Péter Szerdahelyi

Blood-Brain Barrier Damage during the Acute Stage of Subarachnoid Hemorrhage, as Exemplified by a New Animal Model

Models have been devised and characterized in the laboratory rat for studying the neuropathology of subarachnoid hemorrhage. Several ways of injecting blood via different routes have been tried; cortical subarachnoid administration is the most reproducible suitable model. The location of injected blood was detected in histological sections. In this rat model for subarachnoid hemorrhage, the arterial blood pressure and the intracranial pressure did not elevate significantly, and the influence of major ischemic components in the development of brain edema could also be ruled out. Measurements performed on the water, electrolyte, and albumin contents of brain tissue have clearly indicated that the brain edema developing in the acute stage of rat experimental subarachnoid hemorrhage could be classified as having a primarily vasogenic component as well. These findings may have implications in the treatment of subarachnoid hemorrhage.

Involvement of Vasopressin in Brain Edema Formation: Further Evidence Obtained from the Brattleboro Diabetes Insipidus Rat with Experimental Subarachnoid Hemorrhage

Brain water accumulation (1.2%) with an accompanying increase in the sodium content was observed in Wistar rats as early as 1 hour after experimental subarachnoid hemorrhage (SAH). After 6 and 24 hours, the water content was 1.3 and 1.4%, respectively, higher than that of control animals. In contrast, in Brattleboro diabetes insipidus rats the content of brain water and electrolytes had not changed significantly 1 hour after the administration of blood into the subarachnoid space. Increased brain water and sodium and a normal potassium content, indicative of a vasogenic type of brain edema, were seen at 6 hours after SAH. In these animals, known to be devoid of vasopressin, the increase in brain water 24 hours after SAH was 2.6%, compared with 1.4% for Wistar rats with SAH. It is suggested that the lack of vasopressin could alter the course of brain edema formation after experimental SAH in Brattleboro diabetes insipidus rats. It is hypothesized that vasopressin, by regulating the water permeability of the brain capillaries, the choroid plexus, and the cerebrospinal fluid absorption structures, plays an important role in controlling the brain fluid and electrolyte balance during the course of SAH.

Histochemical detection of zinc and copper in various neurons of the central nervous system.

Trace elements (Zn2+, Cu2+, Fe2+) were localized with Timms sulphide silver method in the neurons (pyramidal cells, Purkinjes cells, motoneurons) and in the axon terminals of various regions cortex, hippocampus, nucleus ruber, cerebellum, medulla spinalis) of the central nervous system. After treatment of the same tissues with 15% trichloroacetic acid, a considerable proportion of the coarse granular staining disappeared from certain neurons (Purkinjes cells, ncl. ruber cells, motoneurons) and axon terminals (hippocampus mossy fibres), while in other cells (cortex pyramidal cells) and axon terminals it remained. The results suggest that the decrease in the staining is a consequence of the loss of Zn2+ and Fe2+ from the neuronal perikaryon or axon terminal. The histochemical results are supported by quantitative atomic absorption measurements.

Regulation of Brain Water and Electrolyte Contents: The Possible Involvement of Central Atrial Natriuretic Factor

The intraventricular administration of 0.2 or 2 micrograms of synthetic rat atrial natriuretic factor (syn rANF), sequence 101-126 of the precursor, prevented the water accumulation elicited in rat brain by a systemic hypoosmolar fluid load and led to a statistically significant sodium loss from the nervous tissue, while the potassium content remained unaltered. Similar syn rANF administration to rats not treated with a hypoosmolar fluid load caused no significant change in the water, potassium, and sodium content of the hemispheres. In this experiment, a primary systemic action of centrally administered syn rANF with ensuing secondary changes in brain ion and water homeostasis seems unlikely, as the serum osmolality and sodium and potassium concentrations remained unaltered. Thus, a central influence of the intraventricularly administered hormone upon the water and ion balances of the nervous tissue can be hypothesized. The significant loss of sodium may reflect the primary role of volume regulation of the nervous tissue, i.e., the loss of extracellular osmols such as Na+ in response to a hypoosmolar environment. These data lend further support to the concept that a central neuroendocrine system regulates brain ion and volume homeostasis. The possible role of ANF in the management of brain edema should be considered.

Treatment with ranitidine of ischemic brain edema

Cerebral ischemia was produced by bilateral common carotid artery occlusion in female Sprague-Dawley rats. Ranitidine, a histamine H2 receptor blocking agent, given intraperitoneally 30 min prior to ischemia, exerted a dose-dependent protective effect on water accumulation and ion shifts in the brain (Na+, K+ and Ca2+). To decide whether ranitidine can prevent ischemia-induced brain edema when given in the postischemic period, ranitidine (10 mg/kg i.p.) was administered 1, 2, and 3 h respectively after the onset of cerebral ischemia. Early (1 h) postocclusion treatment was still able to attenuate the ischemia-induced water accumulation and maldistribution of ions in the brain tissue.

Histochemistry of Zinc and Copper

Publisher Summary This chapter discusses the available histochemical procedures for the cellular localization of zinc and copper, allowing a deeper insight into their roles in physiological and biochemical processes. The importance of zinc and copper in biochemical and physiological processes at all levels of cellular complexity is well established and their roles in bacteria, fungi, plants, animals, and man have been studied intensively. Zinc plays a significant role in DNA, RNA, protein, and lipid syntheses, and zinc and copper are intimately involved as cofactors in a number of important enzyme systems, nonenzymatic proteins, and other molecules. The concentrations of the two elements in different tissues can be measured quantitatively by various analytical procedures. However, the amounts of these trace elements do not permit their precise localization at cellular and subcellular levels. Quantitative analytical and histochemical methods demonstrate that a relatively large amount of zinc is present in the hippocampus of the adult rat. The dithizone method and Timms staining suggest that the zinc is present in the axon terminals of the mossy fibers.

Actinomycin D suppresses the protective effect of dexamethasone in rats affected by global cerebral ischemia.

Simultaneous occlusion of both common carotid arteries in female Sprague-Dawley CFY rats produced characteristic symptoms of global cerebral ischemia, such as staggering, circling, convulsions, followed by coma and death. A close correlation existed among these symptoms and the elevation of water and Na+ content, appearing at the stage of staggering; Evans blue extravasation and diminution of K+ content, detected at circling; and the increase in Ca2+ content in the total brain tissue, manifesting itself at the phase of convulsions, indicating the development of cerebral edema due to ischemia. Dexamethasone given subcutaneously in a single 2.0 mg kg-1 dose 5 hours prior to the induction of global cerebral ischemia reduced considerably the morbidity and mortality, the alterations in water and electrolyte content, and albumin leakage in the brain tissue. Actinomycin D, in a dose of 0.5 mg kg-1 injected intravenously 1 hour before steroid treatment, abolished the beneficial effect. This finding suggests that de novo protein synthesis is involved in the cerebroprotective effect of dexamethasone.

Variations in trace metal levels in rat hippocampus during ontogenetic development.

SummaryThe variations in trace metal (zinc, iron, copper and manganese) levels in rat hippocampus were followed by atomic absorption spectrophotometry from the 17th embryonic day to the 100th postnatal day. In agreement with histochemical observations, it was found that the greatest relative increase in the hippocampal zinc level occurs during the 11th–20th postnatal days, simultaneously with the morphological maturation of the mossy fibre terminals. The iron level falls dramatically from the 17th embryonic day to the 3rd postnatal day. Beginning from the 11th postnatal day, the iron level, similarly to the copper level, continuously increases with age. The manganese level rises up to the 20th postnatal day, and subsequently progressively decreases. It is suggested that all of these elements are indispensable for the normal development and functioning of the hippocampus and the mossy fibre terminals.

Histamine H2-receptors participate in the formation of brain edema induced by kainic acid in rat thalamus

At 4 h after the intraperitoneal administration of kainic acid in a dose of 12 mg/kg, Evans blue extravasation was observed preferentially in the thalamus, accompanied by increases in the water and sodium contents and by a decrease in the potassium content. Subcutaneous pretreatment with a histamine H2-receptor blocking agent, ranitidine, in a dose of 5 mg/kg given 2 h before and at the time of kainic acid injection, partially decreased the edema formation in the thalamus. It is assumed that repetitive discharges evoked by the kainic acid result in the thalamus in an excessive release of histamine from internal (mast cell and neuronal) sources and that this leads to the activation of H2-receptor-coupled adenylate cyclase in the brain microvessels and to the induction of brain edema.

Kainic acid neurotoxicity: Characterization of blood-brain barrier damage

The alterations in the water, sodium (Na) and potassium (K) contents of the frontoparietal cortex, hippocampus and thalamus as well as the protein permeability of the blood-brain barrier were investigated in rats 4 h after systemic kainic acid administration. Increases in the water and Na contents and a decrease in the K content were observed together with Evans blue extravasation in the thalamus area indicating the development of vasogenic brain edema. Changes observed in the ion contents of the frontoparietal cortex and hippocampus may be due to a general cell membrane permeability damage but are not caused by a primary disturbance of the blood-brain barrier.