Abstract
Cerebral palsy (CP) is caused by nonprogressive neurological damage and manifested by disordered movement and posture, which leads to motor dysfunction. Two of the known etiologies of CP are perinatal asphyxia and prenatal/perinatal infection. Attempts to better understand the etiology and pathogenesis of CP have brought many investigators to develop animal models that mimic human CP. Mice and rats were extensively used but they have several disadvantages: due to short gestation, the brain at delivery is very immature and therefore most models are of young postnatal animals whose brains are at the developmental stage of the third trimester human fetus. Postnatal young mice and rat offspring are subjected to hypoxia/ischemia or infection/inflammation or a combination of the two. The clinical presentation is different compared to human CP, and there is a tendency for spontaneous recovery. Rabbits have a longer gestation and the injuries can be produced during the last week of pregnancy. Yet, the clinical picture of the induced brain damage is different from that in humans, and here too, there is a tendency for spontaneous recovery. Sheep have a relatively long gestation and the different models more closely resemble human CP. Nonhuman primates show similar nonprogressive motor impairment following either hypoxia/ischemia or infection/inflammation. The extent of the brain damage and the clinical findings are similar to human CP with similar neuropathological brain findings and with good possibilities to assess a variety of treatment modalities. We conclude that the animal model of CP should be chosen according to the aims of the study.
References
Adams Waldorf KM, Rubens CE, Gravett MG (2011) Use of nonhuman primate models to investigate mechanisms of infection-associated preterm birth. BJOG 118(2):136–144
Andreani JC, Guma C (2008) New animal model to mimic spastic cerebral palsy: the brain-damaged pig preparation. Neuromodulation 11(3):196–201
Back SA, Riddle A, Dean J, Hohimer AR (2012) The instrumental fetal sheep as a model of cerebral white matter injury in the premature infant. Neurotherapeutics 9:359–370
Balakrishnan B, Dai H, Janisse J, Romero R, Kannan S (2013) Maternal endotoxin exposure results in abnormal neuronal architecture in the newborn rabbit. Dev Neurosci 35(5):396–400
Balasubramaniam J, Del Bigio MR (2006) Animal models of germinal matrix hemorrhage. J Child Neurol 21(5):365–371
Basso DM, Beattie MS, Bresnahan JC (1995) A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 12(1):1–21
Basso DM, Fisher LC, Anderson AJ, Jakeman LB, McTigue DM, Popovich PG (2006) Basso Mouse Scale for locomotion detects differences in recovery after spinal cord injury in five common mouse strains. J Neurotrauma 23(5):635–659
Boska P (2010) Effects of prenatal infection on brain development and behavior: a review of findings from animal models. Brain Behav Immun 24:881–897, 2010
Brew N, Azhan A, den Heijer I, Boomgardt M, Davies GI, Nitsos I, Miller SL, Walker AM, Walker DW, Wong FY (2016) Dopamine treatment during acute hypoxia is neuroprotective in the developing sheep brain. Neuroscience 316:82–93
Burd I, Breen K, Friedman A, Chai J, Elovitz MA (2010) Magnesium sulfate reduces inflammation-associated brain injury in fetal mice. Am J Obstet Gynecol 202(3):292e1–292e9
Coq JA, Delcour M, Massicotte VS, Baud O, Barbe MF (2016) Prenatal ischemia deteriorates white matter, brain organization and function. Implications for prematurity and cerebral palsy. Dev Med Child Neurol 58(suppl 4):7–11
Derrick M, Luo NL, Bregman JC, Jilling T, Ji X, Fisher K, Gladson CL, Beardsley DJ, Murdoch G, Back SA, Tan S (2004) Preterm fetal hypoxia-ischemia causes hypertonia and motor deficits in the neonatal rabbit: a model for human cerebral palsy? J Neurosci 24(1):24–34
Dos Santos AS, de Almeida W, Popik B, Sbardelotto BM, Torrejais MM, de Souza MA, Centenaro LA (2017) Characterization of a cerebral palsy-like model in rats; analysis of gait pattern and of brain and spinal cord motor areas. Int J Dev Neurosci 60:48–55
Drobyshevsky A, Derrick M, Luo K, Zhang LQ, Wu YN, Takada SH, Yu L, Tan S (2012) Near-term fetal hypoxia-ischemia in rabbits: MRI can predict muscle tone abnormalities and deep brain injury. Stroke 43(10):2757–2763
Duncan JR, Cock ML, Scheerlinck JP, Westcott KT, McLean C, Harding R, Rees SM (2002) White matter injury after repeated endotoxin exposure in the preterm ovine fetus. Pediatr Res 52(6):941–949
Hallak M, Hotra JW, Kupsky WJ (2000) Magnesium sulfate protection of fetal brain from severe maternal hypoxia. Obstet Gynecol 96(1):124–128, 2000
Hirvonen M, Ojala R, Korhonen P, Haataja P, Eriksson K, Gissler M, Luukkaala T, Tammela O (2014) Cerebral palsy among children born moderately and late preterm. Pediatrics 134:e1584–e1593
Kasahara Y, Ihara M, Nakagomi T, Momota Y, Stern DM, Matsuyama T, Taguchi A (2013) A highly reproducible model of cerebral ischemia/reperfusion with extended survival in CB-17 mice. Neurosci Res 76(3):163–168
Kliegman R et al (eds) (2016) Nelson textbook of pediatrics, 20th edn. Elsevier, Prematurity, pp 821–834; Cerebral Palsy, pp 2896–2899
Mallard EC, Waldvogel HJ, Williams CE, Faull RL, Gluckman PD (1995) Repeated asphyxia causes loss of striatal projection neurons in the fetal sheep brain. Neuroscience 65(3):827–836
Mallard C, Welin AK, Peebles D, Hagberg H, Kjellmer I (2003) White matter injury following systemic endotoxemia or asphyxia in the fetal sheep. Neurochem Res 28(2):215–223
Marcuzzo S, Dutra MF, Stigger F, do Nascimento PS, Ilha J, Kalil-Gaspar PI, Achaval M (2008) Beneficial effects of treadmill training in a cerebral palsy-like rodent model: walking pattern and soleus quantitative histology. Brain Res 1222:129–140
Marques MR, Stigger F, Segabinazi E, Augustin OA, Barbosa S, Piazza FV, Achaval M, Marcuzzo S (2014) Beneficial effects of early environmental enrichment on motor development and spinal cord plasticity in a rat model of cerebral palsy. Behav Brain Res 263:149–155
Martin JH, Chakrabarty S, Friel KM (2011) Harnessing activity-dependent plasticity to repair the damaged corticospinal tract in an animal model of cerebral palsy. Dev Med Child Neurol 53(Suppl 4):9–13
Marumo G, Kozuma S, Ohyu J, Hamai Y, Machida Y, Kobayashi K (2001) Generation of periventricular leukomalacia by repeated umbilical cord occlusion in near-term fetal sheep and its possible pathogenetical mechanisms. Biol Neonate 79(1):39–45
McAdams RM, Fleiss B, Traudt C, Schwendimann L, Snyder JM, Haynes RL, Natarajan N, Gressens P, Juul SE (2017a) Long-term neuropathological changes associated with cerebral palsy in a nonhuman primate model of hypoxic-ischemic encephalopathy. Dev Neurosci 39(1-4):124–140
McAdams RM, McPherson RJ, Kapur RP, Juul SE (2017b) Focal brain injury associated with a model of severe hypoxic-ischemic encephalopathy in nonhuman primates. Dev Neurosci 39(1-4):107–123
Moster D, Lie RT, Markestad T (2008) Long-term medical and social consequences of preterm birth. N Engl J Med 359:262–273
Ohyu J, Marumo G, Ozawa H, Takashima S, Nakajima K, Kohsaka S, Hamai Y (1999) Early axonal and glial pathology in fetal sheep brains with leukomalacia induced by repeated umbilical cord occlusion. Brain and Development 21(4):248–252
Rha DW, Kang SW, Park YG, Cho SR, Lee WT, Lee JE, Nam CM, Han KH, Park ES (2011) Effects of constraint-induced movement therapy on neurogenesis and functional recovery after early hypoxic-ischemic injury in mice. Dev Med Child Neurol 53(4):327–333
Saadani-Makki F, Kannan S, Makki M, Muzik O, Janisse J, Romero R, Chugani D (2009) Intrauterine endotoxin administration leads to white matter diffusivity changes in newborn rabbits. J Child Neurol 24(9):1179–1189
Skoff RP, Bessert DA, Barks JD, Song D, Cerghet M, Silverstein FS (2001) Hypoxic-ischemic injury results in acute disruption of myelin gene expression and death of oligodendroglial precursors in neonatal mice. Int J Dev Neurosci 19(2):197–208
Stigger F, Felizzola AL, Kronbauer GA, Couto GK, Achaval M, Marcuzzo S (2011a) 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. Exp Neurol 228(2):183–191
Stigger F, do Nascimento PS, Dutra MF, Couto GK, Ilha J, Achaval M, Marcuzzo S (2011b) Treadmill training induces plasticity in spinal motoneurons and sciatic nerve after sensorimotor restriction during early postnatal period: new insights into the clinical approach for children with cerebral palsy. Int J Dev Neurosci 29(8):833–838
Svedin P, Kjellmer I, Welin AK, Blad S, Mallard C (2005) Maturational effects of lipopolysaccharide on white matter injury in fetal sheep. J Child Neurol 20(120):960–965
Tan S, Drobyshevsky A, Jilling T, Ji X, Ullman LM, Englof I, Derrick M (2005) Model of cerebral palsy in the perinatal rabbit. J Child Neurol 20(12):972–979
Traudt CM, McPherson RJ, Bauer LA, Richards TL, Burbacher TM, McAdams RM, Juul SE (2013) Concurrent erythropoietin and hypothermia treatment improve outcomes in a term nonhuman primate model of perinatal asphyxia. Dev Neurosci 35(6):491–503
Tsuji M, Ohshima M, Taguchi A, Kasahara Y, Ikeda T, Matsuyama T (2013) A novel reproducible model of neonatal stroke in mice: comparison with a hypoxia-ischemia model. Exp Neurol 247:218–225, 2013
Wang X, Hellgren G, Löfqvist C, Li W, Hellström A, Hagberg H, Mallard C (2009) White matter damage after chronic subclinical inflammation in newborn mice. J Child Neurol 24(9):1171–1178
Willette AA, Lubach GR, Knickmeyer RC, Short SJ, Styner M, Gilmore JH, Coe CL (2011) Brain enlargement and increased behavioral and cytokine reactivity in infant monkeys following acute prenatal endotoxemia. Behav Brain Res 219(1):108–111
Wright J, Rang M (1990) The spastic mouse and the search for an animal model of spasticity in human beings. Clin Orthop Relat Res 253:12–19
Wu YW, Colford JR (2000) Chorioamnionitis as a risk factor for cerebral palsy. JAMA 284:1417–1424
Yager JY, Thornhill JA (1997) The effects of age on susceptibility to hypoxic-ischemic brain damage. Neurosci Behav Rev 21:167–174
Yager JY, Shuaib A, Thornhill J (1996) The effects of age on susceptibility to brain damage in a model of global hemispheric hypoxia-ischemia. Dev Brain Res 93:143–154, 1996
Yoon BH, Kim CJ, Romero R, Jun JK, Park KH, Choi ST, Chi JG (1997) Experimentally induced intrauterine infection causes fetal brain white matter lesions in rabbits. Am J Obstet Gynecol 177(4):797–880
Yoshioka H, Lino S, Sato N, Osamura T, Hasegawa K, Ochi M, Sawada T, Kusunoki T (1989) New model of hemorrhagic hypoxic-ischemic encephalopathy in newborn ice. Pediatr Neurol 5:221–225
Yu L, Derrick M, Ji H, Silverman RB, Whitsett J, Vásquez-Vivar J, Tan S (2011) Neuronal nitric oxide synthase inhibition prevents cerebral palsy following hypoxia-ischemia in fetal rabbits: comparison between JI-8 and 7-nitroindazole. Dev Neurosci 33(3–4):312–319
Zaghloul N, Patel H, Ahmed MN (2017) A model of Periventricular Leukomalacia (PVL) in neonate mice with histopathological and neurodevelopmental outcomes mimicking human PVL in neonates. PLoS One 12(4):e0175438
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Ornoy, A. (2018). Animal Models of Cerebral Palsy: What Can We Learn About Cerebral Palsy in Humans. In: Miller, F., Bachrach, S., Lennon, N., O'Neil, M. (eds) Cerebral Palsy. Springer, Cham. https://doi.org/10.1007/978-3-319-50592-3_218-1
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DOI: https://doi.org/10.1007/978-3-319-50592-3_218-1
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