kaolinite and Fibrosis

Fibrosis of the subarachnoid space (SAS) after infection, inflammation, or hemorrhage can impair cerebrospinal fluid absorption and circulation, causing diffuse ventricular dilatation. In the present study, we tested the hypothesis that urokinase (also known as urokinase-type plasminogen activator [uPA]), a fibrinolytic agent, attenuates fibrosis and ventriculomegaly in a rat model of kaolin-induced communicating hydrocephalus and thus may have potential as a therapy for these conditions. Thirty microliters of sterile 25% kaolin suspension was injected into the basal cisterns of adult Sprague-Dawley rats to induce hydrocephalus, and 2 intraventricular injections of either uPA or vehicle (saline) were administered immediately and 3 days thereafter. Ventricular volumes were measured by magnetic resonance imaging (MRI) on days 3, 14, and 28 after kaolin injection. Fibrosis and reactive astrogliosis were evaluated on day 28 by immunofluorescence and Western blotting. Neurocognitive features were tested using the Morris water maze from days 23 to 28. MRI analysis demonstrated that kaolin administration successfully induced hydrocephalus in rats and that uPA treatment significantly attenuated ventricular enlargement. In addition, uPA inhibited the deposition of laminin and fibronectin, extracellular matrix molecules, in the SAS, attenuated gliosis, and improved learning and memory in kaolin-treated rats. Therefore, we concluded that uPA prevents the development of kaolin-induced communicating hydrocephalus by preventing the development of subarachnoid fibrosis and by eliciting improvements in neurocognition. The results of this study indicate that uPA may be a novel clinical therapy for communicating hydrocephalus.

Topics: Animals; Blotting, Western; Cognition; Fibrosis; Gliosis; Hydrocephalus; Injections, Intraventricular; Kaolin; Magnetic Resonance Imaging; Male; Models, Biological; Rats, Sprague-Dawley; Subarachnoid Space; Urokinase-Type Plasminogen Activator

The pathogenesis of adult chronic hydrocephalus is not fully understood, and the temporal relationship between development of the radiological changes and neurological deterioration is unknown.. To clarify the progression of radiological-histological changes and subsequent clinical manifestations of adult chronic hydrocephalus.. Kaolin was injected bilaterally into the subarachnoid space overlying the cranial convexities in 20 adult rats. Magnetic resonance imaging (MRI) was obtained by using an 11.7 T scanner at 14, 60, 90, and 120 days after kaolin injection. Locomotor, gait, and cognitive evaluations were performed independently. Kaolin distribution and the associated inflammatory and fibrotic responses were histologically analyzed.. Evans index of ventriculomegaly showed significant progressive growth in ventricular size over all time points examined. The greatest enlargement occurred within the first 2 months. Evans index also correlated with the extent of kaolin distribution by MRI and by pathological examination at all time points. First gait changes occurred at 69 days, anxiety at 80, cognitive impairment at 81, and locomotor difficulties after 120 days. Only locomotor deterioration was associated with Evans index or the radiological evaluation of kaolin extension. Inflammatory/fibrotic response was histologically confirmed over the cranial convexities in all rats, and its extension was associated with ventricular size and with the rate of ventricular enlargement.. Kaolin injected into the subarachnoid space over the cerebral hemispheres of adult rats produces an inflammatory/fibrotic response leading in a slow-onset communicating hydrocephalus that is initially asymptomatic. Increased ventricular size eventually leads to gait, memory, and locomotor impairment closely resembling the course of human adult chronic hydrocephalus.. NPH, normal pressure hydrocephalus.

Topics: Animals; Cognition; Disease Models, Animal; Female; Fibrosis; Gait; Hydrocephalus; Hydrocephalus, Normal Pressure; Inflammation; Kaolin; Locomotion; Magnetic Resonance Imaging; Radiography; Rats; Rats, Sprague-Dawley; Subarachnoid Space

In post-haemorrhagic and other forms of communicating hydrocephalus, cerebrospinal fluid flow and drainage is obstructed by subarachnoid fibrosis in which the potent fibrogenic cytokine transforming growth factor-β has been aetiologically implicated. Here, the hypothesis that the transforming growth factor-β antagonist decorin has therapeutic potential for reducing fibrosis and ventriculomegaly was tested using a rat model of juvenile communicating hydrocephalus. Hydrocephalus was induced by a single basal cistern injection of kaolin in 3-week-old rats, immediately followed by 3 or 14 days of continuous intraventricular infusion of either human recombinant decorin or phosphate-buffered saline (vehicle). Ventricular expansion was measured by magnetic resonance imaging at Day 14. Fibrosis, transforming growth factor-β/Smad2/3 activation and hydrocephalic brain pathology were evaluated at Day 14 and the inflammatory response at Days 3 and 14 by immunohistochemistry and basic histology. Analysis of ventricular size demonstrated the development of hydrocephalus in kaolin-injected rats but also revealed that continuous decorin infusion prevented ventricular enlargement, such that ventricle size remained similar to that in intact control rats. Decorin prevented the increase in transforming growth factor-β1 and phosphorylated Smad2/3 levels throughout the ventricular system after kaolin injection and also inhibited the deposition of the extracellular matrix molecules, laminin and fibronectin in the subarachnoid space. In addition, decorin protected against hydrocephalic brain damage inferred from attenuation of glial and inflammatory reactions. Thus, we conclude that decorin prevented the development of hydrocephalus in juvenile rats by blocking transforming growth factor-β-induced subarachnoid fibrosis and protected against hydrocephalic brain damage. The results suggest that decorin is a potential clinical therapeutic for the treatment of juvenile post-haemorrhagic communicating hydrocephalus.

Topics: Analysis of Variance; Animals; Brain; CD11b Antigen; Decorin; Disease Models, Animal; Drug Delivery Systems; Ependyma; Fibronectins; Fibrosis; Glial Fibrillary Acidic Protein; Humans; Hydrocephalus; Kaolin; Magnetic Resonance Imaging; Rats; Rats, Sprague-Dawley; Rec A Recombinases; Smad2 Protein; Subarachnoid Space; Time Factors; Transforming Growth Factor beta1

The authors investigated the effects of heavy water (D2O) on intrameningeal fibrosis and on the expression of cytokine production in mice with kaolin-induced hydrocephalus.. Mice in which kaolin was injected into the cisterna magna were divided into two groups: 1) Group H, which had free access to H2O as tap water; and 2) Group D, which had free access to 30% D2O as tap water before and after kaolin injection. A distilled water-injected group, which had free access to H2O as tap water was designated the sham-operated group. The authors examined the effects of D2O within 28 days after injection on the development of hydrocephalus and intrameningeal fibrosis, as well as on the expression levels of several inflammatory and fibrogenic cytokines: transforming growth factor-beta1 (TGFbeta1), fibroblast growth factor-2 (FGF2), platelet-derived growth factor (PDGF)-BB, and interleukin (IL)-6. The cerebral ventricles were less expanded, and intrameningeal fibrosis was milder in Group D than in Group H. The proliferation of fibroblasts was assessed by applying the bromodeoxyuridine labeling index, which was lower in Group D than in Group H. Expression of TGFbeta1 in the macrophages, choroid plexus, and meninges was inhibited in Group D but not in Group H. The serum level of total TGFbeta1 was significantly lower in Group D than in Group H on Day 14, whereas the levels of FGF2, PDGF-BB, and IL-6 did not differ significantly among the groups.. Administration of D2O prevented the development of kaolin-induced hydrocephalus in mice and inhibited intrameningeal fibrosis and upregulation of TGFbeta1.

Topics: Animals; Becaplermin; Brain; Cerebral Ventricles; Deuterium Oxide; Fibroblast Growth Factor 2; Fibrosis; Hydrocephalus; Injections, Intraventricular; Interleukin-6; Kaolin; Male; Meninges; Mice; Mice, Inbred ICR; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Statistics as Topic; Transforming Growth Factor beta; Transforming Growth Factor beta1

The effect of chymopapain and contrast media in the epidural space on meninges has not been studied conclusively. The authors injected chymopapain into the epidural space of monkeys and measured the degree of arachnoid fibrosis that resulted. Animals were given injections of 1.2 mL of diatrizoate (280 mg iodine per milliliter), chymopapain (100 IU/mL), kaolin (100 mg/mL) (as a positive control), or saline (0.9%) (as a negative control). Three months later the animals were killed; the dural sac was removed intact and was fixed, sectioned, stained, and examined with light microscopy. Kaolin-treated animals developed mild to marked fibrosis of the dura. The saline- and diatrizoate-treated animals developed little or no evidence of fibrosis. One of four chymopapain-treated animals developed degenerative changes in dorsal nerve roots and fibrosis in the adjacent arachnoid. The other chymopapain-treated animals had little or no evidence of fibrosis. The studies suggest that neither diatrizoate nor chymopapain causes arachnoid fibrosis.

Topics: Animals; Arachnoid; Chymopapain; Diatrizoate Meglumine; Epidural Space; Fibrosis; Kaolin; Macaca fascicularis; Meninges; Sodium Chloride