Selegiline promotes NOTCH-JAGGED signaling in astrocytes of the peri-infarct region and improves the functional integrity of the neurovascular unit in a rat model of focal ischemia

Nardai, Sándor; Dobolyi, Árpád; Pál, Gábor; Skopál, Judit; Nándor, Pintér; Lakatos, Kinga; Merkely, Béla; Nagy, Zoltán

doi:10.3233/rnn-140420

Cited by 10 publications

(9 citation statements)

References 22 publications

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“…Previous studies indicated expression of JAG and DLL on reactive brain astrocytes, and astrocytes can induce Notch signalling by themselves or with other cell types such as neural stem cells. [31][32][33][34] Moreover, a recent study demonstrated that optic nerve astrocytes express JAG1 with no significant expression of DLL. 35 Since retinal astrocytes are immigrants from the optic nerve, 36 it is possible that they also express Notch ligands.…”

Section: Discussionmentioning

confidence: 99%

Notch signalling suppresses regulatory T‐cell function in murine experimental autoimmune uveitis

Hua

Shen

et al. 2016

Immunology

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Autoimmune uveitis is an intraocular inflammatory disorder in developed countries. Understanding the mechanisms underlying the development and modulation of immune reaction in uveitic eyes is critical for designing therapeutic interventions. Here we investigated the role of Notch signalling in regulatory T-cell (Treg cell) function during experimental autoimmune uveitis (EAU). Using the Foxp3-GFP reporter mouse strain, the significance of Notch signalling for the function of infiltrating Treg cells was characterized in an EAU model. We found that infiltrating Treg cells substantially expressed Notch-1, Notch-2, JAG1 and DLL1 in uveitic eyes. Activation of Notch signalling, represented by expression of HES1 and HES5, was enhanced in infiltrating Treg cells. Treatment with JAG1 and DLL1 down-regulated Foxp3 expression and immunosuppressive activity of isolated infiltrating Treg cells in vitro, whereas neutralizing antibodies against JAG1 and DLL1 diminished Notch ligand-mediated negative effects on Treg cells. To investigate the significance of Notch signalling for Treg cell function in vivo, lentivirus-derived Notch short hairpin RNAs were transduced into in vitro expanded Treg cells before adoptive transfer of Treg cells into EAU mice. Transfer of Notch-1-deficient Treg cells remarkably reduced pro-inflammatory cytokine production and inflammatory cell infiltration in uveitic eyes. Taken together, Notch signalling negatively modulates the immunosuppressive function of infiltrating Treg cells in mouse EAU.

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Section: Discussionmentioning

confidence: 99%

Notch signalling suppresses regulatory T‐cell function in murine experimental autoimmune uveitis

Hua

Shen

et al. 2016

Immunology

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“…Cilostazol is a commonly used antiplatelet drug, which prevents the pathological detachment of astrocyte foot processes or PCs and also stimulates VEGFR2 expression and PC proliferation, thereby protecting the NVU integrity and promoting neurovascular protection 104 . Notch‐Jagged signaling in astrocytes is increased in selegiline‐treated MCAO rats compared with control, helping to preserve the capillary network after IS 105 . Treatment with tPA inhibits the secretion of glial cell‐derived trophic factors and damages PCs, but edaravone can reverse the damage, and maintains NVU integrity after tPA treatment 106 .…”

Section: Is Therapies Targeting the Nvumentioning

confidence: 99%

Neurovascular Unit: A critical role in ischemic stroke

et al. 2021

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Ischemic stroke (IS), a common cerebrovascular disease, results from a sudden blockage of a blood vessel in the brain, thereby restricting blood supply to the area in question, and making a significantly negative impact on human health. Unfortunately, current treatments, that are mainly based on a recanalization of occluded blood vessels, are insufficient or inaccessible to many stroke patients. Recently, the profound influence of the neurovascular unit (NVU) on recanalization and the prognosis of IS have become better understood; in‐depth studies of the NVU have also provided novel approaches for IS treatment. In this article, we review the intimate connections between the changes in the NVU and IS outcomes, and discuss possible new management strategies having practical significance to IS. We discuss the concept of the NVU, as well as its roles in IS blood‐brain barrier regulation, cell preservation, inflammatory immune response, and neurovascular repair. Besides, we also summarize the influence of noncoding RNAs in NVU, and IS therapies targeting the NVU. We conclude that both the pathophysiological and neurovascular repair processes of IS are strongly associated with the homeostatic state of the NVU and that further research into therapies directed at the NVU could expand the range of treatments available for IS.

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“…The exact mechanism of memantine transport across the BBB requires more detailed investigation; however, therapeutic targeting of memantine to the CNS via OCT-dependent drug delivery may prove to be an effective mechanism to enhance the utility of this neuroprotective drug in treatment of ischemic stroke. Other OCT transport substrates that may be effective as stroke therapeutics include the D2/D3 receptor agonist pramipexole [84,85], the monoamine oxidase inhibitor selegiline [86], and the nicotinic receptor agonist varenicline [87]. Further data is required to determine the functional role of OCT isoforms expressed at the BBB in the setting of ischemic stroke.…”

Section: Endogenous Bbb Transportersmentioning

confidence: 99%

Transporter-Mediated Delivery of Small Molecule Drugs to the Brain: A Critical Mechanism That Can Advance Therapeutic Development for Ischemic Stroke

Williams¹,

Betterton²,

Davis³

et al. 2020

Pharmaceutics

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Ischemic stroke is the 5th leading cause of death in the United States. Despite significant improvements in reperfusion therapies, stroke patients still suffer from debilitating neurocognitive deficits. This indicates an essential need to develop novel stroke treatment paradigms. Endogenous uptake transporters expressed at the blood-brain barrier (BBB) provide an excellent opportunity to advance stroke therapy via optimization of small molecule neuroprotective drug delivery to the brain. Examples of such uptake transporters include organic anion transporting polypeptides (OATPs in humans; Oatps in rodents) and organic cation transporters (OCTs in humans; Octs in rodents). Of particular note, small molecule drugs that have neuroprotective properties are known substrates for these transporters and include 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (i.e., statins) for OATPs/Oatps and 1-amino-3,5-dimethyladamantane (i.e., memantine) for OCTs/Octs. Here, we review current knowledge on specific BBB transporters that can be targeted for improvement of ischemic stroke treatment and provide state-of-the-art perspectives on the rationale for considering BBB transport properties during discovery/development of stroke therapeutics.

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Selegiline promotes NOTCH-JAGGED signaling in astrocytes of the peri-infarct region and improves the functional integrity of the neurovascular unit in a rat model of focal ischemia

Cited by 10 publications

References 22 publications

Notch signalling suppresses regulatory T‐cell function in murine experimental autoimmune uveitis

Notch signalling suppresses regulatory T‐cell function in murine experimental autoimmune uveitis

Neurovascular Unit: A critical role in ischemic stroke

Transporter-Mediated Delivery of Small Molecule Drugs to the Brain: A Critical Mechanism That Can Advance Therapeutic Development for Ischemic Stroke

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