Targetability of the neurovascular unit in inflammatory diseases of the central nervous system

Smith, Brandon C.; Tinkey, Rachel A; Shaw, Benjamin; Williams, J. L.

doi:10.1111/imr.13121

Cited by 26 publications

(14 citation statements)

References 158 publications

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“…The blood–brain barrier (BBB) is a selective and permeable physical barrier with the role of protecting the central nervous system (CNS) environment. BBB restricts the access of a wide range of compounds into the CNS, including toxins, pathogens, antibodies, and immune cells, and simultaneously prevents the entrance of many therapeutic drugs [ 50 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

Crotalphine Modulates Microglia M1/M2 Phenotypes and Induces Spinal Analgesia Mediated by Opioid-Cannabinoid Systems

Lopes

Giardini

Sant’Anna

et al. 2022

IJMS

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Pain is a worldwide public health problem and its treatment is still a challenge since clinically available drugs do not completely reverse chronic painful states or induce undesirable effects. Crotalphine is a 14 amino acids synthetic peptide that induces a potent and long-lasting analgesic effect on acute and chronic pain models, peripherally mediated by the endogenous release of dynorphin A and the desensitization of the transient receptor potential ankyrin 1 (TRPA1) receptor. However, the effects of crotalphine on the central nervous system (CNS) and the signaling pathway have not been investigated. Thus, the central effect of crotalphine was evaluated on the partial sciatic nerve ligation (PSNL)-induced chronic neuropathic pain model. Crotalphine (100 µg/kg, p.o.)-induced analgesia on the 14th day after surgery lasting up to 24 h after administration. This effect was prevented by intrathecal administration of CB1 (AM251) or CB2 (AM630) cannabinoid receptor antagonists. Besides that, crotalphine-induced analgesia was reversed by CTOP, nor-BNI, and naltrindole, antagonists of mu, kappa, and delta-opioid receptors, respectively, and also by the specific antibodies for β-endorphin, dynorphin-A, and met-enkephalin. Likewise, the analgesic effect of crotalphine was blocked by the intrathecal administration of minocycline, an inhibitor of microglial activation and proliferation. Additionally, crotalphine decreased the PSNL-induced IL-6 release in the spinal cord. Importantly, in vitro, crotalphine inhibited LPS-induced CD86 expression and upregulated CD206 expression in BV-2 cells, demonstrating a polarization of microglial cells towards the M2 phenotype. These results demonstrated that crotalphine, besides activating opioid and cannabinoid analgesic systems, impairs central neuroinflammation, confirming the neuromodulatory mechanism involved in the crotalphine analgesic effect.

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Section: Discussionmentioning

confidence: 99%

Crotalphine Modulates Microglia M1/M2 Phenotypes and Induces Spinal Analgesia Mediated by Opioid-Cannabinoid Systems

Lopes

Giardini

Sant’Anna

et al. 2022

IJMS

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“…Neuroin ammation processes are strongly associated with multiple CNS pathologies and with loss of BBB integrity, but the connection between the two processes is not fully understood [1,24]. The subclassi cation of GBM into PN, MES and CL subtypes has allowed the establishment of a positive feedback interaction between mesenchymal tumor cells and immune cells [25,26].…”

Section: In Ammatory and Immunosuppressive Processes Associated With ...mentioning

confidence: 99%

BBB dysfunction drives neurotoxic myeloid cells in glioblastoma and Alzheimer’s disease

Segura-Collar,

Mondejar-Ruescas,

Garranzo-Asensio

et al. 2023

Preprint

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Background The blood-brain barrier (BBB) defines the physiological function of the brain and is disrupted in multiple neuropathological diseases. Although vascular abnormalities and BBB leakage characterize glioma progression and occurs in the early stages of Alzheimer's disease (AD), their correlation with the neurodegeneration observed in the brain parenchyma is unclear. Methods Using RNAseq, bioinformatics tools and a cohort of patients with Glioma and Alzheimer's disease for validation of results, we have established an analysis of BBB dysfunction and neuron loss. A mouse model for GBM pathology was also used that reversed BBB disruption and neuron loss, with the incorporation of the IDH mutation. Finally, to establish a characterization of the relevant immune populations with an IHC analysis and transcriptional profile. Results Molecular analysis of the brain’s ecosystem showed that gene expression signatures linked to BBB dysfunction and neuronal synapses correlate directly and inversely, respectively, with the progression of AD and gliomas. Using human samples, patient´s-derived xenografts and mice with orthotopically implanted glioma cells, we observed that neuronal loss is linked to BBB breakdown, particularly in mesenchymal tumors. This involves the extravasation of monocyte-derived macrophages, specifically those with a suppressive phenotype, along with an increase in inflammatory cytokines. Moreover, our data demonstrate that vascular normalization can revert the neuronal loss and aggressiveness in these gliomas. Conclusions We propose that BBB dysfunction is a common brain process that drives chronic inflammation, governed by suppressive myeloid cells. These results could help us to apply common therapies to the progression of central nervous system pathologies associated with BBB dysfunction, since it functions as an enhancer through toxic neuroinflammation and myeloid dysfunction.

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“…Neuroinflammation processes are strongly associated with multiple CNS pathologies and with BBB integrity loss, but the connection between the two processes is not fully understood 1,12 . The subclassification into PN, MES and CL subtypes has made it possible to establish an interaction with positive feedback between mesenchymal tumor cells and immune cells 13,14 .…”

Section: Inflammatory Processes Associated With Suppressive Myeloid C...mentioning

confidence: 99%

BBB Dysfunction Defines the Aging Myeloid Landscape Favoring Immune Evasion for Glioma and Alzheimer's Disease

Gargini,

Segura-Collar,

Mondejar-Ruescas

et al. 2023

Preprint

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The blood-brain barrier (BBB) defines the physiological function of the brain, and it is disrupted in multiple neuropathological diseases. Although vascular abnormalities and BBB leakage characterize the progression of gliomas and occurs in the early stages of Alzheimer's disease (AD), it is unclear their correlation with the neurodegeneration observed in the brain parenchyma. Here, molecular analysis of the brain’s ecosystem showed that gene expression signatures linked to BBB dysfunction and neuronal synapses correlate directly and inversely, respectively, with the progression of AD and gliomas. Using human samples, patient´s-derived xenografts and mice with orthotopically implanted glioma cells, we observed that neuronal loss is linked to BBB breakdown in mesenchymal tumors. This involves the extravasation of monocyte-derived macrophages, specifically those with a suppressive phenotype, in tandem with a surge of inflammatory cytokines. Moreover, our data demonstrate that vascular normalization can revert the neuronal loss and the aggressiveness in those gliomas. Overall, we propose that BBB dysfunction is a common process associated with aging that drives chronic inflammation, which is governed by TREM2+/TIM3+ suppressor myeloid cells. These results could help us to apply therapies to the progression of central nervous system pathologies that are associated with the aging process, with the hallmarks of toxic neuroinflammation and myeloid dysfunction.

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Targetability of the neurovascular unit in inflammatory diseases of the central nervous system

Cited by 26 publications

References 158 publications

Crotalphine Modulates Microglia M1/M2 Phenotypes and Induces Spinal Analgesia Mediated by Opioid-Cannabinoid Systems

Crotalphine Modulates Microglia M1/M2 Phenotypes and Induces Spinal Analgesia Mediated by Opioid-Cannabinoid Systems

BBB dysfunction drives neurotoxic myeloid cells in glioblastoma and Alzheimer’s disease

BBB Dysfunction Defines the Aging Myeloid Landscape Favoring Immune Evasion for Glioma and Alzheimer's Disease

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