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PubMed2006

Blood-brain barrier and chemotherapeutic treatment of brain tumors.

The blood-brain barrier (BBB) is of pivotal importance to maintain homeostasis of the CNS, as it closely regulates the composition of the interstitial fluid in the brain. Unfortunately, malignancies that grow within the CNS may evade chemotherapeutic drugs using the same barrier, making this disease refractory to most chemotherapy regimens. This review will outline the impact of the BBB in brain cancer and discuss the efforts that have been made to enhance the drug exposure of brain tumors. Although this review will focus on the role of the BBB in primary brain cancer (malignant glioma), its impact on brain metastases will also be briefly discussed.

Antineoplastic Agents↗
PubMed2002

Strategies for increasing drug delivery to the brain: focus on brain lymphoma.

The blood-brain barrier (BBB) is a gate that controls the influx and efflux of a wide variety of substances and consequently restricts the delivery of drugs into the central nervous system (CNS). Brain tumours may disrupt the function of this barrier locally and nonhomogeneously. Therefore, the delivery of drugs to brain tumours has long been a controversial subject. The current concept is that inadequate drug delivery is a major factor that explains the unsatisfactory response of chemosensitive brain tumours. Various strategies have been devised to circumvent the BBB in order to increase drug delivery to the CNS. The various approaches can be categorised as those that attempt to increase delivery of intravascularly administered drugs, and those that attempt to increase delivery by local drug administration. Strategies that increase delivery of intravascularly injected drugs can manipulate either the drugs or the capillary permeability of the various barriers (BBB or blood-tumour barrier), or may attempt to increase plasma concentration or the fraction of the drug reaching the tumour (high-dose chemotherapy, intra-arterial injection). Neurotoxicity is a major concern with increased penetration of drugs into the CNS or when local delivery is practised. Systemic toxicity remains the limiting factor for most methods that use intravascular delivery. This review evaluates the strategies used to increase drug delivery in view of current knowledge of drug pharmacokinetics and its relevance to clinical studies of chemosensitive brain tumours. The main focus is on primary CNS lymphoma, as it is a chemosensitive brain tumour and its management routinely utilises specialised strategies to enhance drug delivery to the affected CNS compartments.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Considerations in the use of cerebrospinal fluid pharmacokinetics to predict brain target concentrations in the clinical setting: implications of the barriers between blood and brain.

In the clinical setting, drug concentrations in cerebrospinal fluid (CSF) are sometimes used as a surrogate for drug concentrations at the target site within the brain. However, the brain consists of multiple compartments and many factors are involved in the transport of drugs from plasma into the brain and the distribution within the brain. In particular, active transport processes at the level of the blood-brain barrier and blood-CSF barrier, such as those mediated by P-glycoprotein, may lead to complex relationships between concentrations in plasma, ventricular and lumbar CSF, and other brain compartments. Therefore, CSF concentrations may be difficult to interpret and may have limited value. Pharmacokinetic data obtained by intracerebral microdialysis monitoring may be used instead, providing more valuable information. As non-invasive alternative techniques, positron emission tomography or magnetic resonance spectroscopy may be of added value.

Animals↗
PubMed2001

Asymptomatic brain tumor detected at brain check-up.

Brain check-up was performed in 4000 healthy subjects who underwent medical and radiological examinations for possible brain diseases in our hospital from April 1996 to March 2000. Magnetic resonance imaging revealed 11 brain tumors which consisted of six meningiomas, three pituitary adenomas, one astrocytoma, and one epidermoid cyst. The detection rate of incidental brain tumor in our hospital was 0.3%. Nine patients underwent surgery, with one case of morbidity due to postoperative transient oculomotor nerve paresis. The widespread use of brain check-up may increasingly detect asymptomatic brain tumors. Surgical indications for such lesions remain unclear, and the strategy for treatment should be determined with consideration of the patient's wishes.

Adenoma↗
PubMed2003

Ring-enhanced mass in the brain of a woman with systemic lupus erythematosus and elevated serum CA19-9 level: brain abscess or metastatic tumor?--case report.

A 70-year-old woman with systemic lupus erythematosus presented with a brain abscess manifesting as progressive monoparesis of the right lower extremity over 4 days. She had had no episodes of fever, and did not complain of headache or exhibit any signs of meningeal irritability. Computed tomography of the brain showed a round, low-density mass with strong ring enhancement in the left frontal lobe. Laboratory examination found a moderately elevated serum level of CA19-9, a marker of some digestive organ cancers. Together with the absence of febrile episodes, headache, and a rise in leukocyte count, the initial suspicion was metastatic brain tumor rather than brain abscess. However, diffusion-weighted magnetic resonance imaging depicted the mass as a very hyperintense area. The neuroimaging diagnosis was brain abscess. After conservative treatment with intravenous antibiotics for 6 weeks, the brain abscess completely resolved, and the patient was discharged without neurological deficits.

Aged↗
PubMed1980

Acute intracranial hypertension and auditory brain-stem responses. Part 3: The effects of posterior fossa mass lesions on brain-stem function.

The auditory brain-stem responses (BER's), infratentorial intracranial pressure (ICP), systemic blood pressure (BP), and heart rate were recorded before, during and after expansion of an infratentorial epidural mass in anesthetized cats. Two types of BER's to increasing posterior fossa pressure were noted. In Type 1, there was predominantly suppression of the electrical activity of the auditory nuclei of the upper brain stem (Waves V and IV) and upward transtentorial herniation of the midbrain. In Type 2, the neural activity of the lower brain-stem nuclei (Waves III and II) was affected as well as that of the upper brain stem. There was upward and foraminal impaction of the brain stem and cerebellum which was confirmed by the postmortem brain sections. The change in the amplitudes of BER Waves V and III proved useful in detecting upward transtentorial herniation of the midbrain and foraminal herniation of the cerebellum in acute expanding lesions of the posterior fossa. Medullary paralysis was also detected by observing Wave III.

Animals↗
PubMed1986

The kallikrein-kinin system as mediator in vasogenic brain edema. Part 3: Inhibition of the kallikrein-kinin system in traumatic brain swelling.

Evidence has previously been provided that administration of kinins to the cerebrum causes edema and opening of the blood-brain barrier. It has further been shown that these highly active compounds are formed in the brain under pathophysiological conditions. Their formation was enhanced when cerebral blood flow became compromised by an increase in intracranial pressure. Final evidence, however, was not available as to whether specific inhibition of the kallikrein-kinin (KK) system has a therapeutic function in acute head injury. The authors have demonstrated in rabbits that inhibition of the activating enzyme kallikrein by aprotinin or by aprotinin plus soybean trypsin inhibitor (SBTI), which interfere with plasma and tissue kallikrein, is associated with a decrease in formation of posttraumatic swelling after a standardized cold lesion to the brain. Saline-treated control animals with cerebral cold-induced injury had an increase in hemispheric weight 24 hours later of 13.0% +/- 0.8% (standard error of the mean) in the damaged hemisphere compared to the contralateral nondamaged hemisphere. Administration of aprotinin or aprotinin plus SBTI led to a significant reduction of hemispheric swelling of 10.1% +/- 0.7% or 10.4% +/- 0.7%, respectively. In animals receiving SBTI only, hemispheric swelling evolving from cold injury was not significantly reduced. Therapeutic reduction of brain edema by aprotinin cannot be attributed to a nonspecific effect on the blood pressure, which in the experimental groups remained almost normal as compared to the control animals. Failure of SBTI to influence posttraumatic brain swelling may have resulted from disturbances in intravascular coagulation. Measurements of aprotinin in plasma and tissue demonstrate that the inhibitor doses employed are within an effective therapeutic range. Attenuation of brain edema by specific inhibition of the KK system provides evidence for a mediator role of kinins in vasogenic edema. Clinical trials with inhibitors of the KK system in acute forms of traumatic lesions associated with vasogenic edema appear worthwhile.

Animals↗
PubMed1987

Quantitative study of microvessel ultrastructure in human peritumoral brain tissue. Evidence for a blood-brain barrier defect.

The form and function of blood vessels are determined by the cells that constitute their microenvironment. Brain tissue around tumors contains varying numbers of tumor cells that could influence local capillaries to lose their blood-brain barrier (BBB), as they do in the tumor itself. Microvascular permeability cannot be measured directly in humans but can be inferred from a knowledge of vessel ultrastructure. The authors have examined the vascular ultrastructure associated with the BBB in human peritumoral brain tissue for evidence of BBB compromise and to correlate BBB features with the cellular components of the vessel microenvironment. Light microscopic examination of brain tissue samples in patients with primary brain tumors showed that the tissue lying beyond the visible edge of the tumor ranged from essentially normal to grossly infiltrated with tumor cells. Although some of the vessels were structurally normal, the microvessels as a group had elongated junctional clefts (unfused regions) and an increase in the density of endothelial vesicles. Furthermore, the cleft index (the percentage of the junctional profile that is unfused) varied directly with the local cell density. A subpopulation of vessels enveloped by a layer of tumor cells was grossly abnormal. However, vessels that were not immediately invested by tumor cells also showed some abnormalities. It is concluded that tumor cells infiltrating peritumoral brain tissue cause blood vessels to take on some of the structural characteristics of leaky vessels. Since direct contact is not required, and since the degree of abnormality correlates with the number of tumor cells in the environment, the authors suggest that this inductive influence is exerted over a distance and is dependent on the concentration of the inducing factors.

Adult↗
PubMed1993

Effect of pentobarbital on normal brain protection and on the response of 9L rat brain tumor to radiation therapy.

The authors attempted to confirm published reports that pentobarbital protects against radiation-induced damage to normal rat brain, as well as enhances radiotherapeutic efficacy in a rat brain tumor model. They evaluated animal survival in 9L gliosarcoma-burdened rats that received whole-brain radiation therapy (16, 24, 32, or 40 Gy) while under intraperitoneal pentobarbital (60 mg/kg) or intramuscular ketamine (60 mg/kg) sedation. The animals were examined at autopsy to attribute death to either intracranial tumor growth or normal brain toxicity in the absence of discernible tumor. There was no difference between the two anesthesia groups regarding the survival of unirradiated animals. Radiation therapy produced a significant dose-dependent prolongation in animal survival, which was limited by the development of normal tissue toxicity at the higher doses. When compared to ketamine anesthesia, pentobarbital anesthesia appeared to offer some protection (not statistically significant) against early (but not late) toxicity at selected radiation doses. A reduction in the number of deaths from tissue toxicity suggested an increased antitumor effect, but again this was not statistically significant. Only in one case was there even a marginal significant difference (p = 0.045) between overall therapeutic efficacy in rats sedated with pentobarbital versus ketamine. While there may be a radioprotective effect of pentobarbital in rat brains without intracranial tumor, there is no conclusive evidence for either radioprotection or significant improvement of radiotherapeutic efficacy in this 9L rat brain tumor model.

Animals↗
PubMed2004

Hyperammonemia, brain edema and blood-brain barrier alterations in prehepatic portal hypertensive rats and paracetamol intoxication.

AIM: To study the blood-brain barrier integrity, brain edema, animal behavior and ammonia plasma levels in prehepatic portal hypertensive rats with and without acute liver intoxication. METHODS: Adults male Wistar rats were divided into four groups. Group I: sham operation; II: Prehepatic portal hypertension, produced by partial portal vein ligation; III: Acetaminophen intoxication and IV: Prehepatic portal hypertension plus acetaminophen. Acetaminophen was administered to produce acute hepatic injury. Portal pressure, liver serum enzymes and ammonia plasma levels were determined. Brain cortex water content was registered and trypan blue was utilized to study blood brain barrier integrity. Reflexes and behavioral tests were recorded. RESULTS: Portal hypertension was significantly elevated in groups II and IV. Liver enzymes and ammonia plasma levels were increased in groups II, III and IV. Prehepatic portal hypertension (group II), acetaminophen intoxication (group III) and both (group IV) had changes in the blood brain-barrier integrity (trypan blue) and hyperammonemia. Cortical edema was present in rats with acute hepatic injury in groups III and IV. Behavioral test (rota rod) was altered in group IV. CONCLUSION: These results suggest the possibility of another pathway for cortical edema production because blood brain barrier was altered (vasogenic) and hyperammonemia was registered (cytotoxic). Group IV, with behavioral altered test, can be considered as a model for study at an early stage of portal-systemic encephalopathy.

Acetaminophen↗
PubMed2002

Effects of magnesium sulfate on brain mitochondrial respiratory function in rats after experimental traumatic brain injury.

OBJECTIVE: To study the effects of magnesium sulfate on brain mitochondrial respiratory function in rats after experimental traumatic brain injury and the possible mechanism. METHODS: The middle degree brain injury in rats was made by BIM-III multi-function impacting machine. The brain mitochondrial respiratory function was measured with oxygen electrode and the ultra-structural changes were observed with transmission electron microscope (TEM). RESULTS: 1. The brain mitochondrial respiratory stage III and respiration control rate reduced significantly in the untreated groups within 24 and 72 hours. But treated Group A showed certain degree of recovery of respiratory function; treated Group B showed further improvement. 2. Untreated Group, treated Groups A and B had different degrees of mitochondrial ultra-structural damage respectively, which could be attenuated after the treatment with magnesium sulfate. CONCLUSIONS: The mitochondrial respiratory function decreases significantly after traumatic brain injury. But it can be apparently improved after magnesium sulfate management along with the attenuated damage of mitochondria discovered by TEM. The longer course of treatment can obtain a better improvement of mitochondrial respiratory function.

Animals↗
PubMed2003

Study on changes of partial pressure of brain tissue oxygen and brain temperature in acute phase of severe head injury during mild hypothermia therapy.

OBJECTIVE: To study the changes of partial pressure of brain tissue oxygen (PbtO2) and brain temperature in acute phase of severe head injury during mild hypothermia therapy and the clinical significance. METHODS: One hundred and sixteen patients with severe head injury were selected and divided into a mild hypothermia group (n=58), and a control group (n=58) according to odd and even numbers of hospitalization. While mild hypothermia therapy was performed PbtO2 and brain temperature were monitored for 1-7 days (mean=86 hours), simultaneously, the intracranial pressure, rectum temperature, cerebral perfusion pressure, PaO2 and PaCO2 were also monitored. The patients were followed up for 6 months and the prognosis was evaluated with GOS (Glasgow outcome scale). RESULTS: The mean value of PbtO2 within 24 hour monitoring in the 116 patients was 13.7 mm Hg +/- 4.94 mm Hg, lower than the normal value (16 mm Hg +/- 40 mm Hg ) The time of PbtO2 recovering to the normal value in the mild hypothermia group was shortened by 10 +/- 4.15 hours compared with the control group (P<0.05). The survival rate of the mild hypothermia group was 60.43%, higher than that of the control group (46.55%). After the recovery of the brain temperature, PbtO2 increased with the rise of the brain temperature. CONCLUSIONS: Mild hypothermia can improve the survival rate of severe head injury. The technique of monitoring PbtO2 and the brain temperature is safe and reliable, and has important clinical significance in judging disease condition and instructing clinical therapy.

Adult↗
PubMedDate not supplied

[Transplantation of stem/progenitor cells of human brain into the brain of adult rats].

We studied the development of stem/progenitor cells of the human brain transplanted in the adult rat brain after reproduction in an in vitro tissue culture. It was preliminarily shown by the immunological methods that the stem cells grown in a medium with growth factors formed neurospheres, which were heterogenous and contained both stem and progenitor cells of the human brain. The cells were implanted in the hippocampus, striatum, or lateral ventricle of the rat brain as a suspension or aggregates (neurospheres) and their behavior and differentiation were studies within 10, 20, and 30 days using the morphological and immunochemical methods. The cultured cells of the human brain continued their development in the rat brain, migrated, and formed neurons and astrocytes. The white mater fibers, lateral ventricle wall, and perivascular spaces served as the main pathways of migration. The neuronal differentiation was shown by staining with antibodies to beta-tubulin III, neurofilaments-70, and calbindin. Some growing nerve cells had long processes with growth cones. At the same time, some transplanted cells retained the undifferentiated state within one month after the implantation, as shown by the vimentin expression.

Age Factors↗
PubMed1975

In vitro studies on target cells of oncogenic adenoviruses in hamster brain. II. In vitro transformation of brain cells of hamsters at various ages by human adenovirus type 12.

In vitro transformations of brain cells of hamsters of various ages were examined after the administration of human adenovirus type 12 (Ad 12) to determine the type and origin of the target cell. Hamster brain cells at all examined ages were transformed by Ad12. Although the virus was not isolated, virus specific tumor antigen was demonstrated in the transformed cells. The histological features of tumors that developed by transplantation of transformed cells closely resembled Ad12-induced brain tumors. The transformed cell focus tended to appear near the embryonic brain cell (EB cell) or glioblastic cell (GB cell). The transformed cells were morphologically similar to the EB or GB cell. Some subcultured transformed cells showed a rosette-like pattern, and the surrounding space arrangement was similar to that of the ventricular wall. The incidence of brain cell transformations decreased with increased hamster age. This decreased incidence with age corresponded to the decreased numbers of EB or GB cells present in progressively older hamsters. From these results, it is concluded that the target cells of AD12 in hamster brain cell cultures are probably the EB or GB cells.

Adenoviridae↗
PubMed2004

Changes of interleukin-1 beta, tumor necrosis factor alpha and interleukin-6 in brain and plasma after brain injury in rats.

OBJECTIVE: To study the changes of interleukin-1 beta (IL-1beta), tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) levels in brain and plasma after brain injury and to assess the relationship between the cytokine levels and injury severity in rats. METHODS: A total of 51 male Wistar rats, weighing 280-340 g, were anesthetized with chloral hydrate (400 mg/kg body weight) through intraperitoneal injection and fixed on a stereotaxic instrument. Severe brain injury was created in 16 rats (severe injury group) and moderate brain injury in 18 rats (moderate injury group) by a fluid percussion model, and cytokine levels of IL-1beta, TNFalpha and IL-6 were measured with biological assay. And sham operation was made on the other 17 rats (control group). RESULTS: In the control group, the levels of IL-1beta, TNFalpha and IL-6 were hardly detected in the cortex of the rats, but in the ipsilateral cortex of the rats in both injury groups, they increased obviously at 8 hours after injury. The increasing degree of these cytokines had no significant difference between the two injury groups. The levels of IL-6 in the plasma of all the rats increased slightly, whereas the levels of IL-1beta and TNFalpha were undetectable. CONCLUSIONS: The increase of IL-1beta, TNFalpha and IL-6 levels is closely related to brain injury. The increased cytokine levels in the central nervous system are not parallel to those in the peripheral blood. It suggests that inflammatory cytokines play important roles in the secondary neural damage after brain injury.

Animals↗
PubMed1992

Effects of nimodipine on brain blood flow following acute brain ischemia in the newborn piglet.

We examined the effect of the calcium channel blocker nimodipine on postischemic hypoperfusion in the newborn piglet brain. A severe pneumothorax (SP) was induced by injecting air into the right thorax until the mean arterial blood pressure fell to 25% of baseline and was maintained for 4 min. Blood flow was immediately reduced 70-90% from baseline in each brain region during SP. In untreated animals postischemic hypoperfusion existed at 60 min, following recovery from SP with regional brain blood flow reduced 20-30% from baseline. Nimodipine infusion after SP prevented postischemic hypoperfusion in all brain regions and increased blood flows by as much as 40% above baseline in midbrain and brainstem structures. Nimodipine infusion began after severe brain ischemia prevented postischemic hypoperfusion and enhanced brain blood flow in this model.

Animals↗
PubMed1991

[Specific brain antigens as the indicators of the blood-brain barrier permeability in Alzheimer's disease].

A study was made of the hypothesis of blood-brain barrier dysfunction in Alzheimer's disease (AD) and of the role it plays in the disease pathogenesis. Use was made of the enzyme immunoassay test systems to detect neurospecific proteins in the blood serum within the following sensitivity range: gliofibrillar acid protein 10 ng/ml, alpha 2-glycoprotein of the brain 0.9 ng/ml, alpha 1- and alpha 2-specific brain globulins 50 pg/ml. Gliofibrillar acid protein and alpha 2-glycoprotein of the brain appeared the most sensitive markers of the process. Demonstration of these antigens in the blood serum in a concentration exceeding donor's ones suggests the impairment of the blood-brain integrity in active passage of brain proteins to the blood. A direct relationship is shown between the level of gliofibrillar acid protein in the blood serum and the severity of the clinical picture of AD.

Alzheimer Disease↗
PubMed1985

Growth of human lung tumor in the brain of the nude rat as a model to evaluate antitumor agent delivery across the blood-brain barrier.

We have developed a brain tumor model in the nude rat utilizing NCI-N417D human small cell carcinoma of the lung grown both intracerebrally and s.c. The median latency period from the time of intracerebral tumor inoculation to the onset of neurological symptoms is 13 days with an intracerebral tumor take rate of 91% (29 of 32). The median survival is 13 days, and all animals were dead by Day 26. The tumor is discrete, well circumscribed, with occasional leptomeningeal spread and with minimal evidence of surrounding cerebral edema. Intracerebrally, this tumor is usually impermeable to Evan's blue:albumin (Mr 68,500) but not fluorescein (Mr 376). Although variable, the intracerebral tumor is less permeable to methotrexate than is the same tumor grown s.c. in the same animal (P less than 0.005). The intraarterial and i.v. routes of methotrexate administration in the presence and absence of blood-brain barrier opening were evaluated. Drug delivery to the intracerebral tumor and ipsilateral brain was significantly (P less than 0.025) greater when the methotrexate was given intraarterially and was significantly (P less than 0.0025) increased after osmotic blood-brain barrier opening. After barrier opening, methotrexate concentration was enhanced 3- to 4-fold in tumor and 10- to 20-fold in brain around tumor. Thus, the nude rat provides a model to investigate the biology and therapeutic responsiveness of human small cell carcinoma of the lung grown intracerebrally where it develops a blood-tumor barrier similar to that seen in humans. This model further provides the unique opportunity to investigate the role of osmotic blood-brain barrier opening in the treatment of a tumor which is sensitive to chemotherapeutic agents and for which tumor-specific monoclonal antibodies are available.

Animals↗