Dataset Information

Improving outcomes of neuroprotection by minocycline: guides from cell culture and intracerebral hemorrhage in mice.

ABSTRACT: Minocycline ameliorates deficits in models of acute and chronic neurological diseases, but many publications do not replicate these results. We tested the hypothesis that a key factor in achieving neurological benefits is the exposure of neural cells to local high concentrations of minocycline. This hypothesis was evaluated by using human neurons in culture and in a mouse model of intracerebral hemorrhage (ICH). In culture, neurons were very vulnerable to blood-induced toxicity, with 60% lost within 24 hours in an environment of 5% blood in culture medium. Minocycline reduced blood-induced neurotoxicity in a concentration-dependent manner. In vivo, the introduction of blood into the striatum of mice to simulate ICH resulted in a massive lesion by 24 hours. When minocycline was mixed with the blood used to inflict ICH, the resulting extent of neuropathology was significantly less than that achieved with intraperitoneal administration of medication. The combination of intracerebral and intraperitoneal minocycline improved neuroprotection compared with either alone. We then delayed minocycline treatment and injected it into the hematoma 1 hour after ICH. We found greater alleviation of brain damage and neuronal death with increasing concentrations of minocycline injected locally, which was reflected in limited behavioral and histological recovery. We conclude that the prospect of neuroprotection with minocycline is improved by high concentrations of minocycline delivered locally into the central nervous system with supplementation from systemic administration.

SUBMITTER: Xue M

PROVIDER: S-EPMC2832142 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Improving outcomes of neuroprotection by minocycline: guides from cell culture and intracerebral hemorrhage in mice.

Xue Mengzhou M Mikliaeva Elena I EI Casha Steve S Zygun David D Demchuk Andrew A Yong V Wee VW

The American journal of pathology 20100128 3

Minocycline ameliorates deficits in models of acute and chronic neurological diseases, but many publications do not replicate these results. We tested the hypothesis that a key factor in achieving neurological benefits is the exposure of neural cells to local high concentrations of minocycline. This hypothesis was evaluated by using human neurons in culture and in a mouse model of intracerebral hemorrhage (ICH). In culture, neurons were very vulnerable to blood-induced toxicity, with 60% lost wi ...[more]

PMID: 20110416

Similar Datasets

Project description:Apoptosis is an important factor during the early stage of intracerebral hemorrhage. MiR-181c plays a key regulatory role in apoptosis. However, whether miR-181c is involved in apoptosis of prophase cells after intracerebral hemorrhage remains unclear. Therefore, in vitro and in vivo experiments were conducted to test this hypothesis. In vivo experiments: collagenase type VII was injected into the basal ganglia of adult Sprague-Dawley rats to establish an intracerebral hemorrhage model. MiR-181c mimic or inhibitor was injected in situ 4 hours after intracerebral hemorrhage. Neurological functional defects (neurological severity scores) were assessed 1, 7, and 14 days after model establishment. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling and western blot assay were conducted 14 days after model establishment. In vitro experiments: PC12 cells were cultured under oxygen-glucose deprivation, and hemins were added to simulate intracerebral hemorrhage in vitro. MiR-181c mimic or inhibitor was added to regulate miR-181c expression. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, luciferase reporter system, and western blot assay were performed. Experimental results revealed differences in miR-181c expression in brain tissues of both patients and rats with cerebral hemorrhage. In addition, in vitro experiments found that miR-181c overexpression could upregulate the Bcl-2/Bax ratio to inhibit apoptosis, while inhibition of miR-181c expression could reduce the Bcl-2/Bax ratio and aggravate apoptosis of cells. Regulation of apoptosis occurred through the phosphoinositide 3 kinase (PI3K)/Akt pathway by targeting of phosphatase and tensin homolog deleted on chromosome ten (PTEN). Higher miR-181c overexpression correlated with lower neurological severity scores, indicating better recovery of neurological function. In conclusion, miR-181c affects the prognosis of intracerebral hemorrhage by regulating apoptosis, and these effects might be directly mediated and regulated by targeting of the PTEN\PI3K/Akt pathway and Bcl-2/Bax ratio. Furthermore, these results indicated that miR-181c played a neuroprotective role in intracerebral hemorrhage by regulating apoptosis of nerve cells, thus providing a potential target for the prevention and treatment of intracerebral hemorrhage. Testing of human serum was authorized by the Ethics Committee of China Medical University (No. 2012-38-1) on February 20, 2012. The protocol was registered with the Chinese Clinical Trial Registry (Registration No. ChiCTR-COC-17013559). The animal study was approved by the Institutional Animal Care and Use Committee of China Medical University (approval No. 2017008) on March 8, 2017.

Project description:Traumatic and ischemic brain injury induce plasmalemma permeability and necrosis; however, no studies have examined these aspects of cellular injury in intracerebral hemorrhage models.In vivo propidium iodide (PI) and YOYO-1 were used to assess plasmalemma damage after collagenase-induced intracerebral hemorrhage in mice. Ex vivo aspartylglutamylvalylaspartic acid, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling, and electron microscopy were used to assess the relationship between plasmalemma permeability and mode of cell death. Cell types vulnerable to plasmalemma damage were determined by immunohistochemistry.Plasmalemma permeability was first detected in the lesion at 1 to 3 hours and peaked at 48 to 72 hours. Neurons and IBA-1-positive cells with morphological features of monocytes were sensitive, whereas resident microglia and astrocytes were resistant to plasmalemma permeability. PI+ cells colocalized with fluorescent-labeled caspase substrates and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling beginning at 3 to 6 hours. At 48 hours, greater than half of injured cells were PI+/aspartylglutamylvalylaspartic acid- or PI+/terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling- suggesting necrosis, and <5% were PI-/terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling+ or PI-/aspartylglutamylvalylaspartic acid+. Electron microscopy confirmed ultrastructural features of necrosis at 24 hours after intracerebral hemorrhage, high mobility group box protein-1 was released from permeable cells, and mice deficient in receptor interacting protein kinase (RIPK) 3, a known necrosis trigger, had 50% less PI+ cells at 24 hours. Permeable cells remained in the brain for at least 24 hours with <10% spontaneous resealing.Necrosis contributes to cell demise after intracerebral hemorrhage. Programmed necrosis and plasmalemma damage may represent novel therapeutic targets to prevent cell death or rescue injured cells after intracerebral hemorrhage.

Dataset Information

Improving outcomes of neuroprotection by minocycline: guides from cell culture and intracerebral hemorrhage in mice.

Publications

Improving outcomes of neuroprotection by minocycline: guides from cell culture and intracerebral hemorrhage in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure