Evidence for involvement of prostaglandins in central alpha adrenergic activity and LH release in sheep

Circhoral pulsatile release of immunoreactive luteinising hormone (LH) and prostaglandin F2 alpha (PGF2 alpha) occur synchronously into the jugular vein in ovariectomised sheep. Following a 4-hour control period, intra-carotid injections of phentolamine or intramuscular injections of phenoxybenzamine were given to ovariectomised sheep and the pulsatile release of LH and PGF2 alpha was monitored for a further 6 to 8 hours. Phenoxybenzamine caused a fall in LH and PGF2 alpha in jugular venous plasma. Phentolamine also reduced LH significantly but in this case a marked rise in PGF2 alpha as measured by radioimmunoassay (RIA) occurred after very high doses of phentolamine. Interpretation of the latter results was complicated by the fact that phentolamine at high dose levels interfered with the RIA of PGF2 alpha in plasma. Experiments were repeated in ovariectomised sheep with cannulae placed in the lateral ventricles of the brain for sampling cerebrospinal fluid (CSF). In contrast to the previously observed rise in jugular venous PGF2 alpha following high doses of phentolamine, a fall in CSF levels of immunoreactive PGF2 alpha occurred following intracarotid phentolamine or phenoxybenzamine in 3 out of 7 experiments, while no change was observed in the remaining 4 animals. Phentolamine did not reduce LH significantly in animals with intraventricular cannulae. The work provides support for the view that circhoral pulses of immunoreactive PGF2 alpha in sheep are neural in origin and may be related to sympathetic neurotransmission.     

The relationship between blood and cerebrospinal fluid prolactin in nonhuman primates

We studied the relationship between plasma and cerebrospinal fluid (CSF) concentrations of prolactin (PRL) in repeated and simultaneous samples of blood and CSF from chair-restrained rhesus monkeys. Following administration of thyrotropin releasing hormone (TRH), each of 4 monkeys showed increased plasma and lumbar CSF PRL concentrations. Increases in CSF PRL concentrations were muted and delayed until 60 min after peak plasma concentrations were attained. In 3 other monkeys we compared PRL concentrations in simultaneous lateral ventricular and lumbar CSF samples. Although we found no difference in PRL concentrations under baseline conditions, a ventricular-lumbar PRL concentration gradient became apparent after TRH stimulation. These studies demonstrate that changes in plasma PRL concentrations are reflected in CSF concentrations. They suggest that a significant blood-CSF barrier exists for PRL and that PRL may enter the the CSF selectively via the ventricles.     

Comparative analysis of indices of central dopaminergic functions in man

Various postulated indices of central dopaminergic activity - cerebrospinal fluid (CSF) dopamine (DA), dihydroxy-phenylacetic acid (DOPAC), homovanillic acid (HVA), noradrenaline (NA), plasma NA, serum prolactin, serum dopamine-β-hydroxylase (DBH), and platelet monoamine oxidase (MAO) activity - were measured in 30 drug-free inpatients. The mean values and the ranges were similar to those described in the literature. Plasma NA showed significant positive correlation with age. Significant positive correlation was found between CSF DA and its metabolites DOPAC and HVA. Serum DBH activity showed a slight but significant inverse correlation with CSF DA and its two metabolites. CSF NA showed a significant positive correlation with CSF DOPAC, but only in females. Serum DBH activity had no significant correlation either with CSF or with plasma NA levels. These findings suggest that either CSF HVA or DOPAC and DA may be useful indicators of DA metabolism in humans. Serum DBH activity may be in relationship with the central dopaminergic functions.     

Differential penetration of three anterior pituitary peptide hormones into the cerebrospinal fluid of rhesus monkeys

This paper demonstrates marked differences between blood levels and those in the CSF for three anterior pituitary peptide hormones, prolactin, luteinizing hormone (LH) and adrenocorticotrophin (ACTH) in the rhesus monkey. CSF levels of endogenous prolactin (measured by radioimmunoassay) are about 20% of those in the blood, and this proportion remains constant under conditions of persistent ('steady-state') hyperprolactinaemia (induced by injecting sulpiride). Acutely elevating prulactin, by either an intravenous injection of exogenous ovine prolactin, or sulpiride, resulted in similar rates of entry by prolactin into the CSF, suggesting that retrograde portal flow is not an important mechanism. LH, measured by bioassay, is also present in the CSF, but the CSF/blood ratio is 5-10 times less than for prolactin. Castration, causing blood LH levels to rise, resulted in equivalent changes in CSF, so that the ratio remains constant, though still much lower than for prolactin. There are significant correlations between individual animals in the blood and CSF content of prolactin and LH. In marked contrast, whilst ACTH is found (by cytochemical assay) in the CSF of both intact and adrenalectomized monkeys, no significant change in CSF levels occurs despite 10-fold changes in the plasma of adrenalectomized animals following withdrawal of cortisol. Nor is there any correlation between blood and CSF ACTH levels over a wide range of concentrations. These results show that each of the three peptides studied has a distinct pattern of entry into the CSF from the vascular compartment.     

Homogeneous distribution of prolactin in human cerebrospinal fluid

Concentrations of prolactin were assayed from human cerebrospinal fluid (CSF). Samples were taken from lumbar CSF space (n=105 neurological patients) and from lateral ventricles (n=31 neurosurgical patients). Ventricular CSF samples were taken from operatively treated subarachnoidal hemorrhage (SAH) patients during the monitoring of intraventricular pressure. More voluminous and frequent sampling was obtained from six patients undergoing diagnostic pneumoencephalography (PEG) procedure. Prolactin concentrations in lumbar CSF ranged between undetectable and 2.8 ng/ml with a mean value of 0.78±0.54 (SD) ng/ml. Some fluctuation was seen in the fractionated samples taken at PEG, but no definitive gradient was noticed. Ventricular CSF concentrations of prolactin (n=18) were 0.85±0.67 (SD) ng/ml at operation (range : undetectable ? 2.5 ng/ml). Somewhat lower values were recorded in the 3-day postoperative period, prolactin mean concentrations being 0.3 ? 0.6 ng/ml. The CSF prolactin concentrations in the lateral ventricles and lumbar sac are practically identical with no concentration gradient between these compartments.     

Osmotic regulation of prolactin secretion in the fetal sheep

The functions of prolactin in the fetus remain speculative. No obvious physiological role has been found for the prolactin present in the fetal or maternal plasma and amniotic fluid compartments. The aim of the present study was to investigate changes in fetal plasma prolactin following intracerebroventricular (i.c.r.) administration to the fetus of artificial cerebrospinal fluid of different tonicities. A lateral ventricle catheter was placed in 11 fetuses at 107-128 days of gestation. Either isotonic artificial cerebrospinal fluid (300 mOsm.1(-1);n = 9), 15% polyethylene glycol (340 mOsm.1(-1);n = 5), or 7% distilled water in isotonic artificial cerebrospinal fluid (270 mOsm.1(-1);n = 9) was infused i.c.v. at 35 mu1.min-1 for 240 min. At 180 min thyrotropin releasing hormone (TRH) was administered through a fetal a fetal jugular catheter. Fetal carotid arterial blood gases, plasma osmolality and concentrations of prolactin, vasopressin (AVP), and norepinephrine (NE) were measured. Administration of hypotonic artificial cerebrospinal fluid produced an increase in fetal plasma prolactin from 46.6 +/- 36 ng.ml-1 at 0 min to 83.3 +/- 49 ng.ml-1 at 180 min (mean +/- SEM; P less than 0.05). No changes in either AVP or NE were observed. Administration of hypertonic artificial cerebrospinal fluid produced a decrease in plasma prolactin from 85 +/- 57 at time 0 to 49 +/- 35 at 180 min (P less than 0.05). No changes in either AVP or NE were observed. Fetal plasma prolactin, AVP, and NE did not change during control infusion of isotonic artificial cerebrospinal fluid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Integrated analysis of the cerebrospinal fluid peptidome and proteome

Cerebrospinal fluid (CSF) is the only body fluid in direct contact with the brain and thus is a potential source of biomarkers. Furthermore, CSF serves as a medium of endocrine signaling and contains a multitude of regulatory peptides. A combined study of the peptidome and proteome of CSF or any other body fluid has not been reported previously. We report confident identification in CSF of 563 peptide products derived from 91 precursor proteins as well as a high confidence CSF proteome of 798 proteins. For the CSF peptidome, we use high accuracy mass spectrometry (MS) for MS and MS/MS modes, allowing unambiguous identification of neuropeptides. Combination of the peptidome and proteome data suggests that enzymatic processing of membrane proteins causes release of their extracellular parts into CSF. The CSF proteome has only partial overlap with the plasma proteome, thus it is produced locally rather than deriving from plasma. Our work offers insights into CSF composition and origin.     

Carrier-Mediated Transport of Chloride Across the Blood-Brain Barrier

36Cl concentrations in each of eight brain regions and in cisternal cerebrospinal fluid (CSF) were determined 30 min after the intravenous injection of 36Cl in dialyzed-nephrectomized rats with plasma Cl concentrations between 14 and 120 mumol X ml-1. CSF 36Cl exceeded 36Cl concentrations in brain extracellular fluid. The calculated blood-to-brain transfer constants for Cl, kCl, ranged from 1.8 X 10(-5) S-1 at the parietal cortex to 3.8 X 10(-5) S-1 at the thalamus-hypothalamus. kCl fell by 42-62% when mean plasma [Cl] was elevated from 16 to 114 mumol X ml-1. Brain uptake of [14C]mannitol or of 22Na was independent of plasma [Cl], but 22Na influx into CSF fell when plasma [Cl] was reduced. Cl flux into brain and CSF could be represented by Michaelis-Menten saturation kinetics, where, for the parietal cortex, Km = 43 mumol X ml-1 and Vmax = 2.5 X 10(-3) mumol X S-1 X g-1, and for CSF Km = 68 mumol X ml-1. At least 80% of 36Cl influx into the parietal cortex was calculated to occur at the cerebrovascular endothelium, whereas the remainder was derived from tracer that first entered CSF. The CSF contribution was greater at brain regions adjacent to cerebral ventricles. The results show that Cl transport at the cerebrovascular endothelium as well as at the choroid plexus epithelium is a saturable concentration-dependent process, and that the CSF is a significant intermediate pathway for Cl passage from blood to brain.     

Transport of GABA at the Blood-CSF Interface

Abstract: The entry of GABA into cerebrospinal fluid (CSF) was studied in dogs anesthetized with pentobarbital and relaxed with suxamethonium. GABA was administered intravenously as a priming dose and subsequent maintenance infusion to compensate for the rapid elimination of the amino acid. Steady state concentrations of GABA in CSF were reached between 10 and 60 min after injection, the rate of entry tending to decrease with increasing plasma levels. During steady state conditions CSF concentrations showed great interin-dividual differences and varied between 0.03 and 5.1% of those in plasma. Probenecid and sodium valproate considerably enhanced the CSF/plasma concentration ratio of GABA. When GABA was directly injected into the liquor space, probenecid slowed down the elimination of GABA from CSF. The results suggest a transport of GABA into and out of CSF, the outward transport being inhibited by probenecid and sodium valproate.     

Stimulation of prolactin secretion by L-3,4-dihydroxyphenyl-serine (L-DOPS) via central norepinephrine in the rat

Intracerebroventricular (icv) injection of L-3,4-dihydroxyphenylserine (L-DOPS) (50 and 250 micrograms/rat) raised in a dose-related manner both plasma prolactin (PRL) and CSF norepinephrine (NE) in urethane-anesthetized male rats. Intravenous (iv) injection of larger doses of L-DOPS (5 and 10 mg/100 g BW) slightly but significantly increased plasma PRL and CSF NE. L-DOPS injection (50 micrograms/rat, icv or 5 mg/100 g BW, iv) also raised plasma PRL in conscious rats. There was a good correlation (r = 0.74) between CSF NE and peak plasma PRL in the anesthetized animals. Propranolol (100 micrograms/100 g BW, iv) inhibited plasma PRL responses to L-DOPS (50 micrograms/rat, icv) and NE injection (1 microgram/rat, icv) raised plasma PRL in anesthetized animals. These findings indicate that L-DOPS stimulates PRL secretion via central noradrenergic mechanisms in the rat.     

Effect of chronic maternal hyperkalaemia on plasma, cerebrospinal fluid and brain interstitial fluid potassium in developing rats

Plasma hyperkalaemia was induced in pregnant and lactating rats using a high potassium diet. Fetuses of high-K-diet mothers showed no increase in the potassium concentration [( K+]) of plasma, cerebrospinal fluid (CSF) and brain interstitial fluid, presumably due to placental control. Neonates from high-K-diet rats did show an increase in plasma [K+] but this increase was very small and there was no increase in CSF or interstitial fluid [K+]. Maternal milk [K+] was not affected by plasma hyperkalaemia. Weanling rats fed the high-K diet directly showed marked plasma hyperkalaemia but no increase in CSF or interstitial fluid [K+]. Thus, prior to weaning, a relatively stable plasma [K+] is maintained by maternal influence reducing the need for direct brain fluid K+ regulation.     

Peptides and proteins in plasma and cerebrospinal fluid as biomarkers for the prediction, diagnosis, and monitoring of therapeutic efficacy of Alzheimer's disease

Alzheimer's disease (AD) affects millions of persons worldwide. Earlier detection and/or diagnosis of AD would permit earlier intervention, which conceivably could delay progression of this dementing disorder. In order to accomplish this goal, reliable and specific biomarkers are needed. Biomarkers are multidimensional and have the potential to aid in various facets of AD such as diagnostic prediction, assessment of disease stage, discrimination from normally cognitive controls as well as other forms of dementia, and therapeutic efficacy of AD drugs. To date, biomarker research has focused on plasma and cerebrospinal fluid (CSF), two bodily fluids believed to contain the richest source of biomarkers for AD. CSF is the fluid surrounding the central nervous system (CNS), and is the most indicative obtainable fluid of brain pathology. Blood plasma contains proteins that affect brain processes from the periphery, as well as proteins/peptides exported from the brain; this fluid would be ideal for biomarker discovery due to the ease and non-invasive process of sample collection. However, it seems reasonable that biomarker discovery will result in combinations of CSF, plasma, and other fluids such as urine, to serve the aforementioned purposes. This review focuses on proteins and peptides identified from CSF, plasma, and urine that may serve as biomarkers in AD.     

Some basic chemical components of the cerebrospinal fluid in developing chick embryos.

The development of the chloride ion, glucose and total protein concentration was investigated in the cerebrospinal fluid of 11- to 21-day-old chick embryos and compared with their development in the blood plasma. Developmental changes in the chloride concentration in the plasma and CSF were very small, but it was always higher in the CSF than in the plasma. The plasma/CSF ratio fell during development, from 0.906 in 11-day-old embryos to 0.778 at the end of incubation. The CSF glucose concentration fell up to the 19th day of incubation, but a significant increase was recorded shortly before hatching. The plasma glucose concentration rose throughout the whole of the investigated period of embryogenesis. Up to the 19th day the P/CSF ratio rose from 1.59 to 4.05 and in 21-day-old embryos fell to 2.47. The developmental increase in the plasma total protein concentration was accompanied by the reverse process in the CSF. During the second half of incubation the P/CSF ratio rose from 1.88 to 7.9 Calculation of total osmolarity from the Na+, K+, Ca2+, Cl- and glucose concentration showed permanent hyperosmolarity of the CSF compared with the plasma. The P/CSF ratio was maintained within limits of 0.94 to 0.98.     

Variations of prolactin content in human cerebrospinal fluid after metoclopramide and morphine

Serum and cerebrospinal fluid (CSF) prolactin (PRL) concentrations were determined in fourteen patients of both sexes suffering from hydrocephalus, in basal conditions and after i.m. administration of 10 mg metoclopramide or 10 mg morphine. A significant increase in both serum and CSF hormone values was found after administration of both drugs. Serum and CSF PRL values after metoclopramide administration increased earlier and to a greater extent than after morphine. Furthermore, the metoclopramide induced CSF PRL increase immediately followed the serum peak, whereas after morphine administration an evident delay in the CSF hormone peak with respect to the serum increase was found. These data suggest that PRL entry in the CSF compartment is subject to a controlling mechanism which acts at the blood/brain barrier.     

Origin of α-mannosidase activity in CSF

The α-mannosidase activity in human frontal gyrus, cerebrospinal fluid and plasma has been analyzed by DEAE-cellulose chromatography to investigate the origin of the α-mannosidase activity in cerebrospinal fluid (CSF). The profile of α-mannosidase isoenzymes obtained in CSF was similar to that in the frontal gyrus but different from that in human plasma. In particular the two characteristic peaks of lysosomal α-mannosidase, A and B, which have a pH-optimum of 4.5 and are found in human tissues, were present in both the frontal gyrus and CSF. In contrast the majority of α-mannosidase activity in human plasma was due to the so called intermediate form, which has a pH-optimum of 5.5. The results suggest that the intermediate form of α-mannosidase in plasma does not cross the blood–brain barrier and that the α-mannosidase activity present in the cerebrospinal fluid is of lysosomal type and of brain origin. Thus the α-mannosidase activity in cerebrospinal fluid might mirror the brain pathological changes linked to neurodegenerative disorders such as Parkinson's disease.     

The influence of gestational age and onset of labour on determinants of fetal-maternal fluid and electrolyte balance in sheep.

Our aim was to compare the effects of gestational age and the timing of the onset of labour on factors influencing fetal fluid and electrolyte balance and urine production in fetal sheep. We measured the volume and composition of fetal urine and amniotic and allantoic fluids, as well as fetal and maternal plasma composition and micturition episodes in sheep during late gestation until the onset of labour. We found that daily fetal urine production and urethral urine flow per micturition episode increased significantly in relation to the onset of labour but not to gestational age (P < 0.05). In the 2 days preceding the onset of labour fetal urine and amniotic fluid K+ concentrations and urine osmolality increased significantly and the Na+/K+ ratio in allantoic fluid decreased significantly (P < 0.05). There was also a significant fall in fetal arterial SaO2 (P < 0.05) but no significant changes occurred in fetal plasma electrolyte composition, osmolality or AVP concentrations. Fetal plasma cortisol and prolactin concentrations and amniotic and allantoic fluid prolactin concentrations increased significantly and progressively in association with both advancing gestation and the onset of labour whereas maternal plasma prolactin concentrations increased significantly only in the 2 days before the onset of labour (P < 0.05). We conclude that some developmental aspects of fetal fluid and electrolyte balance, including renal function, are more closely related to the timing of parturition than to gestational age per se.     

Stereochemistry of tissue distribution of racemic propranolol in the dog

Only limited information is available on the stereochemistry of the in vivo distribution of beta-receptor-blocking drugs. In this study we determined the levels of the propranolol enantiomers in plasma, cerebrospinal fluid (CSF) and central nervous system (CNS), and peripheral tissues in the dog following an intravenous dose of a deuterium-labeled pseudoracemate. The appearance of the propranolol enantiomers in the CSF was rapid and nonstereoselective, with maximum concentrations reached at 15 min after dosing. The levels of the enantiomers in both CSF and plasma then declined in a parallel biphasic fashion, with a terminal t1/2 of about 125 min. Except for an early high CSF/plasma concentration ratio of 0.35, the CSF propranolol levels corresponded to the unbound concentration in plasma, CSF/plasma 0.20. All areas of the brain showed a similar uptake of propranolol, with a tissue concentration exceeding that in plasma about 10-fold during the terminal phase of elimination. The uptake of propranolol by peripheral tissues varied widely, ranging from a 50-fold accumulation by the lungs compared to plasma to no accumulation by adipose tissue. However, as for the CSF, there was no evidence of stereoselective uptake of propranolol by any CNS or peripheral tissue except for the liver. A significantly higher level of (+)-vs. (-)-propranolol in liver tissue presumably was a reflection of stereoselective hepatic metabolism of (-)-propranolol by this tissue. The slight stereoselectivity in plasma binding of propranolol known to exist in the dog had no significant influence on tissue or CSF distribution.     

Disassociated increases of adrenomedullin in the rat cerebrospinal fluid and plasma after salt loading and systemic administration of lipopolysaccharide

To determine the role of adrenomedullin (AM) in the fluid electrolyte homeostasis and endotoxin shock, cerebral spinal fluid (CSF) and plasma were sampled from rats after respective challenges. The AM levels were measured by a highly sensitive immunoassay. The AM levels in the CSF of the rats anesthetized with ether (10.7 +/- 0.60 fmol/ml) were significantly higher than those with isoflurane 5.17 +/- 0.70 fmol/ml, P < 0.01), while the plasma level did not differ significantly. The CSF levels of the rats received 2% saline drinking increased to 3 and 4 folds at day 5 and day 7, respectively, while the plasma levels did not differ from controls at both time points. The AM levels in CSF or plasma increased to 1.5 and 3 folds at 1.5 h after intraperitoneal (i.p.) administration of lipopolysaccharide (LPS, 5 mg/kg), reached 6.5 and 30 folds at 6 h, respectively, while no change was observed in the controls. The present findings suggest that AM in the CSF is regulated independently from that in the plasma, the centrally synthesized AM plays and important role in the regulation of the fluid electrolyte homeostasis. Furthermore, the circulatory AM plays an important role in the endotoxin shock.     

Correlation of plasma and CSF prolactin with CSF GABA during neuroleptic treatment

We measured serum and CSF prolactin and CSF 5HIAA, HVA and GABA at two time points separated by an average period of 21 days during the beginning of neuroleptic treatment in 26 psychotic patients. Prolactin levels were higher in females at both time points, and there was little evidence of tolerance during the measurement period. The prolactin values showed considerable intercorrelation. CSF GABA tended to be negatively correlated with prolactin values, particularly in male subjects. There were few significant correlations between the prolactin measures and CSF metabolites or clinical ratings.     

Changes in central and peripheral renin-angiotensin system after furosemide injection

To examine the effects of acute stimulation on the peripheral and central renin-angiotensin system, simultaneous sampling of blood and cerebrospinal fluid (CSF) for measurements of plasma renin activity (PRA), plasma angiotensin I-immunoreactivity (PAng I-ir), plasma angiotensin II-immunoreactivity (PAng II-ir), plasma angiotensinogen and cerebrospinal fluid angiotensin II-ir (CSF Ang II-ir) and CSF angiotensinogen was carried out following intravenous injection of furosemide (5 mg/kg) in conscious dogs. Administration of furosemide induced marked increases in PRA, Ang I-ir, PAng II-ir and CSF Ang II-ir, however, neither plasma nor CSF angiotensinogen was changed. Furthermore, a relatively large dose (20 mg/kg/min) of intravenously infused synthetic Ang II for 20 min produced a five-fold increase in PAng II-ir compared with no significant increase in CSF Ang II-ir. In spite of significant suppression of PRA and PAng I-ir, there were no significant changes in either plasma or CSF angiotensinogen. These results primarily suggest that the peripheral and the brain renin-angiotensin systems may be linked and that acute changes in the peripheral renin-angiotensin system do not alter either plasma or CSF angiotensinogen.