James H. Wood

Physiology, Pharmacology, and Dynamics of Cerebrospinal Fluid

Galen described cerebrospinal fluid (CSF) as a vaporous humor produced in the cerebral ventricles that provides energy and motion to the entire body. In 1760, von Haller suggested that this vapor condenses after death to form water, which then fills the spaces surrounding the brain and spinal cord. However, four years later, Cotugno proposed that the subarachnoid space is filled with water prior to death. In 1825, Magendie55 confirmed the continuity between the ventricular system and the subarachnoid spaces, performed the first cisternal puncture, and attempted to analyze CSF. Luschka identified the lateral connections of the fourth ventricle to the cisterna magna in 1855. Quincke78a performed the first lumbar puncture in vivo in 1891.

Sites of Origin and Cerebrospinal Fluid Concentration Gradients

Determination of neurotransmitter precursors, neurotransmitters, and their metabolites in cerebrospinal fluid (CSF) has recently become a popular method for studying pathological and drug-induced alterations in central nervous system metabolism of living patients. According to Moir et al.,58 interpretation of this CSF analysis requires the absence of CSF contamination with peripheral neurotransmitters and their metabolites. The CSF should also reflect the chemical composition of adjacent areas of nervous tissue. Unfortunately, CSF circulation, regional selective neurochemical absorption, and pathological alterations in the blood-CSF barrier complicate data evaluation.

Pharmacokinetic study of cerebrospinal fluid penetration of cis-diamminedichloroplatinum (II)

SummaryThe ability of cis-DDP and several analogs to enter the CSF was investigated in rhesus monkeys that had subcutaneoulsy implanted Ommaya reservoirs connected to catheters in each monkeys fourth ventricle. Plasma and CSF samples were analyzed for platinum content by atomic absorption spectroscopy. Plasma platinum curves were biphasic with a very slowly declining terminal phase. CSF platinum curves rose to maximum concentrations 30–40 min after an IV bolus injection and declined mono-exponentially (T1/2=60 min) without displaying a detectable slow terminal phase. cis-DDP given as an IV bolus of 1.5 mg/kg or 3.0 mg/kg produced peak CSF concentrations of 0.35 and 0.78 μM platinum. The ratio of CSF platinum:plasma platinum never exceeded 0.04. When cis-DDP at 3.0 mg/kg was given as a 2- or 7-h infusion, the peak CSF concentrations were 0.28 and 0.17 μM platinum, respectively. The total CSF exposure, measured as concentration x time, was the same for bolus and for 2- and 7-h infusions. Studies with analogs showed that neither malonato 1,2-diaminocyclohexane platinum (II) nor 4-carboxyphthalato 1,2-diaminocyclohexane platinum (II) had better CSF penetrance than cis-DDP. Sulfato 1,2-diaminocyclohexane platinum (II) could not be detected in the CSF. The ratio of CSF platinum:plasma platinum was never greater than 0.02–0.03 for any of the analogs.

Relationship Between Cerebrospinal Fluid Norepinephrine and Blood Pressure in Neurologic Patients

In 126 patients hospitalized for various diseases norepinephrine in cerebrospinal fluid correlated with blood pressure (r = 0.41, p < 0.0001). Plasma and cerebrospinal fluid norepinephrine levels correlated with heart rate. Central noradrenergic nerves help control blood pressure and may be involved in human hypertension.

Technical Aspects of Clinical and Experimental Cerebrospinal Fluid Investigations

In recent years, the physical and chemical examination of cerebrospinal fluid (CSF) has become increasingly important in diagnostic patient evaluations and in both clinical and animal research. The CSF bathes the brain and spinal cord, and thus tends to reflect the state of health and activity of the central nervous system.109 Meaningful interpretation of CSF findings requires relatively sophisticated knowledge of CSF physiology and pathology. It is hoped that this information will be supplied by this multidisciplined volume. The purpose of this chapter is to discuss aspects of protocol formulation that ensure the validity of CSF data. In addition, various clinical and experimental techniques of obtaining ventricular, cisternal, and lumbar CSF will be assessed.

Ability of a New Antitumor Agent, AZQ, to Penetrate into Cerebrospinal Fluid

The ability of a new antitumor agent, AZQ (2,5-diaziridinyl-3,6-bis-carboethoxyamino-1,4-benzoquinone), NSC No. 182986, to enter the cerebrospinal fluid (CSF) was studied in nonhuman primates. Following parenteral administration of 14C-AZQ, CSF radioactivity rose quickly and reached a maximum value 60 min after administration. Total radioactivity in the CSF was about 25-35% of the corresponding plasma level at time points subsequent to maximum CSF concentration. Chloroform extraction and thin-layer chromatography revealed that much of the total radioactivity was not parent AZQ and that parent AZQ declined rapidly in both plasma and CSF with a half-life less than 1 h. AZQ clearly entered the CSF and yielded CSF concentrations comparable to plasma values.

Cerebrospinal Fluid γ-Aminobutyric Acid Correlation with Cerebrospinal Fluid and Blood Constituents and Alterations in Neurological Disorders

Biochemical and electrophysiological studies indicate that γ-aminobutyric acid (GABA) functions as an inhibitory neurotransmitter and may be, quantitatively at least, the predominant transmitter in brain.2,20 Recent findings have indicated that brain GABA may be involved in the central regulation of blood pressure and in neuroendocrine function.1,22 Furthermore, numerous neurochemical and pharmacological studies have provided evidence that alterations in GABAergic function may be related to a variety of neuropsychiatric disorders. Abnormal GABAergic activity may underlie seizure activity in some epilepsies23 and may account for some of the symptoms related to Huntington’s disease,6,7,10,27 Parkinson’s disease,18 and possibly schizophrenia.26 For example, using autopsy material, it has been demonstrated that there is a severe loss of GABA-containing neurons in the basal ganglia regions of Huntington patients.27 These losses appear to be related, not to drug treatment, but rather to the neuronal degeneration that is characteristic of this disorder. With regard to epilepsy, drugs that enhance GABAergic transmission, such as the barbituates, benzodiazepines, and GABA transaminase inhibitors, have antiepileptic properties, whereas agents that inhibit brain GABA synthesis, such as the hydrazides, or block GABA receptors, such as picrotoxin or bicuculline, produce seizures.9, 23

Neurotransmitter, Metabolite, and Cyclic Nucleotide Alterations in Cerebrospinal Fluid of Seizure Patients

Recently, Maynert et al. 102 reviewed the role of neu-rotransmitters in the initiation, spread, and termination of seizures. Abnormalities in water, electrolyte, acid-base, vitamin, and hormone metabolism alter seizure thresholds. In addition, the administration of chemical agents and electrical stimulation of the brain have been shown to modify seizure susceptibility. These manipulations influence neuronal activity, possibly by influencing the synthesis, storage, and release of neurotransmitters. The metabolic activity of these neurotransmitters may in turn be reflected in the degree of accumulation of their respective metabolites.

Extracellular Cyclic Nucleotide Metabolism in the Human Central Nervous System

The cyclic nucleotides—adenosine-3′,5′-cyclic mon-ophosphate (cAMP) and guanosine-3′,5′-cyclic monophosphate (cGMP)—serve important metabolic functions in many mammalian tissues (Fig. 1). Glycogen metabolism is the best-studied example of the regulatory function of cAMP in the phosphorylation of phosphorylase b to phosphorylase a.134 The proven and hypothetical roles of cyclic nucleotides in human nonneurological disease have been described in detail elsewhere.7,12,13,69,84,97,149,151 The role of cyclic nucleotides in human neurological diseases is beginning to be explored.24,52,53,158 The evidence defining the importance of cyclic nucleotides in many facets of central and peripheral nervous system functions is briefly reviewed below.34,35,38,81,106,114

Cerebrospinal fluid norepinephrine and free γ-aminobutyric acid in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive degenerative neurological disease of unknown etiology. As the first step in evaluating systematically neurotransmitter metabolism in ALS, we measured norepinephrine (NE) in plasma and cerebrospinal fluid (CSF) by radioimmunoassay and γ-aminobutyric acid (GABA) in CSF by radioreceptor assay of 34 patients with ALS, 31 patients with myopathies but no central nervous system disease and 167 patients with various neurological disorders. CSF GABA was significantly decreased in ALS patients compared to myophathy (p<0.05) and neurological (p<0.01) patients. However CSF NE was significantly increased (p<0.01) with respect to either comparison group. This dichotomy in neurotransmitter concentrations could result from a single neurotoxin leading to neuronal degeneration and a decrease in glutamic acid decarboxylase. The resultant decrease in GABA which is inhibitory on noradrenergic neurons could lead to the observed elevation in CSF NE due to activation of tyrosine hydroxylase.