Effects of fetal exposure to lipopolysaccharide, perinatal anoxia and sensorimotor restriction on motor skills and musculoskeletal tissue: Implications for an animal model of cerebral palsy

Stigger, Felipe de Souza; Felizzola, Arthur L. de S.; Kronbauer, Gláucia Andreza; Couto, Gabriela Klein; Achaval, Matilde; Marcuzzo, Simone

doi:10.1016/j.expneurol.2011.01.001

Cited by 36 publications

(46 citation statements)

References 73 publications

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“…A previous study showed that exposure to LPS during the prenatal period (intraperitoneally, twice a day, from gestational day 17 until the end of the gestation) and perinatal anoxia (PA; on the day of birth, during 20 min in a 100% N2 chamber), alone or in combination, caused various degrees of consequences to motor behavior (Stigger et al, 2011). Given several evidences linking cytokines and oxidative stress to infection and anoxia, we suggest that cytokines could influence neurodevelopment by acting in a period of the rat's gestation that is roughly correspondent to the late second trimester in human CNS development.…”

Section: Introductionmentioning

confidence: 99%

Inflammatory response and oxidative stress in developing rat brain and its consequences on motor behavior following maternal administration of LPS and perinatal anoxia

Stigger

Lovatel

Marques

et al. 2013

Intl J of Devlp Neuroscience

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Cerebral palsy (CP) is a disorder of locomotion, posture and movement that can be caused by prenatal, perinatal or postnatal insults during brain development. An increased incidence of CP has been correlated to perinatal asphyxia and maternal infections during gestation. The effects of maternal exposure to low doses of bacterial endotoxin (lipopolysaccharide, LPS) associated or not with perinatal anoxia (PA) in oxidative and inflammatory parameters were examined in cerebral cortices of newborns pups. Concentrations of TNF-α, IL-1, IL-4, SOD, CAT and DCF were measured by the ELISA method. Other newborn rats were assessed for neonatal developmental milestones from day 1 to 21. Motor behavior was also tested at P29 using open-field and Rotarod. PA alone only increased IL-1 expression in cerebral cortex with no changes in oxidative measures. PA also induced a slight impact on development and motor performance. LPS alone was not able to delay motor development but resulted in changes in motor activity and coordination with increased levels of IL-1 and TNF-α expression associated with a high production of free radicals and elevated SOD activity. When LPS and PA were combined, changes on inflammatory and oxidative stress parameters were greater. In addition, greater motor development and coordination impairments were observed. Prenatal exposure of pups to LPS appeared to sensitize the developing brain to effects of a subsequent anoxia insult resulting in an increased expression of pro-inflammatory cytokines and increased free radical levels in the cerebral cortex. These outcomes suggest that oxidative and inflammatory parameters in the cerebral cortex are implicated in motor deficits following maternal infection and perinatal anoxia by acting in a synergistic manner during a critical period of development of the nervous system.

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Section: Introductionmentioning

confidence: 99%

Inflammatory response and oxidative stress in developing rat brain and its consequences on motor behavior following maternal administration of LPS and perinatal anoxia

Stigger

Lovatel

Marques

et al. 2013

Intl J of Devlp Neuroscience

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“…A similar model has been produced in rabbits [49,50]. This type of injury, however, does not necessarily mimic term infant HI injury and therefore would not be appropriate for a preclinical study of stem cell therapy for chronic HI injury.…”

Section: Animal Models Of Chronic Hiementioning

confidence: 99%

Stem Cell Therapy for Neonatal Hypoxic–Ischemic Brain Injury

Carroll¹

2015

Cell Therapy for Brain Injury

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Various varieties of stem cells and methods of their administration are proposed as therapeutic modalities for neonatal hypoxic-ischemic (HI) brain injury. The widespread use of stem cells for this purpose and others, despite the lack of strong clinical evidence for their efficacy in most clinical situations, makes it incumbent to review the pathophysiology of the clinical condition of neonatal HI brain injury, the preclinical data dealing with animal HI injury, and the available clinical studies.The central problem for the evaluation of treatment for neonatal HI injury is that two vastly different circumstances exist with respect to the condition: (1) the acute and (2) the chronic or long-standing result of the acute injury. The pathophysiology of the two variations, particularly with respect to the possible benefit of stem cell treatment, is quite different.The situation is further complicated by the widespread interest in treating cerebral palsy (CP) with stem cells, an effort of great interest to parents and society at large. This effort has been given impetus by anecdotal stories carried on the Internet. However, only a small component of children with CP has neonatal HI brain injury as the cause for their disability. While the treatment of CP is a popular target for stem cell therapy, CP is a group of disorders of complex and varied cause. This chapter deals only with CP caused by HI injury in the neonatal period of the term infant. Pathophysiology of Neonatal Hypoxic-Ischemic InjuryThe pathophysiology of acute HI injury in term infants is well known. These processes are important for our discussion in that they relate to way stem cells interact with the tissue. The mechanism of injury has been summarized in detail by J. Carroll 308 Volpe [1]. Briefly, the key innate factors are the vulnerable vascular border zones, regional anaerobic mechanisms, and excitatory glutamate synapses. Hypercapnia, hypoxemia, and acidosis lead to loss of regional regulation of blood flow. The latter phenomenon, in combination with systemic hypotension, leads to a compounding of the preceding events with exacerbation of the abnormal blood flow, more anaerobic metabolism with increasing lactate, and a rise in the damaging glutamate. As a consequence, cellular adenosine triphosphate (ATP) is depleted, calcium intrudes into the cell, and excitatory amino acids bring about more cellular damage. Later reperfusion injury eventuates leading to more neuronal damage with cell necrosis followed later by apoptosis. Models of acute HI injury, discussed below, attempt to mimic these events.Most of the studies of HI relate most closely to events in the term infant. The brain injuries in premature infants, however, comprise a significant portion of the pathology in patients with CP. While term infants tend to demonstrate more neuronal and cortical injuries, premature infants are more vulnerable to injury of the white matter. The influence of stem cell therapy in white matter injury is even less well understood and is not the subject here.Th...

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“…One limitation of these models is that these models did not consider the possibility of maternal infection, one of the important etiologic factors inducing CP. In this study, we made a CP animal model using lipopolysaccharide (LPS) for maternal infection with sensorimotor restriction (Stigger et al, 2011). LPS is a structural component of most gram-negative bacteria, and LPS induces cytotoxicity in the fetal brain during pregnancy (Gilstrap and Ramin, 2000).…”

Section: Introductionmentioning

confidence: 99%

Treadmill exercise improves motor and memory functions in cerebral palsy rats through activation of PI3K-Akt pathway

Jung¹,

Kim²

2017

J Exerc Rehabil

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Cerebral palsy (CP) is a chronic disorder characterized by physical disability and disruption of brain function. We evaluated the effects of treadmill exercise on motor and memory functions in relation with phosphatidylinositol 3-kinase (PI3K)-Akt pathway using CP rat model. Rota-rod test, step-down avoidance task, 5-bromo-2′-deoxyuridine (BrdU) immunohistochemistry, and western blot for synapsin I, postsynaptic density-95 (PSD-95), PI3K, Akt, and glycogen synthase kinase-3β (GSK-3β) were performed. CP was induced by maternal lipopolysaccharide (LPS)-injection with sensorimotor restriction. Five weeks after birth, the rats in the exercise groups were made to run on the treadmill for 30 min per one day, 5 times a week, during 4 weeks. Motor and memory functions were impaired in the LPS-induced CP rats and tread-mill exercise increased motor and memory functions in the CP rats. Cell proliferation in the hippocampus was suppressed in the LPS-induced CP rats and treadmill exercise increased hippocampal cell proliferation in the CP rats. Expressions of synapsin I, PSD-95, phosphorylated (p)-PI3K, and p-Akt were decreased in the LPS-induced CP rats and treadmill exercise enhanced the expressions of synapsin I, PSD-95, p-PI3K, and p-Akt in the CP rats. GSK-3β expression was increased in the LPS-induced CP rats and treadmill exercise suppressed GSK-3β expression in the CP rats. The present results suggest that treadmill exercise might improve motor and memory functions through activation of PI3K-Akt pathway.

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Effects of fetal exposure to lipopolysaccharide, perinatal anoxia and sensorimotor restriction on motor skills and musculoskeletal tissue: Implications for an animal model of cerebral palsy

Cited by 36 publications

References 73 publications

Inflammatory response and oxidative stress in developing rat brain and its consequences on motor behavior following maternal administration of LPS and perinatal anoxia

Inflammatory response and oxidative stress in developing rat brain and its consequences on motor behavior following maternal administration of LPS and perinatal anoxia

Stem Cell Therapy for Neonatal Hypoxic–Ischemic Brain Injury

Treadmill exercise improves motor and memory functions in cerebral palsy rats through activation of PI3K-Akt pathway

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