Absence Of Blood-brain Barrier Research Articles

The aquaporin-4 inhibitor AER-271 blocks acute cerebral edema and improves early outcome in a pediatric model of asphyxial cardiac arrest.

Background:Cerebral edema after cardiac arrest (CA) is associated with increased mortality and unfavorable outcome in children and adults. Aquaporin-4 mediates cerebral water movement and its absence in models of ischemia improves outcome. We investigated early and selective pharmacologic inhibition of aquaporin-4 in a clinically relevant asphyxial CA model in immature rats in a threshold CA insult that produces primarily cytotoxic edema in the absence of blood brain barrier permeability.Methods:Postnatal day 16–18 Sprague-Dawley rats were studied in our established 9-min asphyxial CA model. Rats were randomized to aquaporin-4 inhibitor (AER-271) vs vehicle treatment, initiated at return of spontaneous circulation. Cerebral edema (% brain water) was the primary outcome with secondary assessments of the neurologic deficit score (NDS), hippocampal neuronal death, and neuroinflammation.Results:Treatment with AER-271 ameliorated early cerebral edema measured at 3 h after CA vs. vehicle treated rats. This treatment also attenuated early NDS. In contrast to rats treated with vehicle after CA, rats treated with AER-271 did not develop significant neuronal death or neuroinflammation as compared to sham.Conclusion:Early post-resuscitation aquaporin-4 inhibition blocks the development of early cerebral edema, reduces early neurologic deficit, and blunts neuronal death and neuroinflammation post-CA.

DNA damage response in peripheral nervous system: Coping with cancer therapy-induced DNA lesions

In the absence of blood brain barrier (BBB) the DNA of peripheral nervous system (PNS) neurons is exposed to a broader spectrum of endogenous and exogenous threats compared to that of the central nervous system (CNS). Hence, while CNS and PNS neurons cope with many similar challenges inherent to their high oxygen consumption and vigorous metabolism, PNS neurons are also exposed to circulating toxins and inflammatory mediators due to relative permeability of PNS blood nerve barrier (BNB). Consequently, genomes of PNS neurons incur greater damage and the question awaiting investigation is whether specialized repair mechanisms for maintenance of DNA integrity have evolved to meet the additional needs of PNS neurons. Here, I review data showing how PNS neurons manage collateral DNA damage incurred in the course of different anti-cancer treatments designed to block DNA replication in proliferating tumor cells. Importantly, while PNS neurotoxicity and concomitant chemotherapy-induced peripheral neuropathy (CIPN) are among major dose limiting barriers in achieving therapy goals, CIPN is partially reversible during post-treatment nerve recovery. Clearly, cell recovery necessitates mobilization of the DNA damage response and underscores the need for systematic investigation of the scope of DNA repair capacities in the PNS to help predict post-treatment risks to recovering neurons.

Intraparenchymal schwannomas: Report of two new cases studied with MRI and review of the literature

Intraparenchymal schwannomas are very rare tumours. We present two young adult patients operated for this type of lesion who show no signs of recurrence 2 years after surgery. These tumours have a bimodal peak of presentation: most occur in young patients under 25 years, and the rest present in the elderly. Characteristically they show both Antoni A and Antoni B areas, intense inmunoreactivity to S-100 and Vimentin protein, and none to EMA or CD34. Electron microscopy is diagnostic when basal membrane is found around the cytoplasmatic processes. MRI spectroscopy depicts increased myoinositol, choline and lipids, and perfusion MR demonstrates high rCBV with a characteristic curve due to the total absence of blood brain barrier. An origin in the Schwann cells of the perivascular nervous plexus in the subarachnoid space is the most accepted theory for the histogenesis of these tumours. We propose to perform the characterization of a series of markers such as SOX-10 in every new case in order to prove that theory.

Existence of blood brain barrier in brain metastases with breast cancer

13513 Background: Increasing of the incidence of brain metastases in breast cancer patients is an important clinical problem. Brain metastases are refractory to chemotherapy due to existence of blood brain barrier (BBB). However, the structure and mechanism of BBB is not fully understood. We examine expression and localization of BBB with representative immunohistochemical markers of glucose transporter 1 (Glut-1) and breast cancer resistance protein (BCRP) in brain metastases with breast cancer patients. Methods: Between 1999 and 2006 at National Cancer Center Hospital in Japan, 29 patients who had metastatic breast cancer underwent metastatic brain tumor excision. Glut-1 and BCRP expression of brain metastases in 29 patients were examined by immunohistochemistry. We also performed the immunohistochemical analyses for estrogen receptor (ER), progesterone receptor (PgR), HER2 and phosphohistone-H3 (PHH3). If intratumoral microvessels in brain metastases were negative for both Glut-1 and BCRP, we regarded as absence of BBB. Results: Nine (31%) and eleven (38%) out of total 29 in tumor microvessels were negative for Glut-1 and BCRP, respectively. Eight (28%) were negative for both Glut-1 and BCRP. There was significant association between Glut-1 and BCRP (p=0.0001). Glut-1 was significantly associated with HER2 (p=0.004). BBB had no correlation with ER and PgR. PHH3 was not associated with BBB. Conclusions: BBB was absent in 8 (28%) out of total 29 in brain metastases with breast cancer. Although further studies are warranted, drug bioavailability to tumors may be also different in brain metastases of breast cancer. No significant financial relationships to disclose.

In vivo measurements of T1 relaxation times in mouse brain associated with different modes of systemic administration of manganese chloride

To measure regional T1 and T2 values for normal C57Bl/6 mouse brain and changes in T1 after systemic administration of manganese chloride (MnCl2) at 9.4 T. C57Bl/6 mice were anesthetized and baseline T1 and T2 measurements obtained prior to measurement of T1 after administration of MnCl2 at 9.4 T. MnCl2 was administered systemically either by the intravenous (IV), intraperitoneal (IP), or subcutaneous (SC) routes. T1 and T2 maps for each MRI transverse slice were generated using commercial software, and T1 and T2 values of white matter (WM), gray matter (GM), pituitary gland, and lateral ventricle were obtained. When compared with baseline values at low-field, significant lengthening of the T1 values was shown at 9.4 T, while no significant change was seen for T2 values. Significant T1 shortening of the normal mouse brain was observed following IV, IP, and SC administration of MnCl2, with IV and IP showing similar acute effects. Significant decreases in T1 values were seen for the pituitary gland and the ventricles 15 minutes after either IV or IP injection. GM showed greater uptake of the contrast agent than WM at 15 and 45 minutes after either IV or IP injections. Although both structures are within the blood-brain barrier (BBB), GM and WM revealed a steady decrease in T1 values at 24 and 72 hours after MnCl2 injection regardless of the route of administration. Systemic administration of MnCl2 by IV and IP routes induced similar time-course of T1 changes in different regions of the mouse brain. Acute effects of MnCl2 administration were mainly influenced by either the presence or absence of BBB. SC injection also provided significant T1 change at subacute stage after MnCl2 administration.

Enhanced neuroprotective effects of basic fibroblast growth factor in regional brain ischemia after conjugation to a blood-brain barrier delivery vector.

Basic fibroblast growth factor (bFGF) has minimal pharmacological effects in the central nervous system in the absence of blood-brain barrier (BBB) disruption. BBB transport of bFGF occurs via an absorptive-mediated transcytosis mechanism, which is relatively inefficient. To enhance the BBB transport of bFGF, this neurotrophin was reformulated to enable receptor-mediated transport across the BBB via the transferrin receptor. bFGF was monobiotinylated and coupled to a BBB drug-delivery vector comprised of streptavidin (SA) and the OX26 monoclonal antibody to the rat transferrin receptor. The entire conjugate of biotinylated bFGF bound to the OX26-SA is designated bio-bFGF/OX26-SA. The bFGF retains receptor-binding affinity and has increased brain uptake following conjugation to OX26-SA. The bio-bFGF/OX26-SA conjugate protects cortical cell cultures against hypoxia/reoxygenation insult in a dose-dependent manner in vitro. A single intravenous injection of bio-bFGF/OX26-SA, equivalent to a dose of 25 microg/kg bFGF, produces an 80% reduction in infarct volume in the brain of rats subjected to permanent occlusion of the middle cerebral artery in parallel with a significant improvement of neurologic deficit. The neuroprotection is time-dependent, and there is a 67% reduction in stroke volume if the conjugate is administered at 60 min after arterial occlusion, whereas no significant reduction in stroke volume is observed if treatment is delayed 2 h. In conclusion, neuroprotection in regional brain ischemia is possible following the delayed intravenous injection of low doses of bFGF providing the neurotrophin is conjugated to a BBB drug-targeting system.

Regeneration of neurosecretory axons into various types of intrahypothalamic grafts is promoted by the absence of blood brain barrier: fine structural analysis

Isogenous grafts of neural lobe and optic nerve and autologous grafts of sciatic nerve were placed into contact with the intrahypothalamically transected hypothalamo-neurohypophysial tract, and their fine structural characteristics examined at various time periods thereafter. The vascular bed of neural lobe grafts is composed primarily of fenestrated capillaries, that are permeable to blood-borne HRP throughout the entire experimental period. The microvasculature of sciatic nerve grafts consists of continuous, as well as fenestrated capillaries, which are similarly permeable to HRP. Fenestrated capillaries and HRP leakage in optic nerve grafts are observed at 10 days, but only in grafts located ventrally in the hypothalamus at 30 days. Neurosecretory axon regeneration is seen only in grafts or adjacent hypothalamus where the blood-brain barrier is breached. Regenerating axons are closely associated with the specific glial cells of the respective graft. Based on these observations, we conclude that blood-borne factors are necessary to initiate and sustain regeneration of transected neurosecretory axons, and that such regeneration occurs only in the presence of glial cells.

Ultrastructure of hypothalamic and medullary lesions caused by an aliphatic triamine.

The administration of an aliphatic triamine, 3,3'-methylimino-bis-(N-methylpropylamine), was used to produce non-necrotizing lesions in the hypothalamus and medulla oblongata of rats. The distribution of the lesions in the hypothalamus was similar to that produced by goldthioglucose, and consisted ultrastructurally of marked distention and edema of the extracellular space, with no confined to the dorsal aspect, in the region of the area postrema. The data suggest that the absence of blood-brain barrier in these sites plays a role in the production of lesions, at least in the initial stages, as has been proposed for goldthioglucose lesions.