Cerebrospinal fluid circulation

Figure 6.9 Cerebrospinal fluid circulation through the central nervous system. This schematic diagram illustrates the pattern of fluid flow from formation in the choroid plexus, movement through the internal ventricular system, flow around the external surfaces of the brain and spinal cord, and absorption into the venous system through the arachnoid villi. Redrawn from The Ciba Collection of Medical Illustrations, Vol.

Glycosydation AChE and BChE carry 3 and 9, respectively, N-glycosylation consensus sequences attaching carbohydrate residues to the core protein via asparagines. Different molecular forms of the enzymes in various tissues, show different number and composition of carbohydrate residues. N-glycosylation at all sites was shown to be important for effective biosynthesis, secretion and clearance of ChEs from the circulation. Altered patterns of AChE glycosylation have been observed in the brain and cerebrospinal fluid of Alzheimer s disease (AD) patients, with potential diagnostic value. 

The CTZ, located outside the blood-brain barrier (BBB), is exposed to cerebrospinal fluid and blood.2,3 Therefore it is easily stimulated by uremia, acidosis, and the circulation of toxins such as chemotherapeutic agents. The CTZ has many serotonin type 3 (5-HT3), neurokinin-1 (NKj), and dopamine (D2) receptors.2 Visceral vagal nerve fibers are rich in 5-HT3 receptors. They respond to gastrointestinal distention, mucosal irritation, and infection. 

Chemoreceptor trigger zone Located in the area postrema of the fourth ventricle of the brain, it is exposed to cerebrospinal fluid and blood and is easily stimulated by circulating toxins to induce nausea and vomiting. 

Cerebrospinal fluid (CSF) A plasma ultrafiltrate (volume = 125 mL) that circulates through the central nervous system. 

A highly diagrammatic representation of the major CNS elements is shown in Figure 1-3. The entire CNS is bathed both internally and externally by cerebrospinal fluid (CSF), which circulates throughout the ventricular and leptomeningeal spaces. This fluid, a type of plasma... 

Preliminary information useful in prodrug design has been obtained with amino acids attached to model aromatic amines. Thus, N-(naphthalen-2-yl) amides of amino acids (6.1, R=side chain of amino acid, R =H) proved to be of interest as test compounds to monitor peptidase activity such as ami-nopeptidase M (membrane alanyl aminopeptidase, microsomal aminopepti-dase, EC 3.4.11.2) [16][17], In the presence of purified rabbit kidney aminopeptidase M or human cerebrospinal fluid (CSF) aminopeptidase activity, the rate of hydrolysis decreased in the order Ala-> Leu->Arg->Glu-2-naphthyl-amide. Ala-2-naphthylamide, in particular, proved to be a good test compound, as its rate of hydrolysis was influenced by experimental conditions (preparation, inhibitors, etc.), as was the hydrolysis of a number of low-molecular-weight opioid peptides and circulating vasoactive peptides. 

Two major barrier systems separate the central nervous system from the circulation the BBB and the blood-cerebrospinal fluid barrier (B-CSF-B). These barriers have distinct morphological and physiological characteristics, according to their different tasks. Figure 2.1 highlights the salient features of both barrier systems. 

After i.c.v. injection, the rate of elimination from the CNS compartment is dominated by cerebrospinal fluid dynamics. The CSF, which is secreted by the choroid plexus epithelium across the apical membrane, circulates along the surface and convexities of the brain in a rostral to caudal direction. It is reabsorbed by bulk flow into the peripheral bloodstream at the arachnoid vUh within both cranial and spinal arachnoid spaces [62]. Of note is that the turnover rate of total CSF volume is species dependent and varies between approximately... 

The flow of cerebrospinal fluid is essentially unidirectional that is, it flows from its site of formation in the choroid plexus through the ventricles to its site of exit at the arachnoid villi. Drugs in this fluid can either enter the brain tissue or be returned to the venous circulation in the bulk flow of cerebrospinal fluid carried through the arachnoid villi. Some drugs, such as penicillin, wUl not leave the cerebrospinal fluid compartment by bulk flow but will be actively transported by the choroid plexus out of the fluid and back into the blood. Finally, drugs may diffuse from brain tissue directly into blood capUlaries. 

AU of the following statements concerning the blood-brain barrier and the passage of drugs from the systemic circulation into the cerebrospinal fluid are TRUE EXCEPT ... 

Oxytocin, a nine amino acid peptide, is synthesized primarily in the paraventricular and supraoptic (SON) nuclei of the hypothalamus, from which it is released to the general circulation through the posterior pituitary (Insel et ah, 1997). However, oxytocinergic fibers have also been found to project from the PVN to the limbic system and several autonomic centers in the brain stem. This central OT pool appears to be independent of pituitary OT release cerebrospinal fluid (CSF) and plasma OT responses to numerous stimuli are not correlated (Insel, 1997). Oxytocin and its analog (or partner) peptide vasopressin are found only in mammals. A related peptide, vasotocin, thought to be the evolutionary precedent of these peptides, is found in reptiles and birds. The first known actions of OT were its peripheral effects on the physiology of new mothers. In mammals, OT stimulates milk ejection and uterine contraction, essential aspects of maternal physiology (Insel et ah, 1997). 

The blood-brain barrier foils most efforts to use the blood to measure the brain s chemistry, but researchers can get aroimd this obstacle by sampling cerebrospinal fluid (CSF). CSF is the fluid that circulates in the meninges of the brain and spinal cord and keeps the delicate tissues from getting rattled around and damaged in their hard, bony container. The brain makes CSF from blood, and certain metabolites get mixed in. One of these metabolites is 5-hydroxyindole acetaldehyde (5-FIIAA), a major metabolite of serotonin. Researchers who carefully puncture the meninges and extract a sample are rewarded with information concerning serotonin levels in the person s brain, as described below. 

Hypothalamic content and mRNA levels of TNF-a peak during the early light period, when NREM sleep is maximal, in the rat (70,71). IL-1-like activity varies with the sleep-wake cycle in the cerebrospinal fluid of cats (72). IL-lp protein levels in plasma (73) and hypothalamic IL-lp mRNA levels (74) are highest during the sleep period in rats. Sleep deprivation increases IL-ip and TNF-a mRNA levels in the hypothalamus (75-77) and expression of the 55-kD TNFR is also stimulated in the brain (77). In humans, peak levels of IL-1 occur at sleep onset in the blood (78) and IL-1 blood levels also increase during sleep deprivation (79). Blood levels of TNF-a correlate with EEG slow-wave activity (80), and concentrations of circulating TNF-a and the soluble 55-kD TNFR increase after sleep deprivation in humans (81). 

Distribution Sulfa drugs are distributed throughout body water and penetrate well into cerebrospinal fluid, even in the absence of inflammation. They can also pass the placental barrier and into breast milk. Sulfa drugs are bound to serum albumin in the circulation the extent of binding depends on the particular agent. 

Transport of water into the cerebrospinal fluid (CSF) and interstitial fluid (ISF) forms the source of the CSF that fills the cerebral ventricles and the subarachnoid spaces around the brain and spinal cord. Early studies by Weed and Cushing identified the CSF as a Third Circulation, functioning along with the fluid between the cells, the ISF, as the lymph of the brain (Weed, 1935,1938). The ISF circulates between the cells and drains into the CSF it is formed osmotically by the extrusion... 

Patients with schizophrenia have increased concentrations of pro-inflammatory cytokines both in the systemic circulation and cerebrospinal fluid and showed decreased EPA and DHA in the plasma phospholipid. Clinical trials showed that supplementation of ethyl EPA is of significant benefit to these patients (228). 

The posterior cerebral artery supplies the occipital lobe and portions of the medial and inferior temporal lobe. The arterial supply of the spinal cord is derived from the vertebral arteries and the radicular arteries. The brain is supplied by the internal carotid arteries (the anterior circulation) and the vertebral arteries, which join at the pon tomedullary junction to form the basilar artery (collectively termed the posterior circulation). The brainstem is supplied by the posterior system. The medulla receives blood from branches of the vertebral arteries as well as from the spinal arteries and the posterior inferior cerebellar artery (PICA). The pons is supplied by paramedian and short circumferential branches of the basilar artery. Two major long circumferential branches are the anterior inferior cerebellar artery (AICA) and the superior cerebellar artery. The midbrain receives its arterial supply primarily from the posterior cerebral artery as well as from the basilar artery. The venous drainage of the spinal cord drains directly to the systemic circulation. By contrast, veins draining the cerebral hemispheres and brain stem drain into the dural sinuses. Cerebrospinal fluid also drains into the dural sinuses through unidirectional valves termed arachnoid villi. 

Brain and cerebrospinal fluid (CSF). The capillaries of the cerebral circulation differ from those in most other parts of the body in that they lack the filtration channels between endothelial cells through which substances in the blood nominally gain access to the extracellular fluid. Tight junctions between adjacent capillary endothelial cells, together with their... 

Dore-Duffy P, Newman W, Balabanov R, Lisak RP, Mainolfi E, Rothlein R, Peterson M (1995) Circulating, soluble adhesion proteins in cerebrospinal fluid and serum of patients with multiple sclerosis Correlation with clinical activity. Ann Neurol 37 55-62. 

There have been reports that the use of surgical aluminium-containing bone cement can cause epileptic seizures as well as encephalopathy, at least when the cement is in direct contact with the cerebrospinal fluid, as can happen in neurosurgery (23,24) (SEDA-21, 232). In this connection it should be noted that such bone cements can produce high circulating concentrations of aluminium. One French study in six patients (25) noted mean plasma aluminium concentrations of up to 9.2 ng/ml, while up to 176 ng/ml was present in the postauricular cerebrospinal fluid (SEDA-22, 242). This aspect of aluminium cement merits further study. 

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