Altered formation and bulk absorption of cerebrospinal fluid in FGF-2-induced hydrocephalus

Upregulation of certain growth factors in the central nervous system can alter brain fluid dynamics. Hydrocephalus was produced in adult Sprague-Dawley rats by infusing recombinant basic fibroblast growth factor (FGF-2) at 1 μg/day into a lateral ventricle for 2, 3, 5, or 10–12 days. Lateral and third ventricular enlargement progressively increased from 2 to 10 days. Ventriculomegaly was also induced by a 75% reduced dose of FGF-2. At 10–12 days, there was a 29% attenuation in cerebrospinal fluid (CSF) formation rate, from 2.5 to 1.8 μl/min ( P < 0.01). Choroid plexus, the main site of CSF secretion, had an augmented number of dark epithelial cells, which have previously been associated with decreased choroidal fluid formation. The twofold elevated resistance to CSF absorption, i.e., 0.8 to 1.7 mmHg ⋅ min−1 ⋅ μl−1, was attributable, at least in part, to enhanced fibrosis and collagen deposits in the arachnoid villi, a major site for CSF absorption. Normal CSF pressure (2–3 mmHg) was consistent with a patent cerebral aqueduct and reduced CSF formation rate. The FGF-2-induced ventriculomegaly is interpreted as an ex vacuuo hydrocephalus brought about by an altered neuropil and interstitium of the brain.

Atrial natriuretic peptide does not alter cerebrospinal fluid formation in sheep

Because the choroid plexus has been shown to have a high density of atrial natriuretic peptide (ANP) binding sites, we investigated the effect of intracerebroventricular and intravenous administrations of ANP on cerebrospinal fluid (CSF) formation. CSF formation rate was measured in conscious sheep with a dye-dilution method using blue dextran 2000 as an indicator substance. During the experiment animals were partially restrained in a sling, and their ventricular systems were perfused with artificial CSF containing the indicator substance. ANP (alpha-human ANP) administered centrally at rates of 0.015-15 ng/min, resulting in CSF ANP concentrations ranging from physiological to pharmacological CSF hormone levels, was found not to influence CSF formation. Similarly, intravenous administration of ANP at a rate of 10 ng.kg-1.min-1 did not affect CSF formation, i.e., decreases in CSF formation rate in all experiments involving ANP administration were not significantly different from those observed in time control experiments. Our results suggest that ANP does not significantly affect CSF production in sheep. It is possible that the lack of effect of ANP on CSF formation is associated with the predominance in the choroid plexus of clearance receptors over biologically active receptors.

Relationships between intracranial pressure, ventricular size, and resistance to CSF outflow

✓ In 230 patients with normal-pressure hydrocephalus, high-pressure hydrocephalus, or benign intracranial hypertension, measurements of the intracranial pressure (ICP), ventricular size, and cerebrospinal fluid (CSF) outflow resistance (Ro) have revealed a linear relationship between ICP and Ro. It is shown that on average the CSF formation rate tends to decrease with increasing ICP. It is also shown that the size of the ventricles increases as the ICP levels off toward normal values. The clinical implication of this is that a small or normal ventricular size in acute or subacute phases does not preclude defective CSF resorption.

Intracranial pressure, cerebral blood flow, and cerebrospinal fluid formation during hyperammonemia in cat

✓ Intracranial pressure (ICP), cerebral blood flow (CBF), and the cerebrospinal fluid (CSF) formation rate were examined in anesthetized cats during ammonia intoxication. Hyperammonemia, evoked by intravenous infusion of ammonium acetate, caused a significant increase in ICP when the arterial blood ammonia level exceeded 400 µmol ⋅ liter−1. A progressive elevation of blood ammonia concentration was followed by a gradual rise in CBF, measured by the xenon-133 clearance technique. At an arterial blood ammonia level exceeding 500 µmol ⋅ liter−1, the CBF reached a plateau at 30% above the mean control value. Increase in ICP correlated weakly, but significantly, with the increase in CBF (R = 0.489, p < 0.005). Elevation of the arterial blood ammonia level to 780.4 ± 25.5 µmol ⋅ liter−1 for 2 hours elicited a significant gradual increase in CSF formation rate, measured by the ventriculocisternal perfusion method with iodine-125-albumin as an indicator substance. A maximum increase in CSF flow of 81% was noted at the end of the ammonium acetate infusion. It is suggested that hyperammonemia increases ICP both by cerebral vasodilatation and by enhancement of the CSF formation rate.

The effect of cold-induced brain edema on cerebrospinal fluid formation rate

✓ The net contribution of vasogenic brain edema to cerebrospinal fluid (CSF) formation was studied by ventriculocisternal perfusion. Individual cats were perfused both before and 2 ½ hours after a severe cold-induced injury to the cerebral cortex, and the results were compared. Although the edema had occupied the larger part of the hemispheric white matter and bordered the lateral ventricle, a decrease rather than an increase in CSF formation rate was observed. This decrease was related to a decrease in the cerebral perfusion pressure by a regression equation that was not affected by the cold injury.

The effect of dexamethasone on the rate of formation of cerebrospinal fluid in the monkey

✓ The standard ventriculocisternal perfusion technique was used to determine what effect a single large intravenous dose of dexamethasone would have on CSF formation rate in the rhesus monkey over a 4-hour period. Three monkeys received 0.15 mg/kg, four received 0.4 mg/kg and five served as the untreated controls. With time, CSF formation rates decreased in both treated and control groups. The magnitude of the decrease in the treated and untreated controls did not differ significantly. We conclude that the therapeutic benefit of dexamethasone for intracranial spatial decompensation derives from a mechanism of action that leaves the rate of CSF formation unchanged.

Na-K activated adenosine triphosphatase formation of cerebrospinal fluid in the cat

Digitalis-sensitive Na-K activated ATPase (Na-K ATPase), implicated in active cation transport, was shown to occur in cat choroid plexus. Cerebrospinal fluid (CSF) formation rate, measured by collection from cat cerebral aqueduct was inhibited 18% by intravenous desacetyl lanatoside C (0.2 mg/kg). Ouabain, placed intraventricularly, caused inhibition of flow, ranging from 100% by 10–5 mole to 0% by 5 x 10–10 mole. After 10–6 mole ouabain, Na-K ATPase activity in lateral ventricle choroid plexus was inhibited 69% without change in digitalis-insensitive, Mg activated ATPase and carbonic anhydrase activities. Ventriculocisternal perfusion with varying concentrations of ouabain, scillaren A, and hexahydroscillaren A gave CSF flow inhibition (inulin dilution technique) correlating quantitatively with in vitro Na-K ATPase inhibition. Other compounds studied were erythrophleine, cassaine, and l-norepinephrine. It is concluded that the choroid plexus Na-K ATPase system has a primary function in the formation of CSF in the cat, presumably through the active secretion of Na ions into the ventricle.