Biomedical subjects

M Kornfeld

Publications and source records attributed to M Kornfeld.

At least 19 recordsLinked to original sources

PubMed1999

Nitric oxide/cAMP interactions in the control of rat renal vascular resistance.

This study aimed to characterize the interaction between nitric oxide (NO)- and cAMP-related pathways in the control of renal blood flow. Using the isolated perfused rat kidney model, we determined the effects of inhibition of NO formation by Nomega-nitro-L-arginine methyl ester (L-NAME; 1 mmol/L) and of NO administration by sodium nitroprusside (SNP, 10 micromol/L) on renal vascular resistance under conditions of elevated vascular cAMP levels. cAMP levels were increased either by adenylate cyclase activation via isoproterenol or by inhibition of cAMP phosphodiesterases (PDEs) 1, 3, and 4. We found that L-NAME markedly increased vascular resistance and that this effect was completely reversed by SNP. Both isoproterenol and inhibitors of the cAMP PDEs lowered basal vascular resistance. In the presence of isoproterenol (3 nmol/L) and inhibitors of PDE-1 [8-methoxymethyl-l-methyl-3-(2-methylpropyl)-xanthine; 8-MM-IBMX, 20 micromol/L] and PDE-4 (rolipram, 20 micromol/L), L-NAME again substantially increased vascular resistance, and this effect of L-NAME was completely reversed by SNP. In the presence of the PDE-3 inhibitors milrinone (20 micromol/L) and trequinsin (200 nmol/L), however, both L-NAME and SNP failed to exert any additional effects. Because PDE-3 is a cGMP-inhibited cAMP PDE and because the vasodilatory effect of SNP was abrogated by the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) (20 micromol/L), our findings are compatible with the idea that an action of NO on PDE-3 could account for the vasodilatory properties of NO on the renal vasculature. Moreover, our findings suggest that PDE-3 activity is an important determinant of renal vascular resistance.

Adenylyl Cyclases↗

PubMed1999

AT1 receptor inhibition blunts angiotensin II-stimulated nitric oxide release in renal arteries.

Nitric oxide (NO) is known to modulate the vascular effects of angiotensin II (AngII) in the kidney. To investigate the effect of AngII on NO release, a new technique was used that employs an NO-sensitive microelectrode to measure NO release from the vascular endothelium of perfused renal resistance arteries (tertiary branches of the renal artery or primary arcuate arteries) in vitro. The vessels were microdissected from isolated perfused rat kidneys, cannulated, and perfused at constant flow and pressure with Krebs-Ringer bicarbonate solution. The electrode was placed inside the glass collection cannula to measure vessel effluent NO concentration. Addition of AngII to the perfusate stimulated NO release in a dose-dependent manner; 0.1, 10, and 1000 nM AngII increased NO oxidation current by 85+/-18 pA (n=11), 148+/-22 pA (n=11), and 193+/-29 pA (n=11), respectively. These currents correspond to changes in effluent NO concentration of 3.4+/-0.5, 6.1+/-1.1, and 8.2+/-1.3 nM, respectively. The presence of 0.1 mM N(G)-nitro-L-arginine methyl ester in the perfusate significantly reduced the response to 10 nM AngII by 90.5+/-3.4% (n=5). Neither losartan (1 microM) nor candesartan (1 nM) significantly affected basal NO production, but both of these AT1-receptor blockers markedly blunted NO release in response to AngII (10 nM): 77+/-6% inhibition with losartan (n=8) and 63+/-9% with candesartan (n=8). These results demonstrate that AngII stimulates N(G)-nitro-L-arginine methyl ester-inhibitable NO release in isolated renal resistance arteries. Because the response was significantly blunted by AT1 receptor blockade, the findings suggest that endothelium-dependent modulation of AngII-induced vasoconstriction in renal resistance arteries is mediated, at least in part, by AT1 receptor-dependent NO release.

Angiotensin II↗

PubMed1998

Angiotensin-II stimulates nitric oxide release in isolated perfused renal resistance arteries.

Nitric oxide (NO) has been implicated as a modulator of the vascular effects of angiotensin II (ANG II) in the kidney. We used a NO-sensitive microelectrode to study the effect of ANG II on NO release, and to determine the effect of selective inhibition of the ANG II subtype I receptor (AT1) with losartan (LOS) and candesartan (CAN). NO release from isolated and perfused renal resistance arteries was measured with a porphyrin-electroplated, carbon fiber. The vessels were microdissected from isolated perfused rat kidneys and perfused at constant flow and pressure in vitro. The NO-electrode was placed inside the glass collection cannula to measure vessel effluent NO concentration. ANG II stimulated NO release in a dose-dependent fashion: 0.1 nM, 10 nM and 1000 nM ANG II increased NO-oxidation current by 85+/-18 pA (n = 11), 148+/-22 pA (n = 11), and 193+/-29 pA (n = 11), respectively. These currents correspond to changes in effluent NO concentration of 3.4+/-0.5 nM, 6.1+/-1.1 nM, and 8.2+/-1.3 nM, respectively. Neither LOS (1 muM) nor CAN (1 nM) significantly affected basal NO production, but both AT1-receptor blockers markedly blunted NO release in response to ANG II (10 nM): 77+/-6% inhibition with LOS (n = 8) and 63+/-9% with CAN (n = 8). These results are the first to demonstrate that ANG II stimulates NO release in isolated renal resistance arteries, and that ANG II-induced NO release is blunted by simultaneous AT1-receptor blockade. Our findings suggest that endothelium-dependent modulation of ANG II-induced vasoconstriction in renal resistance arteries is mediated, at least in part, by AT1-receptor-dependent NO release.

Angiotensin II↗

PubMed1998

Fibrocartilagenous embolism: an unusual cause of spinal cord infarction.

A 14-year-old girl experienced sudden onset of weakness progressing rapidly to paralysis. She died 7 days later from a massive pulmonary thromboembolus. Autopsy revealed extensive infarction of the spinal cord with a fibrocartilaginous embolus of the corresponding segment of the anterior spinal artery.

Adolescent↗

PubMed1998

Autosomal dominant cerebral arteriopathy: neuropsychiatric syndrome in a family.

Though familial vascular leukoencephalopathy was described two decades ago, recent studies focus on a disorder termed Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a dominantly inherited disorder causing recurrent strokes and eventual dementia. The phenotypic boundaries of CADASIL remain indistinct and novel clinical features continue to arise in the literature. However, the associated histopathology is fairly consistent, typically demonstrating granular thickening of cerebral arterioles. The authors evaluated a 38-year-old man who suffered from progressive change in personality and intellect. His father, paternal aunt, and older sister had succumbed to a similar disorder. The authors examined relatives from three generations, including another sister with transient focal symptoms followed by persisting psychiatric disorder, and reviewed the radiographic studies from the propositus and his siblings. All the siblings showed diffuse white matter signal change on magnetic resonance imaging. Brain biopsy from the propositus revealed normal cortex and white matter but granular sclerosis of leptomeningeal arterioles. While the family's illness likely represents another instance of CADASIL, their presentation is unique because neuropsychiatric disorders predominate over focal ischemic symptoms.

Adult↗

PubMed1997

Neutral proteases and disruption of the blood-brain barrier in rat.

Blood-brain barrier disruption is common in many neurological diseases. Matrix metalloproteinases are induced in brain injury and increase capillary permeability by attacking the extracellular matrix around cerebral capillaries. Other neutral proteases are also increased in sites of secondary injury, and may contribute to the proteolysis of the blood-brain barrier. Therefore, we studied capillary permeability and histological tissue damage after intracerebral injection of neutrophil elastase, cathepsin G, heparatinase and plasmin. Adult rats were injected intracerebrally with an enzyme. After 1, 4 or 24 h, measurements were made of brain uptake of a radiolabeled tracer, [14C]sucrose. Enzymes that significantly increased capillary permeability were injected into other rats for histological assessment of tissue damage. Elastase increased capillary permeability significantly when compared with controls; maximal damage was seen at 4 h. Plasmin produced smaller increases in permeability at 4 h, exerting its maximal effect on sucrose uptake at 24 h. Cathepsin G had a small effect at 4 h. Heparitinase had no effect. Histologic examination of elastase-injected brains at 24 h revealed multifocal perivascular and intraparenchymal acute hemorrhages accompanied by a polymorphonuclear cell infiltrate. Elastase-injected brains were microscopically similar to saline-injected brains at 1 and 4 h. Plasmin produced fibrinoid changes in the blood vessels at 24 h, coinciding with the maximal increase in capillary permeability. We conclude that neutrophil elastase attacks the capillary extracellular matrix, causing extensive hemorrhage, while plasmin leads to increased vascular permeability and fibrinoid necrosis of blood vessel walls. Differential effects of neutral proteases released secondary to injury could be important in both the acute changes in blood vessel permeability and long-term alterations in vessel structure.

Animals↗

PubMed1997

Giant cell arteritis in association with cerebral amyloid angiopathy: immunohistochemical and molecular studies.

Giant cell arteritis (GCA) usually manifests as a transmural vascular infiltrate of mononuclear and multinucleated giant cells (MNGC). We describe six patients with GCA associated with severe cerebral amyloid angiopathy (CAA), all with cerebral hemorrhage or varying degrees of cerebral infarct, and histological evidence of Alzheimer's disease (cortical CAA often predominating over senile plaques and neurofibrillary tangles). One case showed mostly cortical involvement (with old microhemorrhages), and the others were primarily leptomeningeal (with involvement of the underlying cortex and extensive encephalomalacia of adjacent brain). Many vessels with CAA exhibited a pronounced adventitial and perivascular infiltrate of lymphocytes, histiocytes, and MNGC. Immunohistochemical staining showed deposition of beta/A4 peptide primarily in the thickened media of CAA vessels, and within the cytoplasm of MNGC--suggesting phagocytosis of insoluble peptide. Cystatin C antibody stained vascular amyloid and diffusely highlighted astrocytic and MNGC cytoplasm. HAM56-positive macrophages were frequently seen around amyloid-laden vessels. Anti-smooth muscle actin immunohistochemistry suggests the occurrence of medial destruction by amyloid, with relative preservation of intimal cells. Ultrastructural studies performed in one case confirmed the presence of intracytoplasmic amyloid in MNGC. The GCA seen in these cases of CAA most likely represents a foreign body response to amyloid proteins, causing secondary destruction of the vessel wall. DNA from brain tissues of five affected patients was examined to assess whether mutations were present in exon 17 of the APP gene or exon 2 of the cystatin C gene, a finding that might explain the foreign body giant cell response to amyloid proteins in these cases. However, restriction fragment mapping of amplified gene segments showed that previously described mutations were not present in these cases.

Actins↗

PubMed1997

Angiotensin II induces a tachyphylactic calcium response in the rabbit afferent arteriole.

The influence of repeated administration of angiotensin II (AII) on smooth muscle calcium concentration ([Ca2+]i) was studied in isolated rabbit renal afferent arterioles loaded with the calcium-sensitive fluorescent probe Fura-2. [Ca2+]i was evaluated in the proximal and distal parts of the afferent arterioles. AII (10(-8) M) increased the [Ca2+]i in both these regions. A second administration of AII, however, did not elicit any response in [Ca2+]i. The response to noradrenaline administration at the end of the experiment was not affected, i.e. there was no fading or cross-desensitization. Since this desensitization was specific for AII, it was of the tachyphylaxis type. Increasing doses of AII (10(-11)-10(-8) M) did not reverse the tachyphylaxis. However, in the proximal part, pretreatment with the voltage-sensitive calcium channel blocker nifedipine (10(-6) M) blunted the tachyphylactic effect of a second administration of AII. When L-arginine (L-Arg) was administered to the bath solution, thus activating the NO system, the development of tachyphylaxis was suppressed in the proximal region. Pretreatment with the protein kinase C (PKC) inhibitor chelerythrine (10(-6) M) did not affect the tachyphylaxis. We conclude that the calcium response to AII in the isolated rabbit afferent arteriole shows tachyphylaxis. This tachyphylaxis cannot be reversed by applying increasing doses of AII (10(-11)-10(-8) M). PKC does not seem to be involved in the tachyphylactic phenomenon in this preparation. It was also found that nifedipine and NO reduced the tachyphylaxis.

Alkaloids↗

PubMed1997

Effects of stimulation and inhibition of protein kinase C on the cytosolic calcium concentration in rabbit afferent arterioles.

The effect of the protein kinase C (PKC) inhibitor chelerytrine (Ch) and the PKC activator 12-0-tetradecanoyl-phorbol-13-acetate (TPA) on the cytosolic calcium concentration ([Ca2+]i) in isolated intact rabbit afferent arterioles was investigated. [Ca2+]i was measured in the proximal and distal parts of the arteriole. Administration of 1 microM Ch gave rise to a peak followed by an elevated level of [Ca2+]i in both these parts. Neither the peak nor the elevated level of [Ca2+]i was significantly reduced by 1 microM nifedipine. The relative peak increase in [Ca2+]i in response to 1 microM noradrenaline (NA) or to 10 nM angiotensin II (AII) was significantly blunted in both parts after preincubation with 1 microM Ch. Depolarization with 25 mM K+ increased [Ca2+]i in both parts. Preincubation with Ch did not affect the increase in [Ca2+]i induced by 25 mM K+. TPA (10 and 100 nM) did not significantly affect the basal [Ca2+]i in the afferent arteriole. The [Ca2+]i response to NA or 25 mM K+ was not affected by TPA. We conclude that blockade of PKC increases [Ca2+]i in afferent arteriolar smooth muscle by a mechanism independent of L-type voltage-sensitive calcium channels. Inhibition of PKC blunts the relative increase in [Ca2+]i in response to AII and, to a lesser extent, that induced by NA. We conclude that PKC might be important in modulating the calcium changes that occur in response to these vasoconstrictors.

Adrenergic alpha-Agonists↗

PubMed1995

Neurologic manifestations of intravascular lymphomatosis.

Intravascular lymphomatosis is a rare fatal neoplasm characterized by malignant cells of lymphocytic lineage producing vascular occlusions. The cerebral vasculature is particularly affected. Two patients seen at our institution presented with progressive neurologic deficits including dementia, hemiparesis and myelopathy. Review of an additional 64 reported cases with neurologic involvement indicates that patients developed intermittent fevers, an encephalopathy ranging from acute disorientation to rapidly progressive dementia, and focal signs such as hemiparesis and myelopathy. Common laboratory abnormalities include elevated cerebrospinal fluid protein and a lymphocytic pleocytosis, elevated blood erythrocyte sedimentation rate and serum lactate dehydrogenase. Malignant cells are rarely seen in cerebrospinal fluid, blood or bone marrow. Neuroimaging is usually abnormal with parenchymal lesions seen on cerebral tomography and magnetic resonance imaging along with an occasional meningeal pattern of contrast enhancement. Treatment with corticosteroids, chemotherapy, radiation therapy, or plasmapheresis provided limited benefit. Intravascular lymphomatosis should be considered in the differential diagnosis of unexplained progressive encephalopathy with superimposed focal deficits.

Aged↗

PubMed1995

Comparison of magnetic resonance imaging and histology in collagenase-induced hemorrhage in the rat.

Complex changes in the appearance of blood on magnetic resonance images (MRIs) complicate interpretation of intracerebral hemorrhage. In this study serial MRIs of intracerebral hemorrhage were obtained at 1.5 T, using a recently developed model for brain hemorrhage, and the MRI findings were compared with histological findings. Hemorrhages were induced in 24 adult rats by the stereotactic injection of 0.5 unit of bacterial collagenase into the caudate/putamen. Initially, there was hypointensity seen on both T1- and T2-weighted images. Conversion to hyperintensity began on both T1- and T2-weighted images around 10 hours, when red blood cell lysis was observed histologically. By 24 hours, complete conversion to marked hyperintensity had occurred. Calculated T2 values increased twofold to fivefold after lysis, indicating that T2 effects dominate the conversion to hyperintensity seen after red blood cell lysis. At 24 hours there was a rim of intact red blood cells around the lesion, which was hypointense on MRI at a time when iron stains were negative. Fresh blood appears hypointense on T1- and T2-weighted images both at the early stages of a bleed and at later stages when rebleeding occurs. Collagenase-induced hemorrhage is a useful animal model to follow the evolution of paramagnetic effects of blood on MRI.

Animals↗

PubMed1994

Methylmercury poisoning: long-term clinical, radiological, toxicological, and pathological studies of an affected family.

For 3 months in 1969 a family in the United States that included a pregnant mother consumed pork containing methylmercury. Children, aged 20, 13, and 8 years and a neonate, developed severe neurological signs. Twenty-two years later, the 2 oldest had cortical blindness or constricted visual fields, diminished hand proprioception, choreoathetosis, and attentional deficits. Magnetic resonance images showed tissue loss in the calcarine and parietal cortices and cerebellar folia. The youngest had quadriplegia, blindness, and severe mental retardation until their deaths. The brain of the 8-year-old who died at age 30 showed cortical atrophy, neuronal loss, and gliosis, most pronounced in the paracentral and parietooccipital regions. The total mercury level in formalin-fixed, left occipital cortex was 1,974 ng/gm as measured by atomic absorption. Regional brain mercury levels correlated with extent of brain damage. A control patient had 38.5 ng of mercury/gm in the occipital cortex. Systemic organs in the patient and a control subject had comparable mercury levels. In mercury-intoxicated rats, we found that only 5 to 10% of total brain mercury was lost by formalin fixation. Brain inorganic mercury in the patient ranged from 82 to 100%. Since inorganic mercury crosses the blood-brain barrier poorly, biotransformation of methyl to inorganic mercury may have occurred after methylmercury crossed the blood-brain barrier, accounting for its persistence in brain and causing part of the brain damage.

Adolescent↗

PubMed1994

Solvent vapor abuse leukoencephalopathy. Comparison to adrenoleukodystrophy.

Chronic organic solvent vapor inhalation can cause permanent damage to the central nervous system. Clinical features and radiologic abnormalities are well known, but pathology has not been definitely established. This study describes the gross, microscopic and ultrastructural changes and fatty acid composition of cholesterol esters in the brain of two chronic paint sniffers as well as the electron microscopic findings from a third, all with permanent neurological impairment. The abnormalities which were the same in all cases consisted of a demyelinating process which grossly manifested itself as brain atrophy and subtle discoloration of the cerebral and cerebellar white matter. Periodic acid-Schiff-positive macrophages in the absence of foamy macrophages were the histological hallmark of this process. Electron microscopy revealed oval membrane-bound cytoplasmic bodies filled with bundles of trilaminar inclusions composed of 3 nm paired dense leaflets separated by a space 3-7 nm wide in macrophages. Biochemical analysis showed an increase of very long chain fatty acids in the white matter cholesterol esters. This study defines the morphologic substrate of solvent vapor abuse leukoencephalopathy. The novel ultrastructural observations in conjunction with biochemical findings provide a link with adrenoleukodystrophy and raise the possibility of similar mechanisms of myelin degradation in both.

Administration, Inhalation↗

PubMed1994

Cell calcium concentration in glomerular afferent and efferent arterioles under the action of noradrenaline and angiotensin II.

The glomerular arterioles in the juxtaglomerular apparatus seem to function as effectors of the tubuloglomerular feedback mechanism. In this mechanism increased delivery of fluid to the distal nephron activates the macula densa cells through transport via an Na-2Cl-K cotransporter. This activation may lead to vasoconstriction of the afferent arteriole. Furthermore, vasoactive substances seem to affect both afferent and efferent arterioles. There are morphological differences along the afferent arteriole, some parts containing epithelioid cells with renin granules and others regular smooth muscle cells. The aim of the present experiments was to determine whether noradrenaline (10(-6) M) and angiotensin II (10(-6) M) had differential effects on the cell calcium concentration [Ca2+]i and on contraction in isolated perfused afferent and efferent arterioles and in the mesangial region. [Ca2+]i was measured with fura-2, an intensified videocamera and a digital imaging system. From the proximal to the distal part of the arteriole [Ca2+]i increased from about 100 to 250 nM. A [Ca2+]i increase and a contraction were caused by noradrenaline alone in the proximal part of the afferent arteriole and by angiotensin II alone in the distal part of this arteriole. In the mesangial region there was a high basal [Ca2+]i but no response to the vasoactive substances. In the efferent arteriole, application of both noradrenaline and angiotensin II led to an increase in [Ca2+]i and a contraction. The present experiments indicate that the two vasoactive substances tested act in a similar fashion along the whole length of the efferent arteriole, while in the afferent arteriole their actions are not equally distributed.

Angiotensin II↗

PubMed1993

Bacterial collagenase disrupts extracellular matrix and opens blood-brain barrier in rat.

Bacterial collagenase causes hemorrhagic necrosis of brain. We studied the enzyme's effect on blood-brain barrier (BBB) permeability and extracellular matrix (ECM) structure by radiolabeled tracers and electron microscopy. Adult rats had intracerebral injection of bacterial collagenase. Brain uptake from blood of [14C]sucrose was measured in 24 rats 0.5 h to 14 days after injection. 12 rats had ultrastructural studies 1 h after collagenase injection. Brain uptake of [14C]sucrose is maximally increased at 0.5 h, remaining significantly increased for 7 days. Ultrastructurally, some vessels had widening of basal lamina while others had severe disruption of basal lamina with stretching of endothelial cells. We conclude that bacterial collagenase disrupts ECM and opens BBB.

Animals↗

PubMed1993

Devic's neuromyelitis optica: a clinicopathological study of 8 patients.

We report the clinical, imaging, and laboratory features of 8 patients with Devic's neuromyelitis optica. All patients had severe myelopathy and optic neuritis. In no patient was the brain, the brainstem, or the cerebellum affected, even after several years of disease. Various immunosuppressive treatments failed to benefit the patients, 5 of whom died. Autopsies of these 5 patients demonstrated a severe necrotizing myelopathy with thickening of blood vessel walls and no lymphocyte infiltrates. In the appropriate clinical setting, the lack of white matter abnormalities demonstrated by magnetic resonance imaging of the head facilitates the recognition of Devic's syndrome during life. Inasmuch as Devic's myelopathy is necrotizing, rather than demyelinating, the prognosis of this syndrome is poor.

Adult↗

PubMed1993

The cytosolic chloride concentration in macula densa and cortical thick ascending limb cells.

It is believed that chloride transport through the macula densa (MD) cells is a factor involved in the tubuloglomerular feedback (TGF) mechanism and in MD-mediated renin release. In this study isolated and perfused rabbit kidney cortical thick ascending limb (cTAL) segments containing MD plaques and attached glomeruli were loaded with chloride (CL-sensitive) 6 methoxy-1-fluorophore (sulphanate-propyl) quinolinium (SPQ). MD and cTAL intracellular chloride concentration ([Cl-]i) was determined by using image-intensified video microscopy and digital image-processing for measuring the intensity of the emitted SPQ fluorescence. With 150 mM NaCl in lumen and bath the [Cl-]i in MD and cTAL cells was 58.8 +/- 7.2 mM (n = 20) and 68.7 +/- 9.8 mM (n = 14), respectively. When the presumed luminal Na(+)-2Cl(-)-K+ co-transporter was blocked by adding 10(-4)M furosemide, the [Cl-]i was reduced in both, MD and cTAL cells from 55.5 +/- 11.9 to 28.6 +/- 10.0 mM (n = 10) and from 43.8 +/- 2.6 to 13.1 +/- 4.5 mM (n = 5), respectively. A reduction in luminal NaCl from 150 to 30 mM also decreased both, MD and cTAL [Cl-]i from 69.4 +/- 9.1 to 36.5 +/- 5.1 mM (n = 9) and from 82.9 +/- 14.5 to 49.4 +/- 8.0 mM (n = 8), respectively. Basolateral addition of the Cl(-)-channel blocker NPPB increased MD [Cl-]i from 31.1 +/- 2.0 to 100.7 +/- 17.0 mM (n = 5) and cTAL [Cl-]i from 44.4 +/- 12.9 to 89.7 +/- 11.7 mM (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

TIMP-2 reduces proteolytic opening of blood-brain barrier by type IV collagenase.

Intracerebral hemorrhage occurs in tumors, stroke and head trauma. Proteolysis of the extracellular matrix around cerebral capillaries by naturally occurring mammalian 72-kDa type IV collagenase may initiate this pathologic event. To investigate this hypothesis adult rats underwent intracerebral injection of type IV collagenase purified from human melanoma cells. Histologically, at 4 h there was perivascular cellular infiltration with hemorrhage, and by 24 h there was infarction with necrosis, edema and hemorrhage. Ultrastructurally, the basal lamina of endothelial cells was disrupted at 2 h. Brain uptake of [14C]dextran and [3H]sucrose increased after intracerebral injection of type IV collagenase compared to controls (P less than 0.0001). Tissue inhibitor of metalloproteinase-2 (TIMP-2) reduced the tracer uptake (P less than 0.02). Metalloproteinase inhibitors reduce extracellular matrix proteolysis and protect the blood-brain barrier.

Analysis of Variance↗