The Neuroprotective Effects of Necrostatin-1 on Subarachnoid Hemorrhage in Rats Are Possibly Mediated by Preventing Blood–Brain Barrier Disruption and RIP3-Mediated Necroptosis

Autor: Demin Xu, Gao Chen, Jingsen Chen, Hanghuang Jin, Tao Li, Guangyu Ying, Lin Wang, C. Charles Gu, Pingyou He, Hangzhe Xu, Linfeng Fan, Lili Chen, Yucong Peng, Liyong Jie, Chun Wang
Rok vydání: 2019
Předmět:
0301 basic medicine
Indoles
lcsh:Medicine
Brain Edema
Pharmacology
blood–brain barrier
Rats
Sprague-Dawley
chemistry.chemical_compound
0302 clinical medicine
early brain injury
Medicine
Imidazoles
Brain
Magnetic Resonance Imaging
Neuroprotective Agents
medicine.anatomical_structure
Matrix Metalloproteinase 9
Blood-Brain Barrier
Receptor-Interacting Protein Serine-Threonine Kinases
Cytokines
Basal cortex
Signal transduction
Signal Transduction
Subarachnoid hemorrhage
subarachnoid hemorrhage
Necroptosis
Biomedical Engineering
necroptosis
Protein Serine-Threonine Kinases
Blood–brain barrier
Neuroprotection
Tight Junctions
03 medical and health sciences
Animals
cardiovascular diseases
Propidium iodide
Protein kinase A
Transplantation
business.industry
lcsh:R
Original Articles
Cell Biology
medicine.disease
Rats
nervous system diseases
030104 developmental biology
chemistry
necrostatin-1
business
Protein Kinases
030217 neurology & neurosurgery
Zdroj: Cell Transplantation, Vol 28 (2019)
Cell Transplantation
ISSN: 1555-3892
0963-6897
DOI: 10.1177/0963689719867285
Popis: Despite the substantial efforts to elucidate the role of early brain injury in subarachnoid hemorrhage (SAH), an effective pharmaceutical therapy for patients with SAH continues to be unavailable. This study aims to reveal the role of necroptosis after SAH, and explore whether the disruption of the blood–brain barrier (BBB) and RIP3-mediated necroptosis following SAH in a rat SAH model are altered by necrostatin-1 via its selective inhibition of receptor-interacting protein kinase 1 (RIP1). Sixty-five rats were used in the experiments. The SAH model was established using endovascular perforation. Necrostatin-1 was intracerebroventricularly injected 1 h before SAH induction. The neuroprotective effects of necrostatin-1 were evaluated with multiple methods such as magnetic resonance imaging (MRI) scanning, immunohistochemistry, propidium iodide (PI) labeling, and western blotting. Pretreatment with necrostatin-1 attenuated brain swelling and reduced the lesion volume on T2 sequence and ventricular volume on MRI 72 h after SAH induction. Albumin leakage and the degradation of tight junction proteins were also ameliorated by necrostatin-1 administration. In addition, necrostatin-1 decreased the number of PI-positive cells in the basal cortex, reduced the levels of the RIP3 and MLKL proteins, and inhibited the production of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. Based on the findings from the present study, the selective RIP1 inhibitor necrostatin-1 functioned as a neuroprotective agent after SAH by attenuating brain swelling and BBB disruption. Moreover, the necrostatin-1 pretreatment prevented SAH-induced necroptosis by suppressing the activity of the RIP3/MLKL signaling pathway. These results will provide insights into new drugs and pharmacological targets to manage SAH, which are worth further study.
Databáze: OpenAIRE
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