Tetrahydrobiopterin in antenatal brain hypoxia-ischemia-induced motor impairments and cerebral palsy.
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ABSTRACT:
SUBMITTER: Vasquez-Vivar J
PROVIDER: S-EPMC5554922 | biostudies-other | 2017 Oct
REPOSITORIES: biostudies-other
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Project description:We hypothesized that a deficiency in the descending serotonergic input to spinal cord may underlie postnatal muscle hypertonia after global antenatal hypoxic-ischemic injury in a rabbit model of cerebral palsy. Neurotransmitter content was determined by HPLC in the spinal cord of newborns with and without muscle hypertonia after fetal global hypoxic-ischemic brain injury and naïve controls. Contrary to our hypothesis, serotonin levels in both cervical and lumbar expansions and norepinephrine in cervical expansion were increased in hypertonic kits relative to non-hypertonic kits and controls, with unchanged number of serotonergic cells in caudal raphe by stereological count. Serotonergic fiber length per unit of volume was also increased in hypertonic kits' cervical and lumbar spinal cord, both in dorsal and ventral horns. Gene expression of serotonin transporter was increased and 5-HTR2 receptors were decreased in hypertonic kits relative to controls in cervical and lumbar cord. Intrathecal administration of non-selective serotonin receptor inhibitor methysergide decreased muscle tone in hypertonic kits only. Conversely, intrathecal administration of serotonin solution increased muscle tone only in non-hypertonic kits. We speculate that maturation of serotonergic system in spinal cord may be directly affected by decreased corticospinal connectivity after antenatal hypoxic-ischemic brain injury. Following prenatal hypoxia-ischemia, newborn rabbits exhibit elevated levels of serotonin in the spinal cord that were linked to muscle hypertonia. Serotonergic terminal density was also increased in hypertonic newborns' spinal cord. Intrathecal administration of the non-selective serotonin receptor inhibitor methysergide decreased muscle tone in hypertonic newborns only. Elevated spinal serotonin thus suggests a novel pathophysiological mechanism of hypertonia in cerebral palsy.
| S-EPMC4329027 | biostudies-literature
Project description:Cerebral palsy (CP) is caused by a variety of factors attributed to early brain damage, resulting in permanently impaired motor control, marked by weakness and muscle stiffness. To find out if altered physiology of spinal motoneurons (MNs) could contribute to movement deficits, we performed whole-cell patch-clamp in neonatal rabbit spinal cord slices after developmental injury at 79% gestation. After preterm hypoxia-ischemia (HI), rabbits are born with motor deficits consistent with a spastic phenotype including hypertonia and hyperreflexia. There is a range in severity, thus kits are classified as severely affected, mildly affected, or unaffected based on modified Ashworth scores and other behavioral tests. At postnatal day (P)0-5, we recorded electrophysiological parameters of 40 MNs in transverse spinal cord slices using whole-cell patch-clamp. We found significant differences between groups (severe, mild, unaffected and sham control MNs). Severe HI MNs showed more sustained firing patterns, depolarized resting membrane potential, and fired action potentials at a higher frequency. These properties could contribute to muscle stiffness, a hallmark of spastic CP. Interestingly altered persistent inward currents (PICs) and morphology in severe HI MNs would dampen excitability (depolarized PIC onset and increased dendritic length). In summary, changes we observed in spinal MN physiology likely contribute to the severity of the phenotype, and therapeutic strategies for CP could target the excitability of spinal MNs.
| S-EPMC7109297 | biostudies-literature
Project description:BackgroundAlthough, there is no population-level data in Ethiopia, a previous retrospective hospital-based study identified CP as the most common developmental disability in children. The overall aim of this study is to describe the clinical spectrum of CP in Tikur Anbessa Specialized Hospital in Addis Ababa, including CP subtype, gross and fine motor function, presence and pattern of associated impairments, and possible risk factors in children aged 2 to 18 years.MethodsA hospital-based descriptive cross-sectional study conducted- July - September of 2018 among 207 children with suspected motor symptoms. The Surveillance of CP in Europe (SCPE) decision tree was used as a guideline for inclusion and evaluation was by standardized questionnaire and clinical examination. Descriptive, bivariate and multivariate statistical analyses, Chi-square test, crudes association and adjusted odds ratio with 95% confidence interval employed.ResultOne hundred seventy four children who fulfilled the clinical criteria were included. Half (50.6%) were under the age of 5 years with a mean age of 5.6 (SD 3.6) years; 55.2 were male. The majority had bilateral spastic CP (60.4%) followed by unilateral spastic CP 21.8%, dyskinetic CP 10.4%, and ataxic CP 3.4%; 4% were unclassifiable. Of the children, 95.4% had speech difficulty, 87.4% learning disabilities, 60.9% epilepsy, 24.7% visual impairment and 8.6% hearing impairment. On gross motor function (GMFCS) and manual ability (MACS) classification systems, 75.3% of the children had level IV and V functional impairment. More than 80% of the mothers had complications during delivery Half of the neonates did not cry immediately after birth,44% were resuscitated with bag mask ventilation at birth and 64% immediately admitted to NICU. During the first month of life, 50% had infection, 62% had trouble feeding, 49.4% had difficulty breathing, 35% had seizure and 13.8% had jaundice.ConclusionThe severe forms of CP predominate; most children are dependent on their parents for routine activities of daily living and cannot communicate well. Multidisciplinary care approaches and focused functional habilitation services are needed. Causal relationships cannot be drawn from these data but findings make a strong argument for improving maternal and child health care.
| S-EPMC8641229 | biostudies-literature
Project description:Rabbit kits after global antenatal hypoxic-ischemic injury exhibit motor deficits similar to humans with cerebral palsy. We tested several mechanisms previously implicated in spinal hyper-excitability after perinatal brain injury that may explain muscle hypertonia in newborns. Stiffness of hind limb muscles during passive stretch, electromyogram, and spinal excitability by Hoffman reflex, were assessed in rabbit kits with muscle hypertonia after global hypoxic-ischemic brain injury and naïve controls. Affected muscle architecture, motoneuron morphology, primary afferents density, gliosis, and KCC2 expression transporter in the spinal cord were also examined. Decrease knee stiffness after anesthetic administration was larger, but residual stiffness was higher in hypertonic kits compared to controls. Hypertonic kits exhibited muscle shortening and atrophy, in both agonists and antagonists. Sarcomere length was longer in tibialis anterior in hypertonic kits than in controls. Hypertonic kits had decreased rate dependent depression and increased Hmax/Mmax in H-reflex. Motor neuron soma sizes, primary afferent density were not different between controls and hypertonic kits. Length of dendritic tree and ramification index were lower in hypertonic group. Gene expression of KCC2 was lower in hypertonic kits, but protein content was not different between the groups. In conclusion, while we found evidence of decreased supraspinal inhibitory control and increased excitability by H-reflex that may contribute to neuronal component in hypertonia, increased joint resistance to stretch was explained predominantly by changes in passive properties of muscles and joints. We did not find structural evidence of increased sensory afferent input or morphological changes in motoneurons that might explain increased excitability. Gliosis, observed in spinal gray matter, may contribute to muscle hypertonia.
| S-EPMC6344443 | biostudies-literature
Project description:OBJECTIVE:To evaluate the relationship of maternal antenatal magnesium sulfate (MgSO4) with neonatal cranial ultrasound abnormalities and cerebral palsy (CP). STUDY DESIGN:In a randomized trial of MgSO4 or placebo in women at high risk of preterm delivery, up to 3 cranial ultrasounds were obtained in the neonatal period. Images were reviewed by at least 2 pediatric radiologists masked to treatment and other clinical conditions. Diagnoses were predefined for intraventricular hemorrhage, periventricular leukomalacia, intracerebral echolucency or echodensity, and ventriculomegaly. CP was diagnosed at 2 years of age by standardized neurologic examination. RESULTS:Intraventricular hemorrhage, periventricular leukomalacia, intracerebral echolucency or echodensity, and ventriculomegaly were all strongly associated with an increased risk of CP. MgSO4 administration did not affect the risk of cranial ultrasound abnormality observed at 35 weeks postmenstrual age or later. However, for the 82% of infants born at <32 weeks gestation, MgSO4 was associated with a reduction in risk of echolucency or echodensity. The reduction in risk for echolucency explained 21% of the effect of MgSO4 on CP (P = .04), and for echodensity explained 20% of the effect (P = .02). CONCLUSIONS:MgSO4 given prior to preterm delivery was associated with decreased risk of developing echodensities and echolucencies at <32 weeks gestation. However, this effect can only partially explain the effect of MgSO4 on CP at 2 years of age. TRIAL REGISTRATION:ClinicalTrials.gov: NCT00014989.
| S-EPMC4587284 | biostudies-literature
Project description:In the present study, we investigated the role of lncRNA mus distal-less homeobox 6 antisense 1 (DLX6-AS1) during cerebral impairment induced by stroke. DLX6-AS1 levels were upregulated during ischemia/reperfusion (I/R) and downregulation of DLX6-AS1 reduced acute injury and ameliorated long-term neurological impairments induced by cerebral I/R in mice. Additionally, silencing of DLX6-AS1 significantly decreased the neuronal apoptosis in vivo and in vitro. Furthermore, inhibition of miRNA-149-3p led to enhance the apoptosis, which confirmed that DLX6-AS1 could sponge miR-149-3p. Finally, BOK was predicted to be the target of miR-149-3p using TargetScanVert software. And the silencing of DLX6-AS1 inhibited BOK expression both in vivo and in vitro, which was reversed by a miR-149-3p inhibitor. At meantime, BOK promoted OGD/R induced apoptosis in N2a cells. Therefore, this suggests that miR-149-3p sponging by DLX6-AS1 may lead to cerebral neuron I/R-induced impairments through upregulation of apoptotic BOK activity, which offers a new approach to the treatment of stroke impairment.
| S-EPMC7746362 | biostudies-literature
Project description:Insults to the developing brain often result in irreparable damage resulting in long-term deficits in motor and cognitive functions. The only treatment today for hypoxic-ischemic encephalopathy (HIE) in newborns is hypothermia, which has limited clinical benefit. We have studied changes to the blood-brain barriers (BBB) as well as regional cerebral blood flow (rCBF) in a neonatal model of HIE to further understand the underlying pathologic mechanisms. Nine-day old mice pups, brain roughly equivalent to the near-term human fetus, were subjected to hypoxia-ischemia. Hypoxia-ischemia increased BBB permeability to small and large molecules within hours after the insult, which normalized in the following days. The opening of the BBB was associated with changes to BBB protein expression whereas gene transcript levels were increased showing direct molecular damage to the BBB but also suggesting compensatory mechanisms. Brain pathology was closely related to reductions in rCBF during the hypoxia as well as the areas with compromised BBB showing that these are intimately linked. The transient opening of the BBB after the insult is likely to contribute to the pathology but at the same time provides an opportunity for therapeutics to better reach the infarcted areas in the brain.
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Project description:Hypertonia is pathognomonic of cerebral palsy (CP), often caused by brain injury before birth. To understand the early driving events of hypertonia, we utilized magnetic resonance imaging (MRI) assessment of early critical brain injury in rabbit fetuses (79% term) that will predict hypertonia after birth following antenatal hypoxia-ischemia. We examined if individual variations in the tetrahydrobiopterin cofactor in the parts of the brain controlling motor function could indicate a role in specific damage to motor regions and disruption of circuit integration as an underlying mechanism for acquiring motor disorders, which has not been considered before. The rabbit model mimicked acute placental insufficiency and used uterine ischemia at a premature gestation. MRI during the time of hypoxia-ischemia was used to differentiate which individual fetal brains would become hypertonic. Four brain regions collected immediately after hypoxia-ischemia or 48 h later were analyzed in a blinded fashion. Age-matched sham-operated animals were used as controls. Changes in the reactive nitrogen species and gene expression of the tetrahydrobiopterin biosynthetic enzymes in brain regions were also studied. We found that a combination of low tetrahydrobiopterin content in the cortex, basal ganglia, cerebellum, and thalamus brain regions, but not a unique low threshold of tetrahydrobiopterin, contributed etiologically to hypertonia. The biggest contribution was from the thalamus. Evidence for increased reactive nitrogen species was found in the cortex. By 48 h, tetrahydrobiopterin and gene expression levels in the different parts of the brain were not different between MRI stratified hypertonia and non-hypertonia groups. Sepiapterin treatment given to pregnant dams immediately after hypoxia-ischemia ameliorated hypertonia and death. We conclude that a developmental tetrahydrobiopterin variation is necessary with fetal hypoxia-ischemia and is critical for disrupting normal motor circuits that develop into hypertonia. The possible mechanistic pathway involves reactive nitrogen species.
| S-EPMC6928344 | biostudies-literature
Project description:Alzheimer's disease (AD) is heterogeneous and multifactorial neurological disorder; and the risk factors of AD still remain elusive. Recent studies have highlighted the role of vascular factors in promoting the progression of AD and have suggested that ischemic events increase the incidence of AD. However, the detailed mechanisms linking ischemic insult to the progression of AD is still largely undetermined. In this study, we have established a transient cerebral ischemia model on young 5xFAD mice and their non-transgenic (nonTg) littermates by the transient occlusion of bilateral common carotid arteries. We have found that transient cerebral ischemia significantly exacerbates brain mitochondrial dysfunction including mitochondrial respiration deficits, oxidative stress as well as suppressed levels of mitochondrial fusion proteins including optic atrophy 1 (OPA1) and mitofusin 2 (MFN2) in young 5xFAD mice resulting in aggravated spatial learning and memory. Intriguingly, transient cerebral ischemia did not induce elevation in the levels of cortical or mitochondrial Amyloid beta (A?)1-40 or 1-42 levels in 5xFAD mice. In addition, the glucose- and oxygen-deprivation-induced apoptotic neuronal death in A?-treated neurons was significantly mitigated by mitochondria-targeted antioxidant mitotempo which suppresses mitochondrial superoxide levels. Therefore, the simplest interpretation of our results is that young 5xFAD mice with pre-existing AD-like mitochondrial dysfunction are more susceptible to the effects of transient cerebral ischemia; and ischemic events may exacerbate dementia and worsen the outcome of AD patients by exacerbating mitochondrial dysfunction.
| S-EPMC4669173 | biostudies-literature
Project description:Upper limb three-dimensional movement analysis (UL-3DMA) offers a reliable and valid tool to evaluate movement patterns in children with unilateral cerebral palsy (uCP). However, it remains unknown to what extent the underlying motor impairments explain deviant movement patterns. Such understanding is key to develop efficient rehabilitation programs. Although UL-3DMA has been shown to be a useful tool to assess movement patterns, it results in a multitude of data, challenging the clinical interpretation and consequently its implementation. UL-3DMA reports are often reduced to summary metrics, such as average or peak values per joint. However, these metrics do not take into account the continuous nature of the data or the interdependency between UL joints, and do not provide phase-specific information of the movement pattern. Moreover, summary metrics may not be sensitive enough to estimate the impact of motor impairments. Recently, Statistical Parametric Mapping (SPM) was proposed to overcome these problems. We collected UL-3DMA of 60 children with uCP and 60 typically developing children during eight functional tasks and evaluated the impact of spasticity and muscle weakness on UL movement patterns. SPM vector field analysis was used to analyze movement patterns at the level of five joints (wrist, elbow, shoulder, scapula, and trunk). Children with uCP showed deviant movement patterns in all joints during a large percentage of the movement cycle. Spasticity and muscle weakness negatively impacted on UL movement patterns during all tasks, which resulted in increased wrist flexion, elbow pronation and flexion, increased shoulder external rotation, decreased shoulder elevation with a preference for movement in the frontal plane and increased trunk internal rotation. Scapular position was altered during movement initiation, although scapular movements were not affected by muscle weakness or spasticity. In conclusion, we identified pathological movement patterns in children with uCP and additionally mapped the negative impact of spasticity and muscle weakness on these movement patterns, providing useful insights that will contribute to treatment planning. Last, we also identified a subset of the most relevant tasks for studying UL movements in children with uCP, which will facilitate the interpretation of UL-3DMA data and undoubtedly contribute to its clinical implementation.
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