Cerebral edema in developing brain: I. Normal water and cation content in developing rat brain and postmortem changes

doi:10.1016/0014-4886(71)90009-4

Experimental Neurology

Volume 32, Issue 3, September 1971, Pages 431-438

https://doi.org/10.1016/0014-4886(71)90009-4 Get rights and content

Abstract

In preparation for an experimental study of cerebral edema in immature brain, the normal development of rat brain has been studied with respect to brain weight, water, sodium, and potassium content from 16 days of gestation at frequent intervals until adult life. The time course of postmortem alteration of these values has been followed until 96 hr after death in the hope that brains from human autopsy may be assessed for the presence of edema. It has been noted that considerable alterations of composition occur at those stages of brain development corresponding to the perinatal period in humans. The significance of these, and of the differences between immature and mature brain, for the assessment of cerebral edema in babies is discussed.

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The 3D scaffold itself should be adequately designed in terms of architecture and physicochemical properties. The brain is made up of 80 % water and has a Young’s modulus of less than 1 kPa (De Souza & Dobbing, 1971; Engler, Sen, Sweeney, & Discher, 2006; Nava, Raimondi, & Pietrabissa, 2012). Aerogel sponges that can transform into soft hydrogels once hydrated are good candidates to mimic these features; indeed, hydrogel-like bioscaffolds have been pointed out as ideal ones for brain regeneration (Modo, 2019).
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Separate water-unsuppressed spectra were used for eddy current correction and metabolite concentration calibration. The absolute water concentration used for metabolite quantification was corrected to reflect developmental changes of water content in the brain using published data (Tkac et al., 2003; De Souza and Dobbing, 1971). SNR of each whole spectrum was calculated by LCModel as the ratio of the maximum in the spectrum minus baseline over the analysis window to twice the root mean square of the residuals.
We utilized proton magnetic resonance spectroscopy to evaluate the metabolic profile of the hippocampus and anterior cingulate cortex of the developing rat brain from postnatal days 14–70. Measured metabolite concentrations were modeled using linear, exponential, or logarithmic functions and the time point at which the data reached plateau (i.e. when the portion of the data could be fit to horizontal line) was estimated and was interpreted as the time when the brain has reached maturity with respect to that metabolite. N-acetyl-aspartate and myo-inositol increased within the observed period. Gluthathione did not vary significantly, while taurine decreased initially and then stabilized. Phosphocreatine and total creatine had a tendency to increase towards the end of the experiment. Some differences between our data and the published literature were observed in the concentrations and dynamics of phosphocreatine, myo-inositol, and GABA in the hippocampus and creatine, GABA, glutamine, choline and N-acetyl-aspartate in the cortex. Such differences may be attributed to experimental conditions, analysis approaches and animal species. The latter is supported by differences between in-house rat colony and rats from Charles River Labs.
Spectroscopy provides a valuable tool for non-invasive brain neurochemical profiling for use in developmental neurobiology research. Special attention needs to be paid to important sources of variation like animal strain and commercial source.
Brain Development and Susceptibility to Damage; Ion Levels and Movements
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Chloride follows a pattern similar to that of sodium (Vernadakis and Woodbury, 1962). Total brain water, which is 88–90% during the first postnatal week (Agrawal et al., 1968; De Souza and Dobbing, 1971; Vernadakis and Woodbury, 1962), falls somewhat more slowly than sodium and chloride and is still above the adult level (about 78% at 10 weeks of life; De Souza and Dobbing, 1971) at weaning (82% at P21 and 80% at P28; De Souza and Dobbing, 1971; Vernadakis and Woodbury, 1962). Total potassium content decreases from about 80 mmol/kg at birth to 70–75 mmol/kg at P5–8.
Responses of immature brains to physiological and pathological stimuli often differ from those in the adult. Because CNS function critically depends on ion movements, this chapter evaluates ion levels and gradients during ontogeny and their alterations in response to adverse conditions. Total brain Na⁺ and Cl⁻ content decreases during development, but K⁺ content rises, reflecting shrinkage of the extracellular and increase in the intracellular water spaces and a reduction in total brain water volume. Unexpectedly, ${[K^{+}]}_{i}$ seems to fall during the first postnatal week, which should reduce ${[K^{+}]}_{i}$ / ${[K^{+}]}_{e}$ and result in a lower V_m, consistent with experimental observations. Neuronal ${[{Cl}^{-}]}_{i}$ is high during early postnatal development, hence the opening of Cl⁻ conduction pathways may lead to plasma membrane depolarization. Equivalent loss of $K_{i}^{+}$ into a relatively large extracellular space leads to a smaller increase in ${[K^{+}]}_{e}$ in immature animals, while the larger reservoir of ${Ca}_{e}^{2 +}$ may result in a greater ${[{Ca}^{2 +}]}_{i}$ rise. In vivo and in vitro studies show that compared with adult, developing brains are more resistant to hypoxic/ischemic ion leakage: increases in ${[K^{+}]}_{e}$ and decreases in ${[{Ca}^{2 +}]}_{e}$ are slower and smaller, consistent with the known low level of energy utilization and better maintenance of [ATP]. Severe hypoxia/ischemia may, however, lead to large ${Ca}_{i}^{2 +}$ overload. Rises in ${[K^{+}]}_{e}$ during epileptogenesis in vivo are smaller and take longer to manifest themselves in immature brains, although the rate of K⁺ clearance is slower. By contrast, in vitro studies suggest the existence of a period of enhanced vulnerability sometime during the developmental period. This chapter concludes that there is a great need for more information on ion changes during ontogeny and poses the question whether the rat is the most appropriate model for investigation of mechanisms of pathological changes in human neonates.
Sodium, phosphorus, sulphur, chlorine and potassium shifts in rat brain during embryonic development
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Concentrations of sodium (Na), phosphorus (P), sulphur (S), chlorine (Cl) and potassium (K) and their variations during brain development were measured in freeze-dried thick sections from rat brain (16–20 μm). Sprague-Dawley rats were bred and the day of finding vaginal spermatozoa was considered as day zero of pregnancy. On days 12E, 13E, 14E, 16E, 19E, 21E (embryonic) and postnatal day one whole embryos or fetal heads were rapidly frozen in liquid Freon 22 cooled with liquid nitrogen (−180 °C), sectioned in a cryostat (−20 to −40 °C), and processed for X-ray microanalysis on pure carbon plates. Concentrations of Na and Cl differed in the cells of the cerebral cortex, ependyma, choroid plexus and cerebral spinal fluid (CSF). During cerebral development, Na and Cl concentrations appeared to be correlated, while K was more related to P. S was low and unchanged in all compartments during development and was thus considered as an internal control. K was inversely related to Na and Cl fluctuations within the choroid plexus epithelia. Sharp phase changes of elemental composition appeared in all tissues at specific growth stages, e.g. days 14E and 19E. These results demonstrate rhythmic changes in the inorganic components of developing rat brain cells and fluid environment presumably reflecting physiological fluctuations and cell cycle phenomena. Such changes may also be related directly or indirectly to known ‘growth phase changes’ in the developing rat.
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Changes of extracellular potassium concentration during terminal anoxic depolarization were studied in the cerebral cortex of 5-, 9-, 14-, and 19-day-old rats by means of K⁺-specific microelectrodes. Resting level was found to be the same (about 3 mm) in all age groups. Anesthetized rats were killed by an overdose of d-tubocurarine. An increase of extracellular potassium concentration starting immediately after respiratory arrest was divided into four phases according to the slope of the increase. Phase I was the slowest, phase III the fastest. Second and third phases started at [K⁺]_e levels of 6.5 to 8.6 and 20 mm, respectively. Whereas the above transition levels between various phases did not change during ontogenesis, their slope increased with age; phase III started after 31.8, 14.5, 11.9, and 7.8 min in the 5-, 9-, 14-, and 19-day-old rats. Individual phases of extracellular potassium concentration increase could be ascribed to changes of membrane permeability. Slow K⁺ release in young animals reflects their higher resistance against anoxia and developmental changes in the relative volume of extracellular space in the cerebral cortex. The maximal level of extracellular potassium reached during the 5-min period after phase III increased with age (52.6 mm in 5-day-old rats, 75.7 mm in 19-day-olds) in accordance with data on developmental changes of potassium of the brain.
Resuscitation of the monkey brain after one hour's complete ischemia. II. Brain water and electrolytes
1975, Brain Research
Adult normothermic rhesus monkeys were submitted to one hour's complete cerebral ischemia, followed by periods of blood recirculation varying from 45 min to 24 h. The functional impact of ischemia and the subsequent recovery was monitored by electrophysiological recording and a distinction was made between animals with signs of functional recovery and animals without recovery. Prior to ischemia the water content of the gray matter was 81.1 ± 0.3% (mean ± S.D.) and of the white matter 68.9 ± 0.8%. The sodium-potassium ratio in the gray matter was 0.43 ± 0.02 and in the white matter 0.62 ± 0.06. During one hour's ischemia brain water did not change significantly, but the differences in the sodium-potassium ratio in white and gray matter were reduced. Blood recirculation of the brain after ischemia caused a considerable increase in brain water content and a shift in the sodium-potassium ratio up to 1.0. Calculated brain swelling was maximal after 45 min when it reached 11.1% of the total brain volume in an animal with recovery and 12.2% in another one without recovery.
In animals with signs of functional recovery brain swelling rapidly diminished, followed by a more gradual normalization of brain electrolytes within 24 h. In animals without functional recovery electrolyte shifts were irreversible or even progressed further. It is concluded that brain swelling and electrolyte derangements following one hour's cerebral ischemia are fully reversible when signs of functional recovery appear and brain metabolism returns.

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¹: This work was supported by a grant from the Medical Research Council. We are also grateful to the National Fund for Research into Crippling Diseases, to the Spastics Society for their help and to the Special Donations Fund of the Department of Child Health.

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Cerebral edema in developing brain: I. Normal water and cation content in developing rat brain and postmortem changes

Abstract

Brain Res.

Phosphofructokinase and fumarate hydratase in developing rat brain

J. Neurochem.

The developing brain

Undernutrition and the developing brain: the relevance of animal models to the human problem

Amer. J. Dis. Child.