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Neutrophil-mediated and low density lipoprotein receptor-mediated dual-targeting nanoformulation enhances brain accumulation of scutellarin and exerts neuroprotective effects against ischemic stroke.

ABSTRACT: Delivery of poorly permeable drugs across the blood-brain barrier (BBB) is a great challenge in the treatment of ischemic stroke. In order to construct a suitable delivery system for this purpose, we developed a dual-targeting nanoformulation to transfer therapeutic agents targeting the inflammatory sites of the ischemic brain. The matrix of this system is a hydroxyl-terminated polyamidoamine dendrimer with excellent biodegradability. The surface of the matrix is functionalized with two targeting peptides: Angiopep-2 is a low density lipoprotein receptor-mediated peptide with high BBB transcytosis capacity with ligands expressed on brain endothelial cells; N-acetylated proline-glycine-proline (PGP) has high affinity to CXCR2 expressed on infiltrating neutrophils. This system proved to be a high-loading formulation for the neuroprotective compound, scutellarin (STA), and significantly improved its therapeutic efficacy in a rodent model of ischemic stroke. The molecular mechanism underlying the therapeutic efficacy of this formulation is associated with significant down-regulation of the inflammatory cytokines, neutrophils infiltration and intracellular calcium overload and blockade of the inflammatory signaling pathway HMGB1/TLRs/MyD88/TRIF/NF-κB. Our results suggest that this dual-targeting delivery system is a promising drug delivery vehicle for ischemic stroke, and possibly other CNS diseases where neuroinflammation is involved.

SUBMITTER: Dang Y

PROVIDER: S-EPMC9059646 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Neutrophil-mediated and low density lipoprotein receptor-mediated dual-targeting nanoformulation enhances brain accumulation of scutellarin and exerts neuroprotective effects against ischemic stroke.

Dang Yanxin Y An Chiying C Li Yutao Y Han Dandan D Liu Xin X Zhang Fengming F Xu Yuan Y Zhong Haijing H Karim Khan Mewand Khan MK Zou Fengjuan F Sun Xiaojun X

RSC advances 20190110 3

Delivery of poorly permeable drugs across the blood-brain barrier (BBB) is a great challenge in the treatment of ischemic stroke. In order to construct a suitable delivery system for this purpose, we developed a dual-targeting nanoformulation to transfer therapeutic agents targeting the inflammatory sites of the ischemic brain. The matrix of this system is a hydroxyl-terminated polyamidoamine dendrimer with excellent biodegradability. The surface of the matrix is functionalized with two targetin ...[more]

PMID: 35518053

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Project description:Ischemic stroke is associated with high mortality and morbidity rates worldwide. However, the molecular mechanisms underlying the neuronal damage incurred by stroke victims remain unclear. It has previously been reported that ischemic stroke can induce an increase in the levels of brain iron, which is an important factor of in the associated brain damage. Ferroportin 1 (FPN1), the only known cellular iron export protein, is found in brain microvascular endothelial cells (BMVECs) at the blood-brain barrier, and is considered the gateway for entry of plasma iron into the central nervous system. Despite the connection of brain iron to neuronal damage, the role of BMVECs FPN1 in ischemic stroke remains unexplored. Herein, we conditionally deleted Fpn1 in mouse endothelial cells (ECs), using VE-cadherin-Cre transgenic mice, and explored the impact on brain iron homeostasis after stroke. Our data demonstrated that Fpn1 knockout in ECs decreased the brain iron levels in mice, attenuated the oxidative stress and inflammatory responses after stroke, and inhibited both ferroptosis and apoptosis, ultimately alleviating neurological impairment and decreasing cerebral infarct volume during the acute phase of ischemic stroke. By contrast, we found that Fpn1 knockout in ECs delayed the recovery of neurological function in mice following ischemic stroke. We also found that ECs Fpn1 knockout decreased the brain iron levels after stroke, exacerbated glial cell proliferation, and inhibited neuronal development, indicating that the diminished brain iron levels hindered the repair of neural injury in mice. In conclusion, our findings reveal a dual consequence of FPN1 deficiency in ECs in the development of ischemic stroke. More specifically, iron deficiency initially exerts a neuroprotective effect during the acute phase of ischemic stroke but inhibits recovery during the later stages. Our findings are important to the development of iron- or FPN1-targeting therapeutics for the treatment of ischemic stroke.

Project description:Background and purposePrevious studies have demonstrated that angiotensin-converting enzyme (ACE) is involved in brain ischemic injury. In the present study, we investigated whether Scutellarin (Scu) exerts neuroprotective effects by down-regulating the Expression of Angiotensin-Converting Enzyme and AT1 receptor in a rat model of permanent focal cerebral ischemia.MethodsAdult Sprague-Dawley rats were administrated with different dosages of Scu by oral gavage for 7 days and underwent permanent middle cerebral artery occlusion (pMCAO). Blood pressure was measured 7 days after Scu administration and 24 h after pMCAO surgery by using a noninvasive tail cuff method. Cerebral blood flow (CBF) was determined by Laser Doppler perfusion monitor and the neuronal dysfunction was evaluated by analysis of neurological deficits before being sacrificed at 24 h after pMCAO. Histopathological change, cell apoptosis and infarct area were respectively determined by hematoxylin-eosin staining, terminal deoxynucleotidyl transfer-mediated dUTP nick end labeling (TUNEL) analysis and 2,3,5-triphenyltetrazolium chloride staining. Tissue angiotensin II (Ang II) and ACE activity were detected by enzyme-linked immunosorbent assays. The expression levels of ACE, Ang II type 1 receptor (AT1R), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) were measured by Western blot and real-time PCR. ACE inhibitory activity of Scu in vitro was detected by the photometric determination.ResultsScu treatment dose-dependently decreased neurological deficit score, infarct area, cell apoptosis and morphological changes induced by pMCAO, which were associated with reductions of ACE and AT1R expression and the levels of Ang II, TNF-α, IL-6, and IL-1β in ischemic brains. Scu has a potent ACE inhibiting activity.ConclusionScu protects brain from acute ischemic injury probably through its inhibitory effect on the ACE/Ang II/AT1 axis, CBF preservation and proinflammation inhibition.

Dataset Information

Neutrophil-mediated and low density lipoprotein receptor-mediated dual-targeting nanoformulation enhances brain accumulation of scutellarin and exerts neuroprotective effects against ischemic stroke.

Publications

Neutrophil-mediated and low density lipoprotein receptor-mediated dual-targeting nanoformulation enhances brain accumulation of scutellarin and exerts neuroprotective effects against ischemic stroke.

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