsible for regulating expression of the DRD3 in the brain. Our previous study showed that hydroxysafflor yellow A (HSYA) could increase BDNF content in the striatum of PD mice. This experiment aimed to evaluate whether HSYA can improve the motor dysfunction induced by rotenone through regulating the BDNF/TrkB/DRD3 signaling pathway in mice. Male C57/BL6 mice were intraperitoneally treated with HSYA. Thirty minutes later, they were intragastrically administered with rotenone at a dose of 30 mg/kg. Pole, rotarod and open field tests were investigated at 28 d. Then, tyrosine hydroxylase (TH) in substantia nigra was observed by immunohistochemistry. Dopamine content was detected by high-performance liquid chromatography. The expressions of BDNF, phospho-tropomyosin-related kinase B (p-TrkB), tropomyosin-related kinase B (TrkB), phospho-phosphoinositide 3-kinase (p-PI3K), phosphoinositide 3-kinase (PI3K), phospho-protein kinase B (p-AKT), protein kinase B (AKT), and DRD3 were assayed by western blotting. Behavioral tests showed that rotenone-challenged mice displayed motor dysfunction. However, treatment with HSYA improved motor dysfunction induced by rotenone. HSYA treatment increased not only the number of TH-containing dopaminergic neurons in substantia nigra, but also the dopamine content in the striatum in PD mice. Moreover, the expressions of BDNF, p-TrkB/TrkB, DRD3, p-PI3K/PI3K, p-AKT/AKT were significantly increased in rotenone plus HSYA group. Our results indicated that HSYA improved motor dysfunction in rotenone-induced PD model and the pharmacological action of HSYA was related to regulating BDNF/TrkB/DRD3 signaling pathway, at least, in part.

Neuroprotective potential of curcumin in combination with piperine against 6-hydroxy dopamine induced motor deficit and neurochemical alterations in rats.

AIM AND OBJECTIVE: 6-hydroxy dopamine (6-OHDA) is a neurotoxin which on intranigral administration produces severe nigrostriatal damage with motor and cognitive deficit in animals. Curcumin (CMN) in combination with bioenhancer piperine (PP) in 6-hydroxydopamine-induced Parkinsonian rats was used to investigate the antioxidant, neuromodulatory and neuroprotective mechanisms. MATERIALS AND METHODS: Hemi-Parkinson's rat model was developed with intranigral infusion of 6-OHDA (8 µg/2 µl, once, unilaterally), treatment with CMN (25 and 50 mg/kg) and combination of PP (2.5 mg/kg) with CMN (25 mg/kg) was given daily for 21 days starting from the 7th day after 6-OHDA infusion. The behavioral (locomotor, grip strength, and narrow beam walk) parameters were studied on weekly basis. On 22nd day, isolated brain preparations were subjected to biochemical (lipid peroxidation, glutathione, and nitrite), neuroinflammatory (IL-1ß, IL-6, and TNF- α), and neurochemical (DA, NE, 5- HT, GABA, Glutamate, DOPAC, HVA, and 5-HIAA) analysis. RESULTS: Oral administration of CMN had significantly prevented behavioral, neuroinflammatory, and neurochemical changes and preserved the antioxidant potential of the nigrostriatum in rats treated with 6-OHDA. CONCLUSION: In the present study, PP and CMN had afforded a better neuroprotective effect compared to alone treatment on behavior, biochemical, neuroinflammatory, and neurochemical parameters in rats.

Prenatal exposure to low-level methylmercury alters the child's fine motor skills at the age of 18 months.

OBJECTIVES: To compare motor, cognitive and language characteristics in children aged 18 months who were prenatally exposed to low-level methyl-mercury (MeHg), and to analyze the eventual differences in these characteristics in relation to cord blood THg concentration. PATIENTS AND METHODS: The total number of 205 child-mother pairs was included in the study, and total cord blood mercury was measured in 198 of them. Out of the 198 already measured samples, 47 of them have also been tested for methyl-mercury in cord blood. Data regarding the 47 samples of MeHg levels has been used for calculating the correlation between cord blood THg and cord blood MeHg. MeHg and THg showed a significant correlation (r=0.95, p<0.05). One month after the delivery, mothers were asked to complete the questionnaire regarding socioeconomic factors, breastfeeding of their infants, and dietary habits during pregnancy. Neurodevelopmental assessment of motor, cognitive and language skills were conducted on 168 children using The Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). Regarding the cord blood THg concentration, 135 children were divided in 4 quartile groups. Their neurodevelopmental characteristics have been compared. RESULTS: The cord blood THg concentration median and inter-quartile range was 2.98ng/g (1.41-5.61ng/g). There was a negative correlation between cord blood THg concentration and fine motor skills (rho=-0.22, p=0.01). It is evident that children grouped in 2nd ,3rd and 4th quartile had statistically significant lower fine motor skills assessment related to those grouped in 1st quartile (2nd quartile -1.24, p=0.03; 3rd quartile -1.28, p=0.03; 4th quartile -1.45, p=0.01). The differences in fine motor skills assessments between children in 2nd and 3rd and 3rd and 4th quartile were not statistically significant. CONCLUSION: Intrauterine exposure to low-level THg (MeHg) is associated with alterations in fine motor skills at the age of 18 months.

"Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies".

Manganese (Mn) is an essential heavy metal. However, Mn's nutritional aspects are paralleled by its role as a neurotoxicant upon excessive exposure. In this review, we covered recent advances in identifying mechanisms of Mn uptake and its molecular actions in the brain as well as promising neuroprotective strategies. The authors focused on reporting findings regarding Mn transport mechanisms, Mn effects on cholinergic system, behavioral alterations induced by Mn exposure and studies of neuroprotective strategies against Mn intoxication. We report that exposure to Mn may arise from environmental sources, occupational settings, food, total parenteral nutrition (TPN), methcathinone drug abuse or even genetic factors, such as mutation in the transporter SLC30A10. Accumulation of Mn occurs mainly in the basal ganglia and leads to a syndrome called manganism, whose symptoms of cognitive dysfunction and motor impairment resemble Parkinson's disease (PD). Various neurotransmitter systems may be impaired due to Mn, especially dopaminergic, but also cholinergic and GABAergic. Several proteins have been identified to transport Mn, including divalent metal tranporter-1 (DMT-1), SLC30A10, transferrin and ferroportin and allow its accumulation in the central nervous system. Parallel to identification of Mn neurotoxic properties, neuroprotective strategies have been reported, and these include endogenous antioxidants (for instance, vitamin E), plant extracts (complex mixtures containing polyphenols and non-characterized components), iron chelating agents, precursors of glutathione (GSH), and synthetic compounds that can experimentally afford protection against Mn-induced neurotoxicity.

Neurodevelopmental problems at 18 months among children exposed to paracetamol in utero: a propensity score matched cohort study.

Background: Previous studies showed that children exposed to paracetamol during fetal life might have an increased risk of neurodevelopmental problems. Since paracetamol is one of the most commonly used medications during pregnancy, even small increases in the risk of neurodevelopmental problems may have considerable implications for public health. Methods: Using data from the Norwegian Mother and Child Cohort Study, we applied propensity score (PS) matching to examine associations between prenatal paracetamol exposure and neurodevelopmental problems among children at 18 months of age. Paracetamol use was classified into short-term (< 28 days) and long-term (≥ 28 days) of exposure. Results: Of the 51 200 pregnancies included in our study, 40.5% of mothers ( n = 20 749) used paracetamol at least once during pregnancy. In the PS-matched analyses, long-term paracetamol exposure during pregnancy was associated with communication problems [odds ratio (OR): 1.38, 95% confidence interval (CI) 0.98-1.95) and delayed motor milestone attainment (OR: 1.35, 95% CI 1.07-1.70). We did not observe increased risks after short-term exposure. Sensitivity analyses for several indications showed similar effects as the PS-matched analyses, suggesting no confounding by indication. Conclusion: Long-term exposure to paracetamol in utero was associated with modestly increased risks of motor milestone delay and impaired communication skills among children at 18 months. Caution is warranted when considering long-term use of paracetamol during pregnancy; however, women with severe pain conditions should not be deprived of appropriate pharmacotherapy.

Impacts of Perinatal Dioxin Exposure on Motor Coordination and Higher Cognitive Development in Vietnamese Preschool Children: A Five-Year Follow-Up.

Dioxin concentrations remain elevated in the environment and in humans residing near former US Air Force bases in South Vietnam. Our previous epidemiological studies showed adverse effects of dioxin exposure on neurodevelopment for the first 3 years of life. Subsequently, we extended the follow-up period and investigated the influence of perinatal dioxin exposure on neurodevelopment, including motor coordination and higher cognitive ability, in preschool children. Presently, we investigated 176 children in a hot spot of dioxin contamination who were followed up from birth until 5 years old. Perinatal dioxin exposure levels were estimated by measuring dioxin levels in maternal breast milk. Dioxin toxicity was evaluated using two indices; toxic equivalent (TEQ)-polychlorinated dibenzo-p-dioxins/furans (PCDDs/Fs) and concentration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Coordinated movements, including manual dexterity, aiming and catching, and balance, were assessed using the Movement Assessment Battery for Children, Second Edition (Movement ABC-2). Cognitive ability was assessed using the nonverbal index (NVI) of the Kaufman Assessment Battery for Children, Second Edition (KABC-II). In boys, total test and balance scores of Movement ABC-2 were significantly lower in the high TEQ- PCDDs/Fs group compared with the moderate and low exposure groups. NVI scores and the pattern reasoning subscale of the KABC-II indicating planning ability were also significantly lower in the high TCDD exposure group compared with the low exposure group of boys. However, in girls, no significant differences in Movement ABC-2 and KABC-II scores were found among the different TEQ-PCDDs/Fs and TCDD exposure groups. Furthermore, in high risk cases, five boys and one girl highly exposed to TEQ-PCDDs/Fs and TCDD had double the risk for difficulties in both neurodevelopmental skills. These results suggest differential impacts of TEQ-PCDDs/Fs and TCDD exposure on motor coordination and higher cognitive ability, respectively. Moreover, high TEQ-PCDDs/Fs exposure combined with high TCDD exposure may increase autistic traits combined with developmental coordination disorder.

Ferulic acid pretreatment mitigates MPTP-induced motor impairment and histopathological alterations in C57BL/6 mice.

CONTEXT: Ferulic acid (FA) is a potent ubiquitous plant antioxidant found in cereals such as brown rice, whole wheat, and oats. Phytochemical-based antioxidants are shown to be effective in neurodegenerative diseases. This study hypothesizes that supplementation of FA might combat oxidative stress-induced Parkinson's disease (PD). OBJECTIVE: To explore the effect of FA on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced neurotoxicity. MATERIALS AND METHODS: Mice were randomized into five groups: Group I mice served as control. Group II mice received 5 × MPTP [25 mg/kg body weight (i.p.)] in saline 24 h apart starting from the 3rd day and continued till the last day of the experimental period of 7 d. In addition to MPTP injections, mice in Groups III, IV, and V were given FA at a dose of 20, 40, and 80 mg, respectively, for 7 d. Mice were subjected to a battery of behavioral tests along with histological investigations. RESULTS: Our histological findings revealed that MPTP administration enhanced Bax/Bcl2 ratio and microglial cells activation reflecting induction of apoptosis and inflammation, respectively. This dopaminergic neuronal loss caused impairment in motor balance and coordination in MPTP mice as assessed by various behavioral tests. FA at a dose of 40 mg/kg/d body weight effectively attenuated MPTP-induced neurotoxicity. DISCUSSION: Antioxidant, free-radical quenching, and anti-inflammatory activities of FA could contribute to its neuroprotective effect. CONCLUSION: This study provides elementary evidence for the neuroprotective action of FA against MPTP-induced PD in mice and warrants further studies.

Developmental pathways of motor dysfunction.

Recent evidence has revealed unique patterns of behavioral development after prenatal insult similar to those outlined in studies of adult metabolic dysfunction after prenatal malnutrition. The hallmark features of this Developmental Pathway include a prenatal insult to the nervous system (environmental or genetic) followed by a period of Silent Vulnerability, where no or few functional deficits are observed, and finally emergence of later dysfunction. Possible mechanisms leading to later dysfunction from prenatal insult may include secondary or cascade effects due to the timing of prenatal insults relative to later developing structures in the brain. Methods best employed to study the mechanisms of these pathways are microgenetic and longitudinal designs that include behavioral assessment during the prenatal period of development, and animal models such as the guinea pig.

Cyclic phosphatidic acid treatment suppress cuprizone-induced demyelination and motor dysfunction in mice.

Multiple sclerosis is a chronic demyelinating disease of the central nervous system leading to progressive cognitive and motor dysfunction, which is characterized by neuroinflammation, demyelination, astrogliosis, loss of oligodendrocytes, and axonal pathologies. Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator with a unique cyclic phosphate ring structure at the sn-2 and sn-3 positions of the glycerol backbone. cPA elicits a neurotrophin-like action and protects hippocampal neurons from ischemia-induced delayed neuronal death. In this study, we investigated the effects of cPA on cuprizone-induced demyelination, which is a model of multiple sclerosis. Mice were fed a diet containing 0.2% cuprizone for 5 weeks, which induces severe demyelination, astrocyte and microglial activation, and motor dysfunction. Simultaneous administration of cPA effectively attenuated cuprizone-induced demyelination, glial activation, and motor dysfunction. These data indicate that cPA may be a useful treatment to reduce the extent of demyelination and the severity of motor dysfunction in multiple sclerosis. cPA is a potential lead compound in the development of drugs for the treatment of this devastating disease.

PACAP27 prevents Parkinson-like neuronal loss and motor deficits but not microglia activation induced by prostaglandin J2.

Neuroinflammation is a major risk factor in Parkinson's disease (PD). Alternative approaches are needed to treat inflammation, as anti-inflammatory drugs such as NSAIDs that inhibit cyclooxygenase-2 (COX-2) can produce devastating side effects, including heart attack and stroke. New therapeutic strategies that target factors downstream of COX-2, such as prostaglandin J2 (PGJ2), hold tremendous promise because they will not alter the homeostatic balance offered by COX-2 derived prostanoids. In the current studies, we report that repeated microinfusion of PGJ2 into the substantia nigra of non-transgenic mice, induces three stages of pathology that mimic the slow-onset cellular and behavioral pathology of PD: mild (one injection) when only motor deficits are detectable, intermediate (two injections) when neuronal and motor deficits as well as microglia activation are detectable, and severe (four injections) when dopaminergic neuronal loss is massive accompanied by microglia activation and motor deficits. Microglia activation was evaluated in vivo by positron emission tomography (PET) with [(11)C](R)PK11195 to provide a regional estimation of brain inflammation. PACAP27 reduced dopaminergic neuronal loss and motor deficits induced by PGJ2, without preventing microglia activation. The latter could be problematic in that persistent microglia activation can exert long-term deleterious effects on neurons and behavior. In conclusion, this PGJ2-induced mouse model that mimics in part chronic inflammation, exhibits slow-onset PD-like pathology and is optimal for testing diagnostic tools such as PET, as well as therapies designed to target the integrated signaling across neurons and microglia, to fully benefit patients with PD.

Perfluorinated compound levels in cord blood and neurodevelopment at 2 years of age.

BACKGROUND: Epidemiologic data regarding the potential neurotoxicity of perfluorinated compounds (PFCs) are inconclusive. We investigated the associations between in utero exposure to perfluorooctanoic acid (PFOA) and perfluorooctyl sulfonate (PFOS) and early childhood neurodevelopment. METHODS: We recruited 239 mother-infant pairs in northern Taiwan from the Taiwan Birth Panel Study, which was established in 2004. We examined the association between PFCs in cord blood and children's neurodevelopment at 2 years of age, using the Comprehensive Developmental Inventory for Infants and Toddlers. This tool contains cognitive, language, motor, social, and self-help domains; test scores were further transformed into developmental quotients according to standardized norms. All multivariate regression models were adjusted for infant sex and gestational age, maternal education, family income, cord blood cotinine levels, postnatal environmental tobacco smoke exposure, and breastfeeding. RESULTS: Prenatal PFOS concentrations in both untransformed and natural log (Ln)-transformed values were associated with adverse performance on the whole test and the domains related to development. A dose-response relationship was observed when PFOS levels were categorized into four groups. This association was most obvious in relation to the gross-motor subdomain. Across the PFOS interquartile range, the quotients of the gross-motor subdomain decreased by 3.7 points (95% confidence interval [CI] = -6.0 to -1.5), with an increasing odds ratio of poor performance (2.4; 95% CI = 1.3 to 4.2). In contrast, measures of association between PFOA concentrations and test scores were close to null. CONCLUSIONS: Prenatal exposure to PFOS, but not PFOA, may affect children's development, especially gross-motor development at 2 years of age.

Motor functioning during and following treatment with chemotherapy for pediatric acute lymphoblastic leukemia.

This systematic review evaluated empirical studies examining motor skills in children during and following treatment for acute lymphoblastic leukemia. Most studies indicated that children on-treatment display poorer gross and fine motor abilities than healthy peers, but generally have intact visual-motor integration skills. Studies have reported gross motor difficulties in 5-54% of survivors. There is some limited evidence for long-term fine motor deficits. The evidence for visual-motor integration difficulties in the survivor population is less consistent. Larger studies with a longitudinal design are needed to further specify the onset and timing of motor difficulties and ascertain risk factors.