RESUMO
Zika virus (ZIKV) infection during pregnancy has been causally linked to a constellation of neurodevelopmental deformities in the fetus resulting in a disease termed congenital Zika syndrome (CZS). Here we detail how ZIKV infection produces extensive neuropathology in the developing mouse brain and spinal cord of both sexes. Surprisingly, neuropathology differs depending on viral strain with a French Polynesian isolate producing primarily excitotoxicity and a Brazilian isolate being almost exclusively apoptotic but occurring over a prolonged period that is more likely to produce severe hypoplasia. We also show exposure can produce a characteristic pattern of infection that mirrors neuropathology and ultimately results in gross morphological deformities strikingly similar to CZS. This research provides a valuable mouse model mirroring the clinical course of disease that can be used to test potential therapies to improve treatment and gain a better understanding of the disabilities associated with CZS.SIGNIFICANCE STATEMENT Zika virus (ZIKV) infection during pregnancy has been causally linked to a constellation of neurodevelopmental deformities in the fetus resulting in a disease termed congenital Zika syndrome. Despite its devastating effects, very little is known about how ZIKV infection produces fetal neuropathology. Here we detail the temporal progression of ZIKV infection in the mouse brain and spinal cord resulting in massive neurodegeneration of infected regions. We also report a ZIKV strain from a region of Brazil with high levels of microcephaly (abnormally small head circumference) produces particularly devastating neuropathology.
Assuntos
Encéfalo/virologia , Neurônios/virologia , Medula Espinal/virologia , Infecção por Zika virus/patologia , Infecção por Zika virus/virologia , Animais , Animais Recém-Nascidos , Apoptose , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Feminino , Masculino , Camundongos Endogâmicos C57BL , Neurônios/patologia , Medula Espinal/crescimento & desenvolvimento , Medula Espinal/patologia , Zika virus/patogenicidadeRESUMO
Sedatives and anesthetics can injure the developing brain. They cause apoptosis of neurons and oligodendrocytes, impair synaptic plasticity, inhibit neurogenesis and trigger long-term neurocognitive deficits. The projected vulnerable period in humans extends from the third trimester of pregnancy to the third year of life. Despite all concerns, there is no ethically and medically acceptable alternative to the use of sedatives and anesthetics for surgeries and painful interventions. Development of measures that prevent injury while allowing the medications to exert their desired actions has enormous translational value. Here we investigated protective potential of hypothermia against histological toxicity of the anesthetic sevoflurane in the developing nonhuman primate brain. Neonatal rhesus monkeys underwent sevoflurane anesthesia over 5â¯h. Body temperature was regulated in the normothermic (>36.5⯰C), mild hypothermic (35-36.5⯰C) and moderately hypothermic (<35⯰C) range. Animals were euthanized at 8â¯h and brains examined immunohistochemically (activated caspase 3) and stereologically to quantify apoptotic neuronal and oligodendroglial death. Sevoflurane anesthesia was well tolerated at all temperatures, with oxygen saturations, end tidal CO2 and blood gases remaining at optimal levels. Compared to controls, sevoflurane exposed brains displayed significant apoptosis in gray and white matter affecting neurons and oligodendrocytes. Mild hypothermia (35-36.5⯰C) conferred significant protection from apoptotic brain injury, whereas moderate hypothermia (<35⯰C) did not. Hypothermia ameliorates anesthesia-induced apoptosis in the neonatal primate brain within a narrow temperature window (35-36.5⯰C). Protection is lost at temperatures below 35⯰C. Given the mild degree of cooling needed to achieve significant brain protection, application of our findings to humans should be explored further.
Assuntos
Anestésicos Inalatórios/toxicidade , Encéfalo/patologia , Hipotermia Induzida/métodos , Sevoflurano/toxicidade , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Macaca mulatta , Neurônios/efeitos dos fármacos , Neurônios/patologiaRESUMO
Epidemiological studies suggest exposures to anesthetic agents and/or sedative drugs (AASDs) in children under three years old, or pregnant women during the third trimester, may adversely affect brain development. Evidence suggests lengthy or repeated AASD exposures are associated with increased risk of neurobehavioral deficits. Animal models have been valuable in determining the type of acute damage in the developing brain induced by AASD exposures, as well as in elucidating long-term functional consequences. Few studies examining very early exposure to AASDs suggest this may be a critical period for inducing long-term functional consequences, but the impact of repeated exposures at these ages has not yet been assessed. To address this, we exposed mouse pups to a prototypical general anesthetic, isoflurane (ISO, 1.5% for 3 hr), at three early postnatal ages (P3, P5 and P7). We quantified the acute neuroapoptotic response to a single versus repeated exposure, and found age- and brain region-specific effects. We also found that repeated early exposures to ISO induced subtle, sex-specific disruptions to activity levels, motor coordination, anxiety-related behavior and social preference. Our findings provide evidence that repeated ISO exposures may induce behavioral disturbances that are subtle in nature following early repeated exposures to a single AASD.
Assuntos
Anestésicos Inalatórios/toxicidade , Comportamento Animal/efeitos dos fármacos , Encéfalo/patologia , Isoflurano/toxicidade , Animais , Animais Recém-Nascidos , Apoptose , Encéfalo/efeitos dos fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , GravidezRESUMO
Caffeine is the most frequently used medication in premature infants. It is the respiratory stimulant of choice for apnea associated with prematurity and has been called the silver bullet in neonatology because of many proven benefits and few known risks. Research has revealed that sedative/anesthetic drugs trigger apoptotic death of neurons and oligodendrocytes in developing mammalian brains. Here we evaluated the influence of caffeine on the neurotoxicity of anesthesia in developing nonhuman primate brains. Fetal macaques (n = 7-8/group), at a neurodevelopmental age comparable to premature human infants, were exposed in utero for 5 hours to no drug (control), isoflurane, or isoflurane + caffeine and examined for evidence of apoptosis. Isoflurane exposure increased apoptosis 3.3 fold for neurons and 3.4 fold for oligodendrocytes compared to control brains. Isoflurane + caffeine caused neuronal apoptosis to increase 8.0 fold compared to control levels but did not augment oligoapoptosis. Neuronal death was particularly pronounced in the basal ganglia and cerebellum. Higher blood levels of caffeine within the range considered therapeutic and safe for human infants correlated with increased neuroapoptosis. Caffeine markedly augments neurotoxicity of isoflurane in the fetal macaque brain and challenges the assumption that caffeine is safe for premature infants.