research abstracts for cp

Research Abstracts

Toward a methodology of the short-term effects of neurodevelopmental treatment.

Am J Occup Ther. 1983 Jul; 37(7):479-84.DeGangi GA, Hurley L, Linscheid TR.

Abstract

Neurodevelopmental treatment (NDT) is a technique widely used by physical and occupational therapists in the treatment of neuromuscular disorders; however, quantitative evidence supporting its use has yet to be provided. Several studies have attempted to examine the effects of NDT, but because of poor research methodology, conclusions drawn to support the use of NDT are not based on reliable or well-documented evidence. The purpose of this study was to develop a reliable method of measuring short-term, objective changes in children with cerebral palsy and to measure the immediate effects of NDT and play interventions. A single subject design was replicated with four subjects receiving NDT and nonspecific play over a 5-week time period. Pre- and post-test items were designed to reflect qualitative changes in movement, postural tone, and reflex activity, and were videotaped and coded using interval and time-sampling techniques. The results of this study are equivocal; they neither validate nor invalidate NDT. This study provides a methodology for the investigation of the short-term effects of NDT.

The effect of hippotherapy on ten children with cerebral palsy.

Casady RL, Nichols-Larsen DS. (2004) Pediatr Phys Ther. Fall;16(3):165-72.

Abstract

PURPOSE: The purpose of this study was to determine whether hippotherapy has an effect on the general functional development of children with cerebral palsy. METHODS: The study employed a repeated-measures design with two pre-tests and two post-tests conducted 10 weeks apart using the Pediatric Evaluation of Disability Inventory (PEDI) and the Gross Motor Function Measure (GMFM) as outcome measures. A convenience sample of 10 children with cerebral palsy participated whose ages were 2.3 to 6.8 years at baseline (mean +/- 4.1 +/- 1.7 sd). Subjects received hippotherapy once weekly for 10 weeks between pre-test 2 and post-test 1. Test scores on the GMFM and PEDI were compared before and after hippotherapy. RESULTS: One-way analysis of variance of group mean scores with repeated measures was significant (p < 0.05) for all PEDI subscales and all GMFM dimensions except lying/rolling. Post hoc analyses with the Tukey test for honest significant differences on the PEDI and GMFM total measures as well as GMFM crawling/kneeling and PEDI social skills subtests were statistically significant between pre-test 2 and post-test 1. CONCLUSIONS: The results of this study suggest that hippotherapy has a positive effect on the functional motor performance of children with cerebral palsy. Hippotherapy appears to be a viable treatment strategy for therapists with experience and training in this form of treatment and a means of improving functional outcomes in children with cerebral palsy.

Improvements in muscle symmetry in children with cerebral palsy after equine-assisted therapy (hippotherapy).

Benda W, McGibbon NH, Grant KL. (2003) J Altern Complement Med. Dec;9(6):817-25.

Abstract

OBJECTIVE: To evaluate the effect of hippotherapy on muscle activity in children with spastic cerebral palsy. DESIGN: Pretest/post-test control group. SETTING/LOCATION: Therapeutic Riding of Tucson (TROT), Tucson, AZ. SUBJECTS: Fifteen (15) children ranging from 4 to 12 years of age diagnosed with spastic cerebral palsy. INTERVENTIONS: Children meeting inclusion criteria were randomized to either 8 minutes of hippotherapy or 8 minutes astride a stationary barrel. OUTCOME MEASURES: Remote surface electromyography (EMG) was used to measure muscle activity of the trunk and upper legs during sitting, standing, and walking tasks before and after each intervention. RESULTS: After hippotherapy, significant improvement in symmetry of muscle activity was noted in those muscle groups displaying the highest asymmetry prior to hippotherapy. No significant change was noted after sitting astride a barrel. CONCLUSIONS: Eight minutes of hippotherapy, but not stationary sitting astride a barrel, resulted in improved symmetry in muscle activity in children with spastic cerebral palsy. These results suggest that the movement of the horse rather than passive stretching accounts for the measured improvements.

Hippotherapy as a method for complex rehabilitation of patients with late residual stage of infantile cerebral palsy.

Sokolov PL, Dremova GV, Samsonova SV. (2002) Zh Nevrol Psikhiatr Im S S Korsakova.;102(10):42-5.

Abstract

Influence and therapeutic efficacy of horseback riding (hippotherapy) as a method for complex rehabilitation of patients with late residual stage of infantile cerebral palsy were studied. Significant increase of a range of active and passive movements in large joints of lower extremities, higher, indices of hand dynamometry on the left, of vital lung capacity as well as a relief of relief of reactive and personality anxiety and depression, higher motivation for rehabilitation treatment, etc., were registered. Neurophysiological study revealed significant changes of afferentation at stem and thalamus cortical levels and of spectral components of cortical rhythmics. The data obtained allow us to consider hippotherapy as an effective method of complex rehabilitation of patients with late residual stage of infantile cerebral palsy. A combination of sensory stimulation and motor rehabilitation components may be a key mechanism of positive effect.

Complementary and alternative medicine use in families of children with cerebral palsy.

Hurvitz EA, Leonard C, Ayyangar R, Nelson VS.

Dev Med Child Neurol. 2003 Jun;45(6):364-70.

Department of Physical Medicine and Rehabilitation, Pediatric Section, University of Michigan Medical Center/Charles Stewart Mott Children's Hospital, Ann Arbor, MI 48109-0230, USA. ehurvitz@umich.edu

Abstract

In order to assess patterns of usage of complementary and alternative medicine (CAM) in families of children with cerebral palsy (CP), 213 families with a child (0 to 18 years) with CP were recruited at the university medical center in Ann Arbor, MI, USA as part of a descriptive survey. Two hundred and thirty-five surveys were distributed. Mean age of the child was 8 years 6 months (SD 4y : 9mo) and 56% of the sample was male with 35% full-time independent ambulators, while the rest used an assistive device or a wheelchair. Fifty-four percent were in special education classrooms. Families were given a survey on functional status of the child with CP, CAM usage of the child and the parent, factors influencing the decision to use CAM, demographics, and clinical information. Of the families, 56%, used one or more CAM techniques. Massage therapy (25%) and aquatherapy (25%) were the most common. Children of families that used CAM were significantly younger (7y : 9mo, SD 4y : 7mo) than non-users (9y : 6mo, SD 4y : 6mo: t-test p < 0.01 two-tailed). Children with quadriplegic CP, with spasticity, and those who could not walk independently were more commonly exposed to CAM (Pearson's chi2 [P(chi)2] p = 0.01 two-tailed; for mobility, odds ratio [OR] of 2.5 with regression). Mothers with a college degree had a greater tendency to use CAM for their child than those without (P(chi)2 p = 0.01 two-tailed). Fathers of children who used CAM were older than fathers of those who did not (37y : 9mo versus 33y : 2mo, p = 0.04 two-tailed). There was no significant difference between groups for mother's age, father's education, income, or for population of home town. Parents who used CAM for themselves were more likely to try CAM for their child (70% versus 47%, OR 2.1), and were much more likely to be pleased with the outcome (71% versus 42%, OR 3.5). Child's age (younger), lack of independent mobility, and parental use of CAM were the most significant predictive factors identified via logistic regression.

The connection between rhythmicity and brain function

IEEE Eng Med Biol Mag. 1999 Mar-Apr;18(2):101-8.

Thaut MH, Kenyon GP, Schauer ML, McIntosh GC.

Dept. of Music, Theater, Dance, Colorado State University, Ft. Collins, USA.

Abstract

Although rhythm and music are not entirely synonymous terms, rhythm constitutes one of the most essential structural and organizational elements of music. When considering the effect of music on human adaptation, the profound effect of rhythm on the motor system strongly suggests that the time structure of music is the essential element relating music specifically to motor behavior. Why the motor system appears so sensitive to auditory priming and timing stimulation can only be partially answered so far. The high-performance function of the auditory system regarding processing of time information makes good functional sense within the constraints of auditory sensory processing. Thus, the motor system sensitivity to auditory entrainment may simply be an evolutionary useful function of taking advantage of the specific and unique aspects of auditory information processing for enhanced control and organization of motor behavior; e.g, in the time domain. Unlike processes in the motor system, many other physiological processes cannot be effectively entrained by external sensory stimuli. For example, there is probably a very good protective reason why other cyclical physiological processes (e.g., autonomic processes such as heart rate) have only very limited entrainment capacity to external rhythmic cues. Some of the basic auditory-motor arousal connections may also have their basis in adaptive evolutionary processes related to survival behavior; e.g., in fight or flight reactions. Much of the "why" in auditory-motor interactions, however, remains unknown heuristically. In the absence of this knowledge, great care should be taken to not compensate for this lack of understanding of specific cause and effect processes by assigning anthropomorphic descriptions to the behavior of biological and physical systems. The unraveling of the perceptual, physiological, and neuroanatomical basis of the interaction between rhythm and movement has been, and continues to be, a fascinating endeavor with important ramifications for the study of brain function, sensory perception, and motor behavior. One of the most exciting findings in this research, however, may be the evidence that the interaction between auditory rhythm and physical response can be effectively harnessed for specific therapeutic purposes in the rehabilitation of persons with movement disorders.

Neurobiology of rhythmic motor entrainment

Ann N Y Acad Sci. 2003 Nov;999:313-21.

Molinari M, Leggio MG, De Martin M, Cerasa A, Thaut M.

I.R.C.C.S. Santa Lucia Foundation, Rome, Italy. m.molinari@hsantalucia.it

Abstract

Timing is extremely important for movement, and understanding the neurobiological basis of rhythm perception and reproduction can be helpful in addressing motor recovery after brain lesions. In this quest, the science of music might provide interesting hints for better understanding the brain timing mechanism. The report focuses on the neurobiological substrate of sensorimotor transformation of time data, highlighting the power of auditory rhythmic stimuli in guiding motor acts. The cerebellar role of timing is addressed in subjects with cerebellar damage; subsequently, cerebellar timing processing is highlighted through an fMRI study of professional musicians. The two approaches converge to demonstrate that different levels of time processing exist, one conscious and one not, and to support the idea that timing is a distributed function. The hypothesis that unconscious motor responses to auditory rhythmic stimuli can be relevant in guiding motor recovery and modulating music perception is advanced and discussed.

Listening to musical rhythms recruits motor regions of the brain

Cereb Cortex. 2008 Dec;18(12):2844-54. Epub 2008 Apr 3.

Chen JL, Penhune VB, Zatorre RJ.

Montreal Neurological Institute, McGill University, 3801 University St., Montreal, QC H3A 2B4, Canada. joyce.chen@mail.mcgill.ca

Abstract

Perception and actions can be tightly coupled; but does a perceptual event dissociated from action processes still engage the motor system? We conducted 2 functional magnetic resonance imaging studies involving rhythm perception and production to address this question. In experiment 1, on each trial subjects 1st listened in anticipation of tapping, and then tapped along with musical rhythms. Recruitment of the supplementary motor area, mid-premotor cortex (PMC), and cerebellum was observed during listen with anticipation. To test whether this activation was related to motor planning or rehearsal, in experiment 2 subjects naively listened to rhythms without foreknowledge that they would later tap along with them. Yet, the same motor regions were engaged despite no action-perception connection. In contrast, the ventral PMC was only recruited during action and action-coupled perceptual processes, whereas the dorsal part was only sensitive to the selection of actions based on higher-order rules of temporal organization. These functional dissociations shed light on the nature of action-perception processes and suggest an inherent link between auditory and motor systems in the context of rhythm.

The role of biomechanics in understanding dance movement: a review

J Dance Med Sci. 2008;12(3):109-16.

Wilson M, Kwon YH.

Department of Theatre and Dance, University of Wyoming, Dept. 3951, 1000 East University Avenue, Laramie, Wyoming 82071-3951, USA. mawilson@uwyo.edu

Abstract

This review introduces different techniques used in biomechanics that have been used in analyzing dance movement. Biomechanics provides information not only for analysis of motion, but for understanding muscle use, forces acting on the body, issues of motor control, and the interaction between any one body part and the body as a whole. The goal of this review is to highlight the role that biomechanical analysis plays in understanding dance movement, with applications for teaching, skill enhancement, and injury prevention.

Brain injury in the premature infant: overview of clinical aspects, neuropathology, and pathogenesis.

Department of Neurology, Harvard Medical School, Boston, MA, USA.

Brain injury in the premature infant is an extremely important problem, in part because of the large absolute number of infants affected yearly. The two principal brain lesions that underlie the neurological manifestations subsequently observed in premature infants are periventricular hemorrhagic infarction and periventricular leukomalacia. The emphases of this article are the neurology, neuropathology, and pathogenesis of these two lesions. Recent work suggests that the ultimate goal, prevention of the lesions, is potentially achievable. Periventricular hemorrhagic infarction may be preventable by prevention of germinal matrix/intraventricular hemorrhage, and periventricular leukomalacia, by detection of impaired cerebrovascular autoregulation, prevention of impaired cerebral blood flow, and interruption of the cascade to oligodendroglial cell death by such agents as free-radical scavengers.

Semin Pediatr Neurol. 2009 Dec;16(4):207-15.

To autoregulate or not to autoregulate--that is no longer the question.

Greisen G.

Department of Neonatology, Rigshospitalet, Copenhagen, Denmark. greisen@rh.dk

Abstract

In the late 1970s, high cerebral blood flow was perceived as a cause of intracranial hemorrhage in the preterm infant. Intracranial hemorrhage was diagnosed by computed tomography and ultrasound found to be frequent not only in babies who died. Hemorrhage was soon linked to cerebral palsy in survivors. The analogy was hypertensive hemorrhagic stroke in the adult. Cerebral hemorrhage was perceived as the major (preventable) cause of brain injury in the preterm baby. An immature cerebral autoregulation or a vulnerability of the autoregulation exposed by preceding hypoxia or ischemia therefore became a focus of neonatal brain research in the 1980s. Over the years the focus has changed, first to the pathogenesis of hypoxic-ischemic brain injury, then to the effects of pCO(2), and now 30 years later to a more comprehensive, less clearly hypothesis-driven exploration of the multitude of factors involved in cerebral blood flow and oxygenation. Meanwhile, some basic questions regarding autoregulation remain unanswered, and some concepts from the 1970s still direct clinical practice.

Brain Dev. 1988;10(3):143-6.

The "lost autoregulation hypothesis" and brain lesions in the newborn--an update.

Lou HC.

John F Kennedy Institute, Glostrup, Denmark.

Abstract

Autoregulation of cerebral blood flow is an essential homeostatic mechanism which is easily disturbed during the stresses in the birth process. In its absence, moderate hypotension, a frequent complication in neonatal asphyxia, may induce cerebral ischemia, the arterial watershed zones in periventricular regions being particularly prone. The initial ischemia in perinatal stress produces functional disturbance (EEG depression), which is not readily reversible as the circulation improves. Hypotension, cerebral hypoperfusion and EEG depression precedes severe periventricular hemorrhage, which seems to be triggered by fluctuations in arterial blood pressure and flow, with fluctuations in the transmural pressure gradient across the capillary wall. The penetration of the hemorrhaging into surrounding brain tissue is related to the magnitude of the preceding ischemic insult.

Predictability of cerebral palsy in a high-risk NICU population.

Himpens E, Oostra A, Franki I, Vansteelandt S, Vanhaesebrouck P, den Broeck CV.

Ghent University, Belgium. eveline.himpens@ugent.be

Abstract

AIM: This study aims to create a predictive model for the assessment of the individual risk of developing cerebral palsy in a large cohort of selected high-risk infants.

PATIENTS AND METHODS: 1099 NICU-admitted high-risk infants were assessed up to the corrected age of at least 12 months. CP was categorized relative to subtype, distribution and severity. Several perinatal characteristics (gender, gestational age, multiple gestation, small for gestational age, perinatal asphyxia and duration of mechanical ventilation), besides neonatal cerebral ultrasound data were used in the logistic regression model for the risk of CP.

RESULTS: Perinatal asphyxia, mechanical ventilation>7 days, white matter disease except for transient echodensities<7 days, intraventricular haemorrhage grades III and IV, cerebral infarction and deep grey matter lesions were recognized as independent predictors for the development of CP. 95% of all children with CP were correctly identified at or above the cut-off value of 4.5% probability of CP development. Higher gestational age, perinatal asphyxia and deep grey matter lesion are independent predictors for non-spastic versus spastic CP (OR=1.1, 3.6, and 7.5, respectively). Independent risk factors for prediction of unilateral versus bilateral spastic CP are higher gestational age, cerebral infarction and parenchymal haemorrhagic infarction (OR=1.2, 31, and 17.6, respectively). Perinatal asphyxia is the only significant variable retained for the prediction of severe CP versus mild or moderate CP.

CONCLUSION: The presented model based on perinatal characteristics and neonatal US-detected brain injuries is a useful tool in identifying specific infants at risk for developing CP.

J Neurosci. 2010 Jul 14;30(28):9603-11.

Repeated mesenchymal stem cell treatment after neonatal hypoxia-ischemia has distinct effects on formation and maturation of new neurons and oligodendrocytes leading to restoration of damage, corticospinal motor tract activity, and sensorimotor function.

van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ.

Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands.

Abstract

Birth asphyxia is a frequent cause of perinatal morbidity and mortality with limited therapeutic options. We show that a single mesenchymal stem cell treatment at 3 d (MSC-3) after neonatal hypoxia-ischemia (HI) in postnatal day 9 mice improved sensorimotor function and reduced lesion size. A second MSC treatment at 10 d after HI (MSC-3+10) further enhanced sensorimotor improvement and recovery of MAP2 and MBP (myelin basic protein) staining. Ipsilateral anterograde corticospinal tract tracing with biotinylated dextran amine (BDA) showed that HI reduced BDA labeling of the contralateral spinal cord. Only MSC-3+10 treatment partially restored contralateral spinal cord BDA staining, indicating enhanced axonal remodeling. MSC-3 enhanced formation of bromodeoxyuridine-positive neurons and oligodendrocytes. Interestingly, the second gift at day 10 did not further increase new cell formation, whereas only MSC-10 did. These findings indicate that increased positive effect of MSC-3+10 compared with MSC-3 alone is mediated via distinct pathways. We hypothesize that MSCs adapt their growth and differentiation factor production to the needs of the environment at the time of intracranial injection. Comparing the response of MSCs to in vitro culture with HI brain extracts obtained at day 10 from MSC-3- or vehicle-treated animals by pathway-focused PCR array analysis revealed that 29 genes encoding secreted factors were indeed differentially regulated. We propose that the function of MSCs is dictated by adaptive specific signals provided by the damaged and regenerating brain.

J Soc Gynecol Investig. 2002 Nov-Dec;9(6):319-28.

Perinatal brain damage: underlying mechanisms and neuroprotective strategies.

Berger R, Garnier Y, Jensen A.

Department of Obstetrics and Gynecology, University of Bochum, Bochum, Germany. richard.berger@ruhr-uni-bochum.de

Abstract

Children who suffer from perinatal brain injury often deal with the dramatic consequences of this misfortune for the rest of their lives. Despite the severe clinical and socioeconomic significance, no effective clinical strategies have yet been developed to counteract this condition. As shown in recent studies, perinatal brain injury is usually brought about by cerebral ischemia, cerebral hemorrhage, or an ascending intrauterine infection. This review focuses on the pathophysiologic pathways activated by these insults and describes neuroprotective strategies that can be derived from these mechanisms. Fetal cerebral ischemia causes an acute breakdown of neuronal membrane potential followed by the release of excitatory amino acids such as glutamate and aspartate. Glutamate binds to postsynaptically located glutamate receptors that regulate calcium channels. The resulting calcium influx activates proteases, lipases, and endonucleases, which in turn destroy the cellular skeleton. A second wave of neuronal cell damage occurs during the reperfusion phase. This cell damage is thought to be caused by the postischemic release of oxygen radicals, synthesis of nitric oxide, inflammatory reactions, and an imbalance between the excitatory and inhibitory neurotransmitter systems. Furthermore, secondary neuronal cell damage may be brought about in part by induction of a cellular suicide program known as apoptosis. Recent studies have shown that inflammatory reactions not only aggravate secondary neuronal damage after cerebral ischemia, but may also injure the immature brain directly. This damage may be mediated by cardiovascular effects of endotoxins leading to cerebral hypoperfusion and by activation of apoptotic pathways in oligodendrocyte progenitors through the release of proinflammatory cytokines. Periventricular or intraventricular hemorrhage (PIVH) is a typical lesion of the immature brain. The inability of preterm fetuses to redistribute cardiac output in favor of the central organs and their lack of cerebral autoregulation may cause significant fluctuations in cerebral blood flow when oxygen is in short supply. Disruption of the thin-walled blood vessels in the germinal matrix with subsequent cerebral hemorrhage is often the inevitable result and is at times associated with cerebral hemorrhagic infarction. Knowledge of these pathophysiologic mechanisms has enabled scientists to develop new therapeutic strategies, which have been shown to be neuroprotective in animal experiments. The potential of such therapies is discussed here, particularly the promising effects of postischemic induction of cerebral hypothermia, the application of the calcium-antagonist flunarizine, and the administration of magnesium.

Exp Neurol. 2009 Jul;218(1):75-82. Epub 2009 Apr 15.

Neuroprotection against neonatal hypoxia/ischemia-induced cerebral cell death by prevention of calpain-mediated mGluR1alpha truncation.

Zhou M, Xu W, Liao G, Bi X, Baudry M.

Neuroscience Program, University of Southern California, Los Angeles, CA 90089, USA.

Abstract

Many cellular events are involved in ischemic neuronal death, and it has been difficult to identify those that play a critical role in the cascade triggered by lack of oxygen and glucose, although it has been widely recognized that overactivation of glutamate receptors represents one of the initiating factors. Different glutamate receptor antagonists, especially those for N-methyl-D-aspartate (NMDA) receptors, have achieved significant success in animal models of hypoxia/ischemia; however, these antagonists have failed in clinical trials. We previously reported that calpain-mediated truncation of metabotropic glutamate receptor 1alpha (mGluR1alpha) played a critical role in excitotoxicity, and that a TAT-mGluR1 peptide consisting of a peptide surrounding the calpain cleavage site of mGluR1alpha and the peptide transduction domain of the transactivating regulatory protein (TAT) of HIV was neuroprotective against excitotoxicity. In the present study we tested the effect of this peptide in in vitro and in vivo models of neonatal hypoxia/ischemia. TAT-mGluR1 peptide prevented oxygen/glucose deprivation- (OGD) and hypoxia/ischemia- (H/I) induced neuronal death in cultured hippocampal slices and neonatal rats, respectively. TAT-mGluR1 blocked H/I-induced mGluR1alpha degradation but had no effect on H/I-induced spectrin degradation, suggesting that neuroprotection was due to prevention of calpain-mediated mGluR1alpha truncation and not to calpain inhibition. Our results therefore suggest that mGluR1alpha truncation plays a critical role in neonatal hypoxia/ischemia and that blockade of this event may prevent the activation of many downstream cytotoxic cascades. Compared to glutamate receptor antagonists and general calpain inhibitors, TAT-mGluR1 may have limited side effects.

Arch Med Res. 2006 Jan;37(1):11-8.

Role of glutamate transporters in the clearance and release of glutamate during ischemia and its relation to neuronal death.

Camacho A, Massieu L.

Departamento de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico, D.F., Mexico. acamacho@ifc.unam.mx

Abstract

Glutamate neurotransmitter action on postsynaptic receptors is terminated by its clearance from the synaptic cleft by transporter proteins located in neurons and glial cells. Failure of glutamate removal can lead to neuronal death due to its well-known neurotoxic properties. Glutamate transporters are dependent on external Na+, and thus on the activity of Na+/K+ ATPases, which maintain the Na+ concentration gradient. When the energy brain requirements are not fulfilled by the appropriate blood supply of glucose and oxygen, the Na+ gradient collapses leading to impaired glutamate and aspartate removal, or even to the release of these amino acids through the reverse operation of their transporters. Such a scenario would be associated with brain ischemia and hypoglycemia due to the prompt decline in ATP levels. In addition, some evidence suggests that downregulation of glutamate transporters after the ischemic period, or the dysfunction induced by oxidation, contributes to the accumulation of extracellular glutamate and neuronal death. Neuronal damage is associated with excitotoxicity, a type of cell death triggered by the overactivation of glutamate receptors and the loss of calcium homeostasis. Throughout this review we will discuss recent evidence suggesting that failure of glutamate transport during ischemia contributes to the elevation of extracellular glutamate and to the induction of excitotoxicity. We will also discuss the contribution of glial vs. neuronal glutamate transporters in ischemic damage, and the involvement of the different glutamate transporter subtypes. We will focus on experimental data from rodent models, because many of the studies on glutamate transport and ischemic damage have been performed in these animal species.

Int J Dev Neurosci. 2008 Feb;26(1):93-101. Epub 2007 Sep 7.

Hypoxic-ischemic injury in neonatal brain: involvement of a novel neuronal molecule in neuronal cell death and potential target for neuroprotection.

Hossain MA.

Department of Neurology, The Johns Hopkins University School of Medicine and The Kennedy Krieger Research Institute, Baltimore, MD 21205, USA. hossain@kennedykrieger.org

Abstract

Perinatal hypoxia-ischemia (HI) is the most common cause of various neurological disabilities in children with high societal cost. Hypoxic-ischemic brain damage is an evolving process and ample evidence suggests distinct difference between the immature and mature brain in the pathology and consequences of brain injury. Therefore, it is of utmost importance to better understand the mechanisms underlying the hypoxic-ischemic injury in neonatal brain to devise effective therapeutic strategies. Nonetheless, the mechanism(s) involved in this pathology in the developing brain remain inadequately understood. Effective neuroprotective strategies will include either inhibition of the death effector pathways or induction of their regulatory and survival promoting cellular proteins. Neuronal pentraxins (NPs) define a family of novel proteins "long pentraxins" that are exclusively expressed in the central neurons, and are homologous to the C-reactive and acute-phase proteins in the immune system. NPs have been shown to be involved in the excitatory synaptic remodeling. We found that the neuronal protein 'neuronal pentraxin 1' (NP1) is induced in neonatal rat brain following HI, and NP1 induction preceded the time of actual tissue loss in brain. In demonstrating this we also found that NP1 gene silencing is neuroprotective against hypoxia-induced neuronal death. This is the first evidence for a pathophysiological function of NP1 in central neurons. Our results suggest that NP1 is part of a death program triggered by HI. Most importantly, our findings of specific interactions of NP1 with the excitatory glutamate receptors AMPA GluR1 subunit and their co-localization suggest a role for this novel neuronal protein NP1 in the excitotoxic cascade. Blockade of AMPA-induced neuronal death following inhibition of NP1 expression further implicates a regulatory interaction between NP1 and AMPA glutamate receptors. Subsequent experiments using NP1 loss-of-function strategies, we have demonstrated specific requirements of NP1 induction in HI-induced neuronal death. Together our findings clearly identify a novel role for NP1 in the coupling between HI and cerebral cell death. Thus, NP1 could be a new molecular target in the central neurons for preventing hypoxic-ischemic neuronal death in developing brain. These very novel results could lead to more effective neuroprotective strategies against hypoxic-ischemic brain injury in neonates.

Exp Neurol. 2009 Jul;218(1):75-82. Epub 2009 Apr 15.

Neuroprotection against neonatal hypoxia/ischemia-induced cerebral cell death by prevention of calpain-mediated mGluR1alpha truncation.

Zhou M, Xu W, Liao G, Bi X, Baudry M.

Neuroscience Program, University of Southern California, Los Angeles, CA 90089, USA.

Abstract

Many cellular events are involved in ischemic neuronal death, and it has been difficult to identify those that play a critical role in the cascade triggered by lack of oxygen and glucose, although it has been widely recognized that overactivation of glutamate receptors represents one of the initiating factors. Different glutamate receptor antagonists, especially those for N-methyl-D-aspartate (NMDA) receptors, have achieved significant success in animal models of hypoxia/ischemia; however, these antagonists have failed in clinical trials. We previously reported that calpain-mediated truncation of metabotropic glutamate receptor 1alpha (mGluR1alpha) played a critical role in excitotoxicity, and that a TAT-mGluR1 peptide consisting of a peptide surrounding the calpain cleavage site of mGluR1alpha and the peptide transduction domain of the transactivating regulatory protein (TAT) of HIV was neuroprotective against excitotoxicity. In the present study we tested the effect of this peptide in in vitro and in vivo models of neonatal hypoxia/ischemia. TAT-mGluR1 peptide prevented oxygen/glucose deprivation- (OGD) and hypoxia/ischemia- (H/I) induced neuronal death in cultured hippocampal slices and neonatal rats, respectively. TAT-mGluR1 blocked H/I-induced mGluR1alpha degradation but had no effect on H/I-induced spectrin degradation, suggesting that neuroprotection was due to prevention of calpain-mediated mGluR1alpha truncation and not to calpain inhibition. Our results therefore suggest that mGluR1alpha truncation plays a critical role in neonatal hypoxia/ischemia and that blockade of this event may prevent the activation of many downstream cytotoxic cascades. Compared to glutamate receptor antagonists and general calpain inhibitors, TAT-mGluR1 may have limited side effects.

Neuroscience. 2005;136(3):779-94.

Ionotropic glutamate receptors and glutamate transporters are involved in necrotic neuronal cell death induced by oxygen-glucose deprivation of hippocampal slice cultures.

Bonde C, Noraberg J, Noer H, Zimmer J.

Anatomy and Neurobiology, Institute of Medical Biology, University of Southern Denmark, Winslowparken 21, DK-5000 Odense, Denmark.

Abstract

Organotypic hippocampal slice cultures represent a feasible model for studies of cerebral ischemia and the role of ionotropic glutamate receptors in oxygen-glucose deprivation-induced neurodegeneration. New results and a review of existing data are presented in the first part of this paper. The role of glutamate transporters, with special reference to recent results on inhibition of glutamate transporters under normal and energy-failure (ischemia-like) conditions is reviewed in the last part of the paper. The experimental work is based on hippocampal slice cultures derived from 7 day old rats and grown for about 3 weeks. In such cultures we investigated the subfield neuronal susceptibility to oxygen-glucose deprivation, the type of induced cell death and the involvement of ionotropic glutamate receptors. Hippocampal slice cultures were also used in our studies on glutamate transporters reviewed in the last part of this paper. Neurodegeneration was monitored and/or shown by cellular uptake of propidium iodide, loss of immunocytochemical staining for microtubule-associated protein 2 and staining with Fluoro-Jade B. To distinguish between necrotic vs. apoptotic neuronal cell death we used immunocytochemical staining for active caspase-3 (apoptosis indicator) and Hoechst 33342 staining of nuclear chromatin. Our experimental studies on oxygen-glucose deprivation confirmed that CA1 pyramidal cells were the most susceptible to this ischemia-like condition. Judged by propidium iodide uptake, a selective CA1 lesion, with only minor affection on CA3, occurred in cultures exposed to oxygen-glucose deprivation for 30 min. Nuclear chromatin staining by Hoechst 33342 and staining for active caspase-3 showed that oxygen-glucose deprivation induced necrotic cell death only. Addition of 10 microM of the N-methyl-D-aspartate glutamate receptor antagonist MK-801, and 20 microM of the non-N-methyl-D-aspartate glutamate receptor antagonist 2,3-dihyroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline to the culture medium confirmed that both N-methyl-D-aspartate and non-N-methyl-D-aspartate ionotropic glutamate receptors were involved in the oxygen-glucose deprivation-induced cell death. Glutamate is normally quickly removed, from the extracellular space by sodium-dependent glutamate transporters. Effects of blocking the transporters by addition of the DL-threo-beta-benzyloxyaspartate are reviewed in the last part of the paper. Under normal conditions addition of DL-threo-beta-benzyloxyaspartate in concentrations of 25 microM or more to otherwise untreated hippocampal slice cultures induced neuronal cell death, which was prevented by addition of 2,3-dihyroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline and MK-801. In energy failure situations, like cerebral ischemia and oxygen-glucose deprivation, the transporters are believed to reverse and release glutamate to the extracellular space. Blockade of the transporters by a subtoxic (10 microM) dose of DL-threo-beta-benzyloxyaspartate during oxygen-glucose deprivation (but not during the next 48 h after oxygen-glucose deprivation) significantly reduced the oxygen-glucose deprivation-induced propidium iodide uptake, suggesting a neuroprotective inhibition of reverse transporter activity by DL-threo-beta-benzyloxyaspartate during oxygen-glucose deprivation under these conditions. Adding to this, other results from our laboratory have demonstrated that pre-treatment of the slice cultures with glial cell-line derived neurotrophic factor upregulates glutamate transporters. As a logical, but in some glial cell-line derived neurotrophic factor therapy-related conditions clearly unwanted consequence the susceptibility for oxygen-glucose deprivation-induced glutamate receptor-mediated cell death is increased after glial cell-line derived neurotrophic factor treatment. In summary, we conclude that both ionotropic glutamate receptors and glutamate transporters are involved in oxygen-glucose deprivation-induced necrotic cell death in hippocampal slice cultures, which have proven to be a feasible tool in experimental studies on this topic.

Am J Hum Genet. 2009 Jul;85(1):40-52. Epub 2009 Jun 25.

Mutation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy.

Verkerk AJ, Schot R, Dumee B, Schellekens K, Swagemakers S, Bertoli-Avella AM, Lequin MH, Dudink J, Govaert P, van Zwol AL, Hirst J, Wessels MW, Catsman-Berrevoets C, Verheijen FW, de Graaff E, de Coo IF, Kros JM, Willemsen R, Willems PJ, van der Spek PJ, Mancini GM.

Department of Bioinformatics, Erasmus Medical Center, 3015 GE Rotterdam, The Netherlands.

Abstract

Cerebral palsy due to perinatal injury to cerebral white matter is usually not caused by genetic mutations, but by ischemia and/or inflammation. Here, we describe an autosomal-recessive type of tetraplegic cerebral palsy with mental retardation, reduction of cerebral white matter, and atrophy of the cerebellum in an inbred sibship. The phenotype was recorded and evolution followed for over 20 years. Brain lesions were studied by diffusion tensor MR tractography. Homozygosity mapping with SNPs was performed for identification of the chromosomal locus for the disease. In the 14 Mb candidate region on chromosome 7q22, RNA expression profiling was used for selecting among the 203 genes in the area. In postmortem brain tissue available from one patient, histology and immunohistochemistry were performed. Disease course and imaging were mostly reminiscent of hypoxic-ischemic tetraplegic cerebral palsy, with neuroaxonal degeneration and white matter loss. In all five patients, a donor splice site pathogenic mutation in intron 14 of the AP4M1 gene (c.1137+1G-->T), was identified. AP4M1, encoding for the mu subunit of the adaptor protein complex-4, is involved in intracellular trafficking of glutamate receptors. Aberrant GluRdelta2 glutamate receptor localization and dendritic spine morphology were observed in the postmortem brain specimen. This disease entity, which we refer to as congenital spastic tetraplegia (CST), is therefore a genetic model for congenital cerebral palsy with evidence for neuroaxonal damage and glutamate receptor abnormality, mimicking perinatally acquired hypoxic-ischemic white matter injury.

Am J Hum Genet. 1999 Feb;64(2):526-32.

A gene for autosomal recessive symmetrical spastic cerebral palsy maps to chromosome 2q24-25.

McHale DP, Mitchell S, Bundey S, Moynihan L, Campbell DA, Woods CG, Lench NJ, Mueller RF, Markham AF.

Molecular Medicine Unit Clinical Sciences Building, St. James's University Hospital, Leeds, LS9 7TF United Kingdom. mrpdpm@leeds.ac.uk

Abstract

Cerebral palsy has an incidence of approximately 1/500 births, although this varies between different ethnic groups. Genetic forms of the disease account for approximately 1%-2% of cases in most countries but contribute a larger proportion in populations with extensive inbreeding. We have clinically characterized consanguineous families with multiple children affected by symmetrical spastic cerebral palsy, to locate recessive genes responsible for this condition. The eight families studied were identified from databases of patients in different regions of the United Kingdom. After ascertainment and clinical assessment, we performed a genomewide search for linkage, using 290 polymorphic DNA markers. In three families, a region of homozygosity at chromosome 2q24-q25 was identified between the markers D2S124 and D2S148. The largest family gave a maximum LOD score of 3.0, by multipoint analysis (HOMOZ). The maximum combined multipoint LOD score for the three families was 5.75. The minimum region of homozygosity is approximately 5 cM between the markers D2S124 and D2S2284. We have shown that a proportion of autosomal recessive symmetrical spastic cerebral palsy maps to chromosome 2q24-25. The identification of genes involved in the etiology of cerebral palsy may lead to improved management of this clinically intractable condition.