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Nerve growth factor infusions combined with fetal hippocampal grafts enhance reconstruction of the lesioned septohippocampal projection.

A combination of intracerebral grafting and intraventricular infusion of nerve growth factor was used to attempt to reconstruct the cholinergic component of the septohippocampal pathway following fimbria-fornix lesions in the rat. Four groups were tested: lesion only, lesion plus fetal hippocampal graft, lesion plus nerve growth factor, and lesion plus graft plus nerve growth factor. Choline acetyltransferase immunoreactivity, acetylcholinesterase fiber staining and behavior-dependent theta activity on electroencephalogram were used to assess the extent of pathway reconstruction. Nerve growth factor was infused for the first two weeks following the fimbria-fornix lesion, while electrophysiological measurements and histological analysis were conducted six to eight months later. The lesion plus graft plus nerve growth factor infusion group had long-term savings of choline acetyltransferase-immunoreactive cells as compared to the lesion only or lesion plus graft groups. In addition the lesion plus graft plus nerve growth factor infusion group had more extensive reinnervation of the hippocampus compared to all other groups. Behavioral-dependent theta activity on electroencephalogram was observed in some animals of both lesion plus graft and lesion plus graft plus nerve growth factor infusion groups, but not in other groups; however, unlike intact animals, the restored theta could be blocked completely by scopalamine. These results demonstrate that a combination of short-term intraventricular nerve growth factor infusion and fetal hippocampal grafts enhances reconstruction of the damaged septohippocampal circuit.

Animals↗

Dopamine distribution and behavioral alterations resulting from dopamine infusion into the brain of the lesioned rat.

In an effort to verify the "dopamine secretion hypothesis" as the mechanism responsible for the antiparkinsonian efficacy of adrenal medullary transplants into the brain, the effects of dopamine infusion into the brains of rats with unilateral substantia nigra lesions were examined. The apomorphine-induced rotation, characteristic of this animal model, was diminished after 7 days of continuous dopamine infusion (10 micrograms/hr) into the ipsilateral striatum, whereas intraventricular infusion was without effect. Chromatographic analysis of the dopamine distribution after 10 days of infusion into either region revealed that ipsilateral delivery of dopamine did not result in contralateral increases in dopamine content. Examination of the adjacent striatum following ipsilateral intraventricular delivery indicated that dopamine had only penetrated 1 mm. Even with intrastriatal delivery, there were still parts of the infused striatum which had below-normal levels of dopamine. The fact that striatal tissue presents a significant barrier to the penetration of dopamine is discussed in relation to adrenal medullary and fetal nigral transplants.

Adrenal Medulla↗

Unsuccessful intraventricular pentosan polysulphate treatment of variant Creutzfeldt-Jakob disease.

Pentosan polysulphate, delivered by chronic intraventricular infusion, has been proposed as a potential therapy for human prion disease. The first treated patient is still alive several years after treatment started. Here we describe in detail a case of variant Creutzfeldt-Jakob disease in which this treatment was started at a relatively early stage but had no definite clinical benefit. The patient died from disease progression 16 months after diagnosis and 5 months after pentosan polysulphate treatment was commenced.

Adult↗

Intraventricular CCK inhibits food intake and gastric emptying in baboons.

To evaluate the role of cholecystokinin (CCK) as a physiological regulator of meal size and gastric emptying in the baboon, we measured plasma CCK bioactivity during 30-min meals alone and after intravenous or intraventricular infusions of CCK COOH-terminal octapeptide (CCK-8). Both intravenous (2 micrograms/kg) and intraventricular (1 microgram/kg) CCK-8 administration resulted in plasma CCK elevations comparable with normal prandial CCK levels: peak plasma levels were 4.1 +/- 0.9, 7.1 +/- 1.1, and 4.9 +/- 2.2 pM for pooled intravenous and intraventricular control, intravenous, and intraventricular conditions. Also, both treatments appeared to reduce gastric emptying as indicated by a significant suppression of postprandial plasma insulin and glucose levels. However, only intraventricular CCK reliably reduced meal size (percent of control meal size was 91 +/- 5% or 43 +/- 19% with intravenous or intraventricular CCK). We conclude that circulating endogenous CCK is a potent postprandial endocrine regulator of gastric emptying. However, the ability of CCK to decrease meal size may require direct interaction with the central nervous system.

Animals↗

Intraventricular ethanol and ethanol intake: a behavioral and radiographic study.

Ethanol (10% w/v) was infused intraventricularly at a rate of 11 mul/hr, delivered over 50 sec every 10 min for 10 days into 5 Sprague-Dawley and 5 Wistar rats. Thereafter, preference testing with ascending concentrations of alcohol solutions vs . water vs. food gave no significant differences between treated and sham-operated controls, in contradiction to previously reported increases in alcohol consumption. Ethanol's rate of elimination from the ventricle and its pattern of diffusion into the brain were determined using radioactive ethanol: elimination from the brain is rapid with a half-like of 24 to 35 sec, and the amount diffused throughtout the brain small, with a maximal concentration in any one section of 0.004% (such a concentration is at least 20 times less than would result from a moderately intoxicating parenteral dose of ethanol). The character of the elimination and the lack of effect on alcohol intake found here indicate that intraventricularly administered ethanol is a technique with no usefulness in elucidating the processes affecting alcohol addiction.

Alcohol Drinking↗

Factors in cerebrospinal fluid from goats that affect sleep and activity in rats.

1. Intraventricular infusion in the rat of 0.1 ml. cerebrospinal fluid (c.s.f.) from sleep-deprived goats increases the duration of sleep (measured by e.e.g.) and decreases locomotor activity (measured photo-electrically) for at least 6 hr subsequent to the infusion. Subarachnoid infusions are ineffective.2. C.s.f. from control and sleep-deprived goats was fractionated by ultrafiltration through molecular sieves. The sleep-promoting Factor S is found in the low molecular weight fraction (mol. wt. < 500) of c.s.f. from sleep-deprived but not from control goats.3. The concentration of Factor S in c.s.f. increases progressively during the first 48 hr of sleep deprivation.4. The sleep promoting effects of Factor S cannot be duplicated by serotonin, 4-OH-butyrate, butyrolactone, GABA (gamma-amino butyric acid), glutamic acid or 3',5'-cyclic AMP when these substances are added to control fluids in concentrations up to 10 times greater than those found in normal c.s.f.5. Intraventricular or subarchnoid infusion in the rat of 0.1 ml. proteinfree c.s.f. containing molecules in the mol. wt. range of 500-10,000 at 10-30 x normal concentration causes hyperactivity which persists for several days and nights following the infusion. The excitatory material, probably a peptide, is present in c.s.f. from both control and sleep-deprived goats.6. The properties of Factor S suggest that it may play a role in the normal regulation of sleep and wakefulness.

Aminobutyrates↗

Fibrinolytic agents in the treatment of intraventricular hemorrhage in adults

This paper aims to review current literature on the treatment of acute intraventricular hemorrhage in adults with intraventricular infusion of fibrinolytic agents. A literature search on the topics of "intraventricular hemorrhage" or "intracerebral hemorrhage" with "thrombolytic therapy", "fibrinolytic therapy", "urokinase", "streptokinase", "tissue plasminogen activator" or "tPA" covering the years 1966-1997 was carried out electronically. This was supplemented by searching the reference lists of the identified articles. Articles regarding exclusively intracerebral hemorrhage or hematoma, neonatal intraventricular hemorrhage, non-therapeutic issues, and laboratory research were excluded. The included articles are summarized in evidence and evaluation tables. Six articles evaluating the treatment of intraventricular hemorrhage in adults with intraventricular fibrinolytic agents were identified. One reports a small randomized clinical trial including 16 patients and appears to show a statistically insignificant preference for urokinase treatment. Five other reports present case series for which a total of 58 patients were exposed to either streptokinase, urokinase, or recombinant tissue plasminogen activator (rt-PA) and suggest good outcome. Two of them were with non-randomized retrospective or prospective controls, and three have no controls. Despite important limitations, all reports suggest that blood is more rapidly cleared from the ventricles and outcome is better when administering a fibrinolytic agent intraventricularly. While the experience presented in these papers suggests that intraventricular administration of fibrinolytic agents may be associated with fewer complications, more rapid clearing of blood from the ventricles, less late hydrocephalus, and better long-term outcome than is seen in patients treated with ventricular drainage alone, it is insufficient to recommend such treatment as a matter of policy. Substantial methodologic flaws render these findings suggestive at best. If the suggestive findings of these studies were confirmed in well-designed randomized clinical trials, an important impact on clinical practice could be expected.

Journal Article↗

Intraventricular but not intraparaventricular nucleus metergoline elicits feeding in satiated rats.

Previous research has shown that systemic injections of the nonselective serotonin (5-HT) antagonist metergoline (MET) can stimulate feeding in both rats and humans. Five experiments were conducted to determine if this drug would elicit feeding in otherwise satiated rats after direct injections into the brain. In experiment 1, intraventricular infusions of 100 nmol MET produced reliable enhancements of feeding for 1 h compared with control infusions of a 5% tartaric acid (vehicle) solution. In experiment 2, a dose-response study of 0, 50, 100, and 150 nmol MET intraventricularly revealed that both 100 and 150 nmol doses reliably enhanced 1-h feeding, whereas 50 nmol did not. In experiment 3, tests of 90-min locomotor activity and water intake in the absence of food revealed that 100 nmol MET intraventricularly did not modify either behavior compared with vehicle infusions, suggesting a degree of feeding specificity to this effect. In an attempt to determine the site of intraventricular MET effects on feeding, experiment 4 tested 1-h feeding responses after 0, 5, 10, 20, 40, or 60 nmol MET were infused unilaterally into the paraventricular nucleus (PVN) of the hypothalamus. No reliable feeding was induced at any of these drug doses, although injections of 30 nmol norepinephrine (NE) were effective in doubling food intake. Experiment 5 further showed that bilateral infusions of 50 nmol MET in each PVN (total dose, 100 nmol) were ineffective in altering 1-h feeding. This contrasted markedly to the high potency of 15 nmol NE per site (total dose, 30 nmol), which elicited fivefold greater feeding than control infusions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Effect of inhibition of central angiotensin pressor mechanisms on blood pressure in spontaneously hypertensive rats.

The present experiments were designed to elucidate the role of central angiotensin II (AII) mechanisms in maintenance of established hypertension in adult spontaneously hypertensive rats (SHR) by determining the blood pressure response to chronic intraventricular (i.v.t.) infusion of the converting enzyme inhibitor teprotide or the AII receptor antagonist 1sar,8Thr-AII (sarthran). Male SHR (240-300 g) were given chronic indwelling arterial and venous catheters and bilateral lateral cerebral ventricular cannulae. The acute pressor responses to successive intravenous infusions of AII (sarthran experiments) or angiotensin I (AI; teprotide experiments) and to an intraventricular bolus injection of AII or AI were determined in the conscious rats. A 5-day intraventricular infusion of sarthran (1 or 6 micrograms/h) or teprotide (10 micrograms/h) in isotonic saline was maintained by subcutaneously implanted osmotic minipumps, and pressor responses were retested on the 5th day of intraventricular infusion. Five-day intraventricular sarthran infusion at 1 and 6 micrograms/h reduced the pressor response to intraventricular AII by 48 and 74%, respectively, while intraventricular teprotide (10 micrograms/h) inhibited the pressor response to intraventricular AI by 25%. None of the intraventricular infusions significantly decreased pressor responsiveness to intravenous AII or AI. In separate groups of SHR, tail-cuff blood pressure was monitored before, during, and after a 1-week intraventricular teprotide infusion (10 micrograms/h) or successive intraventricular infusions of sarthran at 1 microgram/h for 2 weeks followed by 6 micrograms/h for 1 week. Neither chronic intraventricular sarthran or teprotide caused a significant lowering of blood pressure in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

Effects of Limbic stimulation and the microinontophoresis of aminergic drugs on the single unit activity of hypothalamic neurosecretory cells (author's transl).

Attempts were made to investigate the chemical nature of hypothalamic afferents from the extrahypothalamic structures which participate in the control of hypothalamic neurosecretory cells. Experimental procedures were discribed in the preceding report, except that of the electrical stimulation and the microinontophoresis. Some part of data obtained in this study were referred in the preceding report for improvement of statistic reliability. For electrical stimulation, side-by-side bipolar electrodes were placed in the medial preoptic area (MPO), medial amygdala (mAMYG) and dorsal hippocampus (dHPC) from the parietal surface of the brain and fastened to the cranium by dental resin. Microintophoresis of norepinephrine (NE), dopamine (DA) and acetylcholine (Ach) was carried out by using five-barrelled glass pipette on the antidromically activated units in the medical basal hypothalamus by the median eminence stimulation. Extracellular potentials were recorded by the central barrel of each electrode. One of the outer barrels was filled with physiological saline and used for control purpose. (1) Eelctrical stimulation of the MPO with train pulses of 0.2 msec duration and 300 muA intensity in 100 HZ for 5 sec, induced facilitation and inhibition in 26.4% and 9.4% of 106 tests, respectively. By the mAMYG stimulation with 500 muA, facilitation was seen in 18.8% and inhibition in 10.4%, of 96 tests. The HPC stimulation induced facilitation in 10.0% and inhibition in 23.3% of 90 tests. (2) Facilitatory effect of the MPO was most frequently seen in the ovariectomized and estrogen primed rats (58.8% of the tests). In contrast, the inhibitory effect of the dHPC was striking in the diestrus-I (40.0%). (3) Microiontophoresis of NE induced facilitation in 60.0% and inhibition in 10.6% of 66 identified cells. DA induced facilitation in 45%, and inhibition in 11.7% of 60 tests. Ach induced facilitation in 41.4%, and inhibition in 13.8% of 58 tests. (4) By NE infusion, facilitation was most commonly seen in the proestrus (70.6%). Inhibition was most readily elicited by Ach infusion on the diestrus-I (30%). Facilitative effect of DA was eminent in the diestrus-I (81.8%). (5) Successive administration of NE and DA on identical units revealed that in 56.0%, the units were responsive to only one agent and the other was effectless. 25.5% of the units responded to both of NE and DA. (6) The conceidence of effects, either facilitation or inhibition, between that of electrical stimulation of the microinontophoresis, was calculated on 46 units. The facilitatory effect of the MPO was most commonly mimicked by NE infusion (81.8%), and the inhibitory effect of the dHPC by Ach infusion (46.7%). NE also mimicked facilitatory effect of mAMYG stimulation (73.3%). (7) Intraventricular infusion of 20 mug of NE induced significant increase of serum LH (p less than 0.05 to saline) when measured by radioimmunoassay, whereas DA resulted in a decrease of LH (p less than 0.01).

Acetylcholine↗

Selective effects of nerve growth factor on spatial recent memory as assessed by a delayed nonmatching-to-position task in the water maze.

Nerve growth factor (NGF) ameliorates age-related deficits in certain types of memory in rats. Although the effects of NGF on reference memory are well documented, the influence of NGF on recent memory is less well understood. The issue of recent memory is of primary importance in the design of therapies for cognitive disorders, because this type of memory is impaired in elderly humans and is severely affected early in the course of Alzheimer's disease (AD). The present study was designed to evaluate the efforts of NGF on recent memory in a task that used escape from water as the motivating stimulus and used the same design as forced-choice recognition tasks given to humans. Fischer-344 rats, 4 months old (4MO) or 23 months old (23MO), were pretested in a new spatial recent memory task designed for the Morris water maze, a delayed nonmatching-to-position task, and infused intraventricularly with recombinant human NGF or vehicle. After 2 weeks of NGF infusion, no substantial changes in behavior were observed in either age group. However, NGF treatment extended over 4 weeks improved considerably the choice accuracy of 23MO rats to a level similar to the performance of 4MO rats. These results, together with our previous work (Markowska et al., 1994), indicate that the effects of NGF on spatial recent memory are more intense than on spatial reference memory. NGF suppressed the body weight gain in 4MO rats but did not affect 23MO rats. In 23MO rats, NGF mildly counteracted age-related deficits in inhibitory avoidance, but did not have an effect in young rats.

Aging↗

Effects of central norepinephrine depletion on the initiation and maintenance of maternal behavior in the rat.

The catecholaminergic neurotoxin, 6-hydroxydopamine (6-OHDA), was used to test the hypothesis that increased transmission across selected noradrenergic synapses is involved in the initiation of maternal behavior. Specifically, 6-OHDA was infused intraventricularly either two days before parturition or four days after parturition. Control animals were infused with the vehicle alone. Among prepartum animals, NE depletion of more than 30% of control levels interfered with the initiation of maternal behavior. Among lactating animals, similar degrees of NE depletion had no significant effect on the maintenance of maternal behavior. Thus, NE appears to be involved in the initiation of maternal behavior, but not in the maintenance of the behavior once that behavior is established.

Animals↗

Little sleep-promoting effect of three sleep substances diurnally infused in unrestrained rats.

Delta-sleep-inducing peptide (2.5 nmol), prostaglandin D2 (0.36 nmol) and uridine (10 pmol) were intraventricularly infused for 10 h at daytime in otherwise saline-infused freely moving male rats. In contrast to a nocturnal infusion which may result in marked sleep-promoting effects, such a diurnal infusion brought about almost no change in sleep parameters. It is postulated that the requirement of sleep in rats might be fully achieved at the environmental light period to cancel the effect of the exogenously administered sleep substances. It is proposed that an endogenous sleep substance should be characterized by a property not to cause excessive sleep at the time when sleep is physiologically saturated.

Animals↗

Morphological changes following experimental intraventricular haemorrhage and intraventricular fibrinolytic treatment with recombinant tissue plasminogen activator.

Intraventricular haemorrhage (IVH) occurs in up to 50% of patients with primary intracerebral haemorrhage and aneurysmal subarachnoid haemorrhage. It is a significant and independent contributor to mortality and morbidity in these intracranial haemorrhages. Using a model of isolated IVH, we assessed the morphological changes induced by intraventricular bleeding and investigated the effects of intraventricular fibrinolytic treatment following IVH. IVH was induced in 32 pigs by intraventricular infusion of 10 ml autologous blood along with thrombin. The treatment group received an intraventricular injection of 1.5 mg (1 mg/ml) tissue plasminogen activator (tPA) following the injection of blood. The placebo group received the same volume of normal saline. Morphological examinations of the brains were carried out 7 days and 6 weeks following IVH. The ventricles were incompletely filled with blood and significantly enlarged in the placebo group 7 days after the IVH. In contrast, no residual intraventricular clots were visible in the animals treated with tPA, and the diameters of the lateral ventricles had returned to normal within 7 days. Marked losses of the ependymal covering of the ventricular walls were found in the placebo-treated animals, while the ependymal layer was largely intact in the animals treated with tPA. No haemorrhages induced by tPA were observed. The results indicate that intraventricularly administered tPA significantly enhances the lysis of intraventricular blood clots, accelerates the resolution of acute posthaemorrhagic hydrocephalus, and preserves the integrity of the ependymal layer.

Animals↗

The effects of nerve growth factor on spatial recent memory in aged rats persist after discontinuation of treatment.

Nerve growth factor (NGF) infusion significantly reduces spatial recent memory deficits in aged rats, an effect that has great relevance to the treatment of memory impairments characteristic of patients with Alzheimer's disease. The present study was designed to examine whether this NGF-induced improvement in spatial recent memory persists after the discontinuation of NGF treatment, an issue of crucial importance for the potential clinical use of this compound. Spatial recent memory was tested in a Morris water maze delayed nonmatch-to-position task. In addition to memory, sensorimotor skills were also examined. Four- and 22-month-old rats were tested preoperatively, infused intraventricularly with recombinant human NGF or vehicle, and tested both during the 4 week infusion period and during the 4 weeks after discontinuation of the infusion. NGF significantly improved spatial recent memory in 22-month-old rats only, during the 4th week of infusion and for up to 4 weeks after discontinuation of the infusion. Although NGF did not affect overall sensorimotor skills during infusion in either age group, sensorimotor skills were significantly improved both 2 and 4 weeks after discontinuation of infusion in 22-month-old rats. These findings demonstrate that the beneficial effects of NGF on spatial recent memory can persist for up to 1 month after discontinuation of infusion and suggest that NGF can be used intermittently for the treatment of age-associated memory dysfunction and Alzheimer's disease.

Aging↗

Drinking and natriuresis during volume expansion and intracranial angiotensin or carbachol.

Two methods of sodium loading were used to counteract the body fluid dilution resulting from natriuresis and water drinking during sustained lateral ventricular infusions of carbachol (CBC) or angiotensin II (ANG II) in rats. It was expected that preventing dilution would also prevent the precipitous decline of both drinking and natriuresis during the later hours of CBC infusion. In the first study, rats having isotonic saline as the sole drinking fluid during CBC infusions drank less fluid and had only slightly higher plasma osmolality and sodium concentration than rats drinking water, which showed extreme dilution. In the second study, rats with only water to drink were given intravenous infusions of 0.15, 0.45, or 1.00 M NaCl solutions at 1.8 ml/h concurrently with the intraventricular infusions. Significant dilution of plasma was found at the two lower rates but not at 1.00 M NaCl in CBC-infused rats. Only the latter group showed both persistent drinking and natriuresis throughout the 4-h infusion period, and this was not because of elevated plasma osmolality. Infusions of ANG II generated less severe body fluid dilution and more persistent drinking in both experiments. The study demonstrates that body fluid dilution may control the offset of both drinking and natriuresis during sustained infusions of CBC and that the more persistent drinking to ANG II vs. CBC probably occurs because of a lesser natriuresis and consequent fluid dilution.

Administration, Oral↗

An intracerebral, physiological role for angiotensin: effects of central blockade.

Although exogenous angiotensin II (AII) exerts a multitude of effects on the central nervous system, there is little evidence supporting a physiological role for the endogenously produced peptide. Some investigators have tested the hypothesis that AII is physiologically active in the brain with intracerebral infusions of blockers of the renin-angiotensin system. If blocker infusions produce effects that are opposite to exogenous AII infusions, it is evidence supporting a physiological role for endogenously generated angiotensin. Previous work has demonstrated that intraventricular infusion of AII elicits thirst and stimulates antidiuretic hormone and ACTH release. Intracerebral administration of AII also suppresses aldosterone secretion. Experiments that employed the blockers saralasin, a competitive inhibitor of AII, and SQ 20881, a converting enzyme blocker, are presented; results suggest that endogenous AII is involved in the control of thirst and peripheral hormone levels. Infusion of the blockers in the ventricular system led to changes in peripheral hormone concentrations opposite to that observed following infusions of AII.

Adrenocorticotropic Hormone↗

Effects of chronic beta-amyloid treatment on fatty acid incorporation into rat brain.

The present study evaluated the effects of chronic A beta administration on radio-labeled plasma fatty acid incorporation in rat brain. A beta was chronically infused intraventricularly via an osmotic minipump, for 1 week, at a concentration of 460 microM. After the infusion, fatty acid incorporation was quantified using an in vivo method developed in this laboratory. Three radiolabeled fatty acids were separately infused IV in awake animals. Biochemical analyses of fatty acid incorporation and histology for A beta showed no differences between control (vehicle infusion only) and experimental groups. However, in vitro tests on the cytotoxicity of A beta showed that it caused significant cell death relative to controls (PC-12 cells). The lack of effect of infused A beta on radiolabeled fatty acid incorporation is discussed.

Amyloid beta-Peptides↗