Electrical kindling of rats treated discontinuously or continuously with haloperidol.

Intermittent as opposed to continuous treatment of rats with haloperidol resulted in a long-lasting potentiation of oral activity. To examine if this behavioural sensitization to discontinuous neuroleptic treatment facilitates seizure development in electrical kindling, rats treated either intermittently or continuously with haloperidol for 15 weeks were kindled in the nucleus amygdala. Development of kindled seizures was significantly faster in the intermittently treated group (P < 0.01) than in controls or continuously treated rats. Furthermore, discontinuously treated animals displayed electroencephalographic afterdischarges in the substantia nigra from the beginning of treatment. The findings of cross-sensitivity between electrical amygdala kindling and pharmacological sensitization and of early appearance of epileptiform nigral activity have implications for the pathogenesis of both conditions. We suggest that depressed gamma-aminobutyric acid activity in substantia nigra could be a common mechanism.

Hippocampal kindling in the rat is associated with time-dependent increases in the concentration of glial fibrillary acidic protein.

The effect of hippocampal kindling on the regional brain concentration of total glial fibrillary acidic protein (GFAP), a marker of reactive astrocytes, was studied in partially kindled rats, and in fully kindled rats after a post-kindling period of 24 h, 1 week, and 2 months. GFAP concentration was measured in arbitrary units by dot-blots. In the hippocampus, dentate gyrus, basolateral amygdala, pyriform cortex, and entorhinal cortex, limbic structures which are known to be involved in the kindling process, there was an increase in GFAP concentration which was maximal in the fully kindled animals studied after 24 h. In most brain areas, GFAP concentration was still elevated 1 week post-kindling, but had declined to control level 2 months post-kindling. A significant increase in GFAP was also found in septum, ventral pallidum/accumbens nucleus, and primary motor cortex of kindled rats with a post-kindling period of 24 h, whereas in several other brain regions GFAP was unchanged. These results suggest that astrocyte activation, indicative of degenerative changes in nearby neurons, is a transient and regional phenomenon in kindling occurring only during the development of the kindled state.

Cerebrovascular effects of angiotensin converting enzyme inhibition involve large artery dilatation in rats.

BACKGROUND AND PURPOSE: The aim of the study was to selectively examine the effects of converting enzyme inhibition on the large brain arteries by using concomitant inhibition of carbonic anhydrase to cause severe dilatation of mainly parenchymal resistance vessels. METHODS: Cerebral blood flow was measured using the xenon-133 injection technique in three groups of Wistar rats either during carbonic anhydrase inhibition with acetazolamide (treatment A, n = 8), during carbonic anhydrase inhibition followed by converting enzyme inhibition with captopril 40 minutes later (treatment B, n = 10), or during carbonic anhydrase inhibition preceded by converting enzyme inhibition 20 minutes earlier (treatment C, n = 7). RESULTS: After treatment A, cerebral blood flow rose rapidly and stabilized within 20 minutes at an average of 220 ml/100 g.min; flow remained stable until at least 60 minutes. After treatment B, cerebral blood flow increased by a further 17.4%, from an average of 219 ml/100 g.min to an average of 257 ml/100 g.min (p less than 0.01). After treatment C, cerebral blood flow stabilized at an average of 238 ml/100 g.min, with flow from 20 to 60 minutes always being higher (from 5% to 17%) than during carbonic anhydrase inhibition alone (p less than 0.02). Thus the additional inhibition of converting enzyme resulted in higher cerebral blood flow than during inhibition of carbonic anhydrase alone. CONCLUSIONS: These results suggest that converting enzyme inhibition reduced resistance of large brain arteries and support the hypothesis that there is some angiotensin II-induced tone in large cerebral arteries.

Cerebral Edema and Vascular Permeability to Serum Proteins Following Electroconvulsive Shock in Rats.

The regional brain specific gravity and the cerebrovascular permeability to serum proteins were investigated in rats subjected to electroconvulsive shock (ECS) with different stimulus intensity and different stimulus periods. The following experimental situations were studied: one ECS daily for 9 days (50 mA in 0.3 s), one ECS daily for 9 days (50 mA in 0.9 s), and one ECS three times weekly for 4 weeks (50 mA in 0.3 s). Age-matched animals receiving sham ECS served as controls. In the group having stronger stimulus intensity and in the one treated for 4 weeks, there was an increase in tissue water content in the hypothalamus and in both hypothalamus and hippocampus, respectively. In none of the experimental groups could cerebral edema be demonstrated in parietal cortex or in white matter. The findings point to an increased blood-to-brain transfer of water with increasing stimulus intensity and with the length of the ECS series. The study showed no increased cerebrovascular permeability to serum proteins and no signs of neuronal damage in any of the experimental groups.

Hippocampal kindling alters the concentration of glial fibrillary acidic protein and other marker proteins in rat brain.

The effect of hippocampal kindling on neuronal and glial marker proteins was studied in the rat by immunochemical methods. In hippocampus, pyriform cortex and amygdala there was an increase in glial fibrillary acidic protein (GFAP), indicating reactive gliosis, and an increase in the glycolytic enzyme NSE, suggesting increased anaerobic metabolism. Neuronal cell adhesion molecule (NCAM) decreased in pyriform cortex and amygdala of kindled rats, indicating neuronal degeneration.

Increased somatostatin and enkephalin-like immunoreactivity in the rat hippocampus following hippocampal kindling.

As neuropeptides may play a role in the electrical kindling model of epileptogenesis, hippocampal somatostatin, Met-enkephalin and cholecystokinin were studied by immunocytochemistry in rats 24 h following full hippocampal kindling (three stage 5 seizures). As control animals we used sham-kindled rats, unoperated rats and rats subjected to a single electroshock-induced seizure. In addition, the distribution of septohippocampal, cholinergic fibers and hippocampal mossy fibers were studied by histochemistry. The important finding was that after kindling there was, as compared to unoperated control, (1) a marked increase of somatostatin immunoreactivity in cell bodies in the dentate hilus and their presumed projections area in the outer parts of the dentate molecular layer, and (2) a marked increase of Met-enkephalin immunoreactivity in hippocampal mossy fiber terminals. We found no evidence of aberrant sprouting of mossy fiber collaterals in the fascia dentata.

Grafts of fetal locus coeruleus neurons in rat amygdala-piriform cortex suppress seizure development in hippocampal kindling.

Hippocampal kindling was investigated in rats with a 6-hydroxydopamine-induced lesion of the forebrain catecholamine system after implantation of neural tissue from the fetal locus coeruleus region either bilaterally into the amygdala-piriform cortex (i.e., distant to the kindling site) or unilaterally into the hippocampus (close to the kindling site). Lesioned animals with either sham grafts or control grafts consisting of fetal striatal tissue showed a kindling rate much faster than that of normal controls. In contrast, in rats with bilateral locus coeruleus grafts in the amygdala-piriform cortex (implanted at three sites) the development of seizures was similar to that of controls and significantly slower than that in lesioned animals with sham grafts. All these animals had bilateral surviving grafts with a mean of 125 noradrenergic cells per implantation site. In the animals with locus coeruleus grafts in the stimulated hippocampus the kindling rate did not differ from that in the lesioned animals with control grafts. Most of these animals had large surviving grafts and showed a dense noradrenergic reinnervation of the implanted hippocampus. The present findings indicate that grafting of fetal pontine tissue (rich in noradrenergic neurons) to a site distant to the stimulation focus, but important for the generalization and spread of seizures, can retard the development of seizures in hippocampal kindling. Together with the data of our previous report this study also indicates that noradrenergic reinnervation of both hippocampi is important for the seizure-suppressant action in hippocampal kindling of locus coeruleus grafts implanted in the hippocampus.

Impaired beta-adrenergic mediated cerebral blood flow response in streptozotocin diabetic rats.

The influence of intracarotic infusion of isoproterenol on cerebral blood flow, on cerebrovascular CO2-reactivity, and on cerebral glucose metabolism were investigated in streptozotocin diabetic rats. Resting cerebral blood flow in diabetic rats decreased by 26% from a control value of 90 ml/100 g.min. to 66 ml/100 g.min. Intracarotid isoproterenol infusion leads to a significant increase in cerebral blood flow in both groups. The increase in cerebral blood flow in control rats (70%), significantly exceeded that in the streptozotocin diabetic rats (33%). Cerebrovascular reactivity to carbon dioxide was preserved after isoproterenol infusion in both groups and there was no significant difference in the relative cerebral blood flow increase in the two groups. Cerebral glucose metabolism was also unaffected by the isoproterenol infusion. The results indicate that impaired beta-adrenergic mechanisms may play a role for alterations in cerebral blood flow that is seen in diabetes mellitus.

Angiotensin converting enzyme inhibition and the upper limit of cerebral blood flow autoregulation: effect of sympathetic stimulation.

The effect of stimulation of the cervical sympathetic ganglia on the upper limit of cerebral blood flow (CBF) autoregulation was studied in normotensive Wistar-Kyoto rats (WKY) and in spontaneously hypertensive rats (SHR) following intravenous administration of the angiotensin converting enzyme inhibitor captopril (10 mg/kg). CBF was measured using the intracarotid 133Xe injection method in halothane/nitrous oxide anaesthetized WKY and SHR. Arterial blood pressure was raised stepwise by the intravenous infusion of noradrenaline. Toward the end of the study, Evans blue was injected and the brains examined for gross blood-brain barrier breakdown. In SHR, sympathetic stimulation reextended the upper limit of CBF autoregulation, which was at a mean arterial blood pressure level of 120-139 mm Hg in the control group of eight SHR and above 170 mm Hg in the stimulated group of nine SHR. In the group of nine WKY subjected to sympathetic stimulation, the upper limit of CBF autoregulation was reached at a mean arterial blood pressure level of 110-129 mm Hg as opposed to 90-109 mm Hg in a previous unstimulated group of WKY. In the two groups subjected to sympathetic stimulation, there was no extravasation of Evans blue in any of the brains. In the control group of SHR, in which there had been marked increases in CBF, three out of eight brains had foci with extravasation of the dye. It is concluded that in normotensive and in hypertensive rats sympathetic stimulation attenuates the downward shift of the upper limit of CBF autoregulation, which is known to accompany intravenous administration of captopril.

Cerebrovascular aspects of antihypertensive treatment.

Although the treatment of hypertension clearly benefits the brain in most patients, there are, however, unfortunate exceptions. Overzealous blood pressure lowering especially, and sometimes conservative blood pressure lowering, occasionally compromise the supply of blood to the brain to such an extent that neurological dysfunction or death results. Despite an awareness of this problem for more than a decade, the number of reports of such cases is increasing. An understanding of the problem requires detailed knowledge of both the pathophysiology of the cerebral circulation in hypertension and the cerebrovascular effects of antihypertensive drugs. If antihypertensive treatment, in particular emergency blood pressure lowering, is to always be safe, thought must be given to the cerebrovascular effects of the drugs to be used. This topic is discussed in relation to the observed (i.e., experimentally determined) and inferred (i.e., from clinical observation) effects of antihypertensive drugs and treatment on the cerebral circulation, especially with regard to autoregulation of cerebral blood flow.

Myo-inositol normalizes decreased sodium permeability of the blood-brain barrier in streptozotocin diabetes.

The effect of a dietary supplement of an aldose reductase inhibitor (ponalrestat) or of myo-inositol on sodium transport into the rat brain and on concentrations of saccharide and polyols in cortical brain tissue and sciatic nerve was investigated in control rats and in streptozotocin-diabetic rats after a diabetes duration of 2 weeks. In untreated diabetes, the neocortical blood-brain barrier permeability for sodium decreased by 28% (3.4 +/- 0.4 vs 4.7 +/- 1.6 x 10(-5) ml/s g, mean +/- SD) as compared to controls. Levels of glucose, sorbitol and fructose increased in brain as well as in nerve tissues, whereas myo-inositol depletion was not demonstrable. Ponalrestat treatment of diabetic animals had no effect upon the decreased neocortical blood-brain barrier permeability to sodium (3.5 +/- 0.9 vs 4.7 +/- 1.1 x 10(-5) ml/s g) despite normalization of brain and nerve content of sorbitol and fructose. Myo-inositol supplementation of diabetic rats normalized sodium passage into the brain (4.2 +/- 1.1 vs 4.4 +/- 0.5 x 10(-5) ml/s g). Brain concentrations of monosaccharides and polyols were normalized as compared to the myo-inositol treated control group and nerve concentrations of glucose, sorbitol, and fructose were significantly increased. Myo-inositol treatment leads to a normalization of blood-brain barrier permeability; it is suggested that myo-inositol exerts a restituting effect upon Na+/K+-ATPase activity of the cerebral endothelial cells.

Extraction of [99mTc]-d,l-HM-PAO across the blood-brain barrier.

The initial extraction (E) across the blood-brain barrier (BBB) of [99mTc]-d,l-HM-PAO after intracarotid injection was measured in 14 Wistar rats and 6 patients using the double indicator, single injection method with Na-24 as the cotracer. In both series, cerebral blood flow (CBF) was measured using the initial slope of the xenon-133 washout curve after intracarotid bolus injection. In rats, bolus size (20 or 120 microliters), bolus type (saline or 10% albumin), or CBF were changed. First-pass extraction was dependent on CBF (p less than 0.001): With a small bolus of saline and at resting CBF (0.75 ml/g/min), E was 0.81, decreasing to 0.56 at a high CBF (1.5 ml/g/min). The calculated permeability surface area product (PS) increased linearly from 1.2 to 1.5 ml/g/min when CBF increased from 0.8 to 1.5 ml/g/min (p less than 0.01). E was found to increase when the bolus volume of saline was increased from 20 to 120 microliters, while using a 120 microliters bolus containing 10% albumin resulted in a decrease in E. This suggests that HM-PAO binding to albumin is not totally and rapidly reversible during a single passage through brain capillaries and that binding to blood elements may reduce the apparent extraction across brain capillaries. In patients using a bolus of 1 ml saline, E decreased linearly with increasing CBF (r = -0.81, p less than 0.001). For a CBF of 0.59 ml/g/min and an average apparent E of 0.72, an apparent PS product of 0.76 ml/g/min was calculated.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of angiotensin in autoregulation of cerebral blood flow.

The presence of the renin-angiotensin system (RAS) in extrarenal tissues, namely the vascular wall and brain tissue, is well established. The availability of effective blocking agents, converting-enzyme inhibitors, has made it possible to further elucidate important functions of the extrarenal RAS. We have found that the angiotensin converting-enzyme inhibitor captopril shifts the limits of cerebral blood flow autoregulation to lower blood pressure levels in normotensive and in spontaneously hypertensive rats. This effect may explain our finding of a remarkable preservation of cerebral blood flow, despite significant blood pressure reduction, in patients with chronic heart failure. We suggest that the effect of angiotensin converting-enzyme inhibition on autoregulation of cerebral blood flow is mediated by a dilatation of larger cerebral arteries, which results from inhibition of the vascular tone normally maintained by locally produced angiotensin II.

Grafted noradrenergic neurons suppress seizure development in kindling-induced epilepsy.

Norepinephrine-rich cell suspensions, prepared from the locus coeruleus region of rat fetuses, were grafted bilaterally into the hippocampus of rats made hypersensitive to hippocampal kindling by a neurotoxic lesion of the central catecholamine system. The animals with grafts showed a marked suppression of the onset and progression of kindling-induced epilepsy, and this effect was correlated with the degree of graft-derived noradrenergic innervation of the host hippocampal formation. We conclude that grafted neurons can modulate the excitability of epileptic brain regions.

Brain marker protein changes after short- and long-term ethanol intoxication and withdrawal in the rat.

The brain marker proteins, D1, D2, and D3, localised to neuronal membranes, and mitochondrial and cytoplasmic marker proteins (MM and CM), were studied during 1-6 days (short term) intragastrically-induced severe ethanol intoxication and during 1 month (long-term) ethanol intoxication established by a liquid diet regimen. The concentrations of the same brain proteins were also measured during withdrawal from the ethanol intoxication periods. Three categories of effect were encountered: decreased concentration of brain marker proteins during severe short-term intoxication the effect being most marked for D3, possibly indicating degradation of mature synapses; increased concentration of proteins D2 and MM during withdrawal, the D2 changes possibly indicating formation of new synapses; increased concentration of D1 protein and MM during long-term intoxication. We suggest that the changes in brain marker proteins reflect dynamic changes of subcellular neuronal structures which may form a part of the basis of functional tolerance to and physical dependence upon ethanol or the reversion of these states after withdrawal of ethanol.

Cerebral blood flow during early cardiopulmonary bypass in man. Effect of procaine in cardioplegic solutions.

Cerebral blood flow (CBF), plasma procaine concentrations, and somatosensory evoked potentials (SSEP) were recorded in 2 groups of patients in whom either a high-procaine cardioplegic solution (Bretschneider's n = 29), or a low-procaine cardioplegic solution (St. Thomas', n = 13) was used. In the Bretschneider's group, marked changes in CBF occurred (p less than 0.001). Mean CBF was 27 (range 18 to 51) ml/(100 g X min) between sternotomy and the onset of extracorporeal circulation (ECC). A mean of 6 minutes after the onset of ECC, and before the administration of Bretschneider's cardioplegic solution, CBF increased to 39 ml/(100 g X min). After administration of the cardioplegic solution, CBF decreased significantly within the first 15 minutes, and then gradually increased to a mean of 68 (range 43 to 108) ml/(100 g X min). Cerebral blood flow was 45 ml/(100 g X min) just after ECC was stopped. Marked plasma procaine concentrations, up to 100 mg/l, were reached just after the infusion of Bretschneider's solution. The flow was significantly reduced (p less than 0.015) in patients with plasma procaine greater than or equal to 10 mg/l, when compared to patients with plasma procaine values less than 10 mg/l. In the St. Thomas' cardioplegic solution group the same reduction in CBF did not occur (p less than 0.02). Despite the depressant effect of procaine on CBF in the Bretschneider group, a consistent brain hyperperfusion was observed in all patients during hypothermic ECC if their blood pressure was sufficient to produce hyperemia. In rats (n = 6), during normothermia without extracorporeal circulation, the effect of procaine was much more pronounced. The CBF fell from a mean resting level of 108 ml/(100 g X min) to 68 and 54 ml/(100 g X min) after 15 and 35 minutes, respectively, of continuous infusion of Bretschneider's solution. The flow returned to the resting level about 40 minutes after termination of the infusion.

The distribution of immunoglobulins and albumin in the central nervous system in acute experimental allergic encephalomyelitis.

Experimental allergic encephalomyelitis (EAE) was induced in young male Lewis rats. Immunohistochemical visualisation of albumin and IgG in the nervous tissue was performed at intervals after induction. The results were correlated to the histological appearance of the tissue. Albumin appeared in the tissue about day 10, 1-2 days before IgG. Within one day both proteins spread from sharply defined perivascular subpial locations to diffuse distribution throughout the tissue. Cellular inflammation was not seen until 3-4 days after extravasation of proteins. The cells also spread from perivascular locations to a diffuse infiltration of the tissue.

Cerebral blood flow in hypertension.

The most important aspect of cerebral blood flow (CBF) in hypertension is the change that occurs in CBF autoregulation: increased cerebrovascular resistance causes the lower and upper limits of CBF autoregulation to be at higher pressure levels. The mechanism seems to be mainly structural thickening and luminal narrowing of cerebral resistance vessels. These adaptive changes, while protecting the brain against high intravascular pressure, render the brain more susceptible to ischemia at low blood pressure. An obvious consequence of the shift in the lower limit of CBF autoregulation in hypertension is that if the hypertensive patient's blood pressure is lowered acutely to "normal" levels, the pressure is below the patient's lower limit of autoregulation and ischemic damage may result. Basically, antihypertensive drugs can be placed into four groups as regards their effects on the cerebral circulation. First are the drugs without any direct effect: in this case, CBF remains constant until pressure reaches the lower limit of autoregulation and then decreases with any further pressure decrease. Diazoxide is in this category. Second are the drugs that directly dilate the small resistance levels in such a way that CBF is higher than normal at every pressure including pressures below the lower limit of autoregulation. However, perfusion may be uneven and autoregulation may be lost; an example of this kind of drug is dihydralazine. Third are the drugs which by alpha-or ganglion-blockade prevent the sympathetic vasoconstriction of large cerebral arteries (pial and larger), which can compromise CBF during a fall in blood pressure and hence shift the lower limit of autoregulation to a higher pressure than during blockade.(ABSTRACT TRUNCATED AT 250 WORDS)