scholarly journals The blood-brain barrier internalisesCryptococcus neoformansvia the EphA2-tyrosine kinase receptor

2018 ◽  
Vol 20 (3) ◽  
pp. e12811 ◽  
Author(s):  
Phylicia A. Aaron ◽  
Mantana Jamklang ◽  
John P. Uhrig ◽  
Angie Gelli
Keyword(s):  
Tyrosine Kinase ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Tyrosine Kinase Receptor ◽  
Blood Brain

BMS-354825, a Dual SRC/ABL Kinase Inhibitor, Displays Potent Anti-Tumor Activity in a Model of Intracranial CML Growth.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1988-1988 ◽  
Author(s):  
Robert Wild ◽  
Stephen Castaneda ◽  
Christine Flefleh ◽  
Krista Fager ◽  
Ivan Inigo ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Blood Brain Barrier ◽  
Small Molecule ◽  
Kinase Inhibitor ◽  
High Rate ◽  
Brain Barrier ◽  
Preclinical Model ◽  
Dual Function ◽  
Imatinib Resistance ◽  
Blood Brain

Abstract Chronic myeloid leukemia (CML) is a stem cell disorder caused by a constitutively activated tyrosine kinase, the BCR-ABL oncoprotein. Imatinib (STI571, Gleevec) is a small-molecule inhibitor of this kinase that produces clinical remissions in CML patients and is now frontline therapy for this disease. While this agent has a high rate of clinical success in early phases of CML, development of resistance to this drug is increasingly becoming problematic, particularly in later stages of the disease. Moreover, growing evidence suggests that imatinib has very poor penetration of the blood brain barrier, likely due at least partly to its being a substrate of P-glycoprotin (Pgp), resulting in subtherapeutic levels in the CNS. As a result, several clinical cases have been reported where CNS relapses occurred in imatinib treated CML patients despite peripheral blood and bone marrow complete responses (Leis et al., Leuk Lymphoma. 2004 Apr;45(4):695–8). This phenomenon has also been recapitulated in at least one preclinical model, where the limited ability of imatinib to cross the blood-brain barrier allowed the CNS to become a sanctuary for BCR-ABL-induced leukemia (Wolff et al., Blood. 2003 Jun 15;101(12):5010–3). BMS-354825, a small-molecule dual-function SRC/ABL tyrosine kinase inhibitor, was designed to overcome many of the limitations associated with imatinib therapy. BMS-354825 has more than 500-fold increased potency relative to imatinib versus BCR-ABL and more importantly retains activity against 14 of 15 imatinib-resistant BCR-ABL mutants (Shah et al., Science, 2004 Jul 16;305(5682):399–401). In addition, BMS-354825 proved to be equally effective against several preclinically- and clinically-derived tumor models of imatinib resistance (Lee et al., Proceedings of the AACR, Volume 45, March 2004). In the current study, we assessed the efficacy of BMS-354825, which is not a Pgp substrate, in a model of established intracranial CML tumors. SCID-beige mice bearing K562 CML tumors implanted intracranially (2x106 cells per animal) were treated with BMS-354825 orally b.i.d. for a period of up to 40 days. BMS-354825 proved to be exceptionally efficacious resulting in increased lifespan of animals by 450% and 268% for the 15 mg/kg and 5 mg/kg dose levels, respectively. In order to more directly assess the anti-tumor activities of BMS-354825 in this intracranial CML model, we implanted K562 cells stably transfected with the firefly luciferase gene intracranially into SCID-beige animals. Bioluminescent imaging (BLI) then allowed the non-invasive monitoring of in vivo growth of these tumors. BMS-354825 at 15 mg/kg (2qdx14;6 po) achieved tumor regressions and subsequent complete stasis of intracranial K562 growth while animals were on therapy. In summary, these results suggest that BMS-354825 may have therapeutic advantages over imatinib in the management of intracranial CML disease and warrants further clinical investigation.

scholarly journals EphrinB2 Activation Enhances Vascular Repair Mechanisms and Reduces Brain Swelling After Mild Cerebral Ischemia

2017 ◽  
Vol 37 (5) ◽  
pp. 867-878 ◽  
Author(s):  
Adnan Ghori ◽  
Florian B. Freimann ◽  
Melina Nieminen-Kelhä ◽  
Irina Kremenetskaia ◽  
Karen Gertz ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Blood Brain Barrier ◽  
Major Complication ◽  
Artery Occlusion ◽  
Brain Barrier ◽  
Tyrosine Kinase Receptor ◽  
Vascular Repair ◽  
Brain Swelling ◽  
Blood Brain ◽  
Repair Mechanisms

Objective— Cerebral edema caused by the disruption of the blood–brain barrier is a major complication after stroke. Therefore, strategies to accelerate and enhance neurovascular recovery after stroke are of prime interest. Our main aim was to study the role of ephrinB2/EphB4 signaling in mediating the vascular repair and in blood–brain barrier restoration after mild cerebral ischemia occlusion/reperfusion. Approach and Results— Here, we show that the guidance molecule ephrinB2 plays a key role in neurovascular protection and blood–brain barrier restoration after stroke. In a focal stroke model, we characterize the stroke-induced damage to cerebral blood vessels and their subsequent endogenous repair on a cellular, molecular, and functional level. EphrinB2 and its tyrosine kinase receptor EphB4 are upregulated early after stroke by endothelial cells and perivascular support cells, in parallel to their reassembly during neurovascular recovery. Using both retroviral and pharmacological approaches, we show that the inhibition of ephrinB2/EphB4 signaling suppresses post-middle cerebral artery occlusion neurovascular repair mechanisms resulting in an aggravation of brain swelling. In contrast, the activation of ephrinB2 after brain ischemia leads to an increased pericyte recruitment and increased endothelial–pericyte interaction, resulting in an accelerated neurovascular repair after ischemia. Conclusions— We show that reducing swelling could result in improved outcome because of reduction in damaged brain tissue. We also identify a novel role for ephrinB2/EphB4 signaling in the maintenance of the neurovascular homeostasis and provide a novel therapeutic approach in reducing brain swelling after stroke.

The non-receptor tyrosine kinase Lyn is localised in the developing murine blood-brain barrier

1995 ◽  
Vol 59 (1) ◽  
pp. 15-24 ◽  
Author(s):  
Marc G. Achen ◽  
Matthias Clauss ◽  
Harald Schnürch ◽  
Werner Risau
Keyword(s):  
Tyrosine Kinase ◽  
Blood Brain Barrier ◽  
Receptor Tyrosine Kinase ◽  
Brain Barrier ◽  
Blood Brain

scholarly journals Brain Metastasis Treatment: The Place of Tyrosine Kinase Inhibitors and How to Facilitate Their Diffusion across the Blood–Brain Barrier

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1446
Author(s):  
Eurydice Angeli ◽  
Guilhem Bousquet
Keyword(s):  
Brain Metastases ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Blood Brain Barrier ◽  
Kinase Inhibitors ◽  
Brain Barrier ◽  
Molecular Alterations ◽  
Blood Brain ◽  
Recent Advances ◽  
Breast Cancer Brain Metastases

The incidence of brain metastases has been increasing constantly for the last 20 years, because of better control of metastases outside the brain, and the failure of most drugs to cross the blood–brain barrier at relevant pharmacological concentrations. Recent advances in the molecular biology of cancer have led to the identification of numerous molecular alterations, some of them targetable with the development of specific targeted therapies, including tyrosine kinase inhibitors. In this narrative review, we set out to describe the state-of-the-art in the use of tyrosine kinase inhibitors for the treatment of melanoma, lung cancer, and breast cancer brain metastases. We also report preclinical and clinical pharmacological data on brain exposure to tyrosine kinase inhibitors after oral administration and describe the most recent advances liable to facilitate their penetration of the blood–brain barrier at relevant concentrations and limit their physiological efflux.

scholarly journals Axl Deficiency Promotes the Neuroinvasion of Japanese Encephalitis Virus by Enhancing IL-1α Production from Pyroptotic Macrophages

2020 ◽  
Vol 94 (17) ◽  
Author(s):  
Zhao-Yang Wang ◽  
Zi-Da Zhen ◽  
Dong-Ying Fan ◽  
Cheng-Feng Qin ◽  
Dai-Shu Han ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Japanese Encephalitis Virus ◽  
Blood Brain Barrier ◽  
Japanese Encephalitis ◽  
Receptor Tyrosine Kinase ◽  
Protective Role ◽  
Encephalitis Virus ◽  
Multiple Roles ◽  
Brain Barrier ◽  
Blood Brain

ABSTRACT Japanese encephalitis virus (JEV) is a flavivirus that causes Japanese encephalitis (JE), which has an unclear pathogenesis. Despite vaccination, thousands of deaths attributed to JE are reported annually. In this study, we report that mice deficient for Axl, a receptor tyrosine kinase that plays multiple roles in flaviviral infection, displayed greater mortality upon JEV infection. The effect of Axl deficiency on JEV infection was mediated by markedly elevated serum interleukin-1α (IL-1α) levels, which devastated the blood-brain-barrier and promoted viral neuroinvasion within 24 h postinfection. Using an in situ infection model, we showed that dead macrophages were the primary source of observed increased serum IL-1α levels. Axl deficiency enhanced cell death and caused pyroptosis in 80% of JEV-infected macrophages by disrupting phosphatidylinositol 3-kinase (PI3K)-Akt signaling. Intriguingly, the primary effector released by pyroptotic macrophages in our model was IL-1α rather than IL-1β. Finally, we assessed the effect of an IL-1α antagonist and demonstrated that it effectively prevented the incidence of JE. Our results indicate that Axl plays a protective role in JEV infection, identify IL-1α released by pyroptotic macrophages as a crucial factor promoting JEV neuroinvasion, and suggest that an IL-1α antagonist may be a candidate for JE therapy. IMPORTANCE Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus that causes Japanese encephalitis (JE), the most commonly diagnosed viral encephalitis worldwide. The fatality rate of JE is 20%, and nearly half of the surviving patients develop neuropsychiatric sequelae. Axl is a receptor tyrosine kinase that plays multiple roles in flaviviral infections. Currently, the involvement of Axl in JEV infection remains enigmatic. In this study, we demonstrate that Axl impedes the pathogenesis of severe JE in mice by maintaining blood-brain-barrier (BBB) integrity and restricting viral neuroinvasion. Furthermore, serum IL-1α is a key mediator of this process and is primarily released by JEV-infected pyroptotic macrophages to elicit BBB breakdown, while an IL-1α antagonist can effectively reduce the incidence of severe JE. Our work uncovers the protective role of Axl in antagonizing severe JE and shows that the use of an IL-1α antagonist may be a promising tactic to prevent severe JE.

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