cytochalasin-b and Brain-Injuries

Nur77 is a potent proapoptotic member of the nuclear receptor superfamily that is expressed predominantly in brain tissue. It has been demonstrated that Nur77 mediates apoptosis in multiple organs. Nur77-mediated early brain injury (EBI) involves a conformational change in BCL-2 and triggers cytochrome C (cytoC) release resulting in cellular apoptosis. This study investigates whether Nur77 can promote cerebral cell apoptosis after experimentally induced subarachnoid hemorrhage (SAH) in rats. Sprague Dawley rats were randomly assigned to three groups: 1) untreated group, 2) treatment control group, and 3) SAH group. The experimental SAH group was divided into four subgroups, corresponding to 12 hr, 24 hr, 48 hr, and 72 hr after experimentally induced SAH. It remains unclear whether Nur77 can play an important role during EBI after SAH as a proapoptotic protein in cerebral cells. Cytosporone B (Csn-B) was used to demonstrate that Nur77 could be enriched and used to aggravate EBI after SAH. Rats treated with Csn-B were given an intraperitoneal injection (13 mg/kg) 30 min after experimentally induced SAH. We found that Nur77 promotes cerebral cell apoptosis by mediating EBI and triggering a conformational change in BCL-2, resulting in cytoC release. Nur77 activity, along with cerebral cell apoptosis, peaked at 24 hr after SAH onset. After induction of SAH, an injection of Csn-B, an agonist for Nur77, enhanced the expression and function of Nur77. In summary, we have demonstrated the proapoptotic effect of Nur77 within cerebral cells, an effect that can be further exacerbated with Csn-B stimulation.

Topics: Analysis of Variance; Animals; Apoptosis; Brain Edema; Brain Injuries; Cerebral Cortex; Cytochalasin B; Cytochalasins; Disease Models, Animal; Gene Expression Regulation; In Situ Nick-End Labeling; Male; Neurologic Examination; Nuclear Receptor Subfamily 4, Group A, Member 1; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; RNA, Messenger; Subarachnoid Hemorrhage; Time Factors

Our previous studies showed that the intracerebral injection of apotransferrin (aTf) attenuates white matter damage and accelerates the remyelination process in a neonatal rat model of cerebral hypoxia-ischemia (HI) injury. However, the intracerebral injection of aTf might not be practical for clinical treatments. Therefore, the development of less invasive techniques capable of delivering aTf to the central nervous system would clearly aid in its effective clinical use. In this work, we have determined whether intranasal (iN) administration of human aTf provides neuroprotection to the neonatal mouse brain following a cerebral hypoxic-ischemic event. Apotransferrin was infused into the naris of neonatal mice and the HI insult was induced by right common carotid artery ligation followed by exposure to low oxygen concentration. Our results showed that aTf was successfully delivered into the neonatal HI brain and detected in the olfactory bulb, forebrain and posterior brain 30 min after inhalation. This treatment successfully reduced white matter damage, neuronal loss and astrogliosis in different brain regions and enhanced the proliferation and survival of oligodendroglial progenitor cells (OPCs) in the subventricular zone and corpus callosum (CC). Additionally, using an in vitro hypoxic model, we demonstrated that aTf prevents oligodendrocyte progenitor cell death by promoting their differentiation. In summary, these data suggest that iN administration of aTf has the potential to be used for clinical treatment to protect myelin and to induce remyelination in demyelinating hypoxic-ischemic events in the neonatal brain.

Topics: 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; Administration, Intranasal; Age Factors; Animals; Animals, Newborn; Antigens; Apoproteins; Autophagy-Related Proteins; Brain Injuries; Bromodeoxyuridine; Caspase 3; Cell Death; Cell Proliferation; Cells, Cultured; Cerebral Cortex; Colchicine; Corpus Callosum; Cytochalasin B; Female; Gene Expression Regulation; Green Fluorescent Proteins; Humans; Hypoxia; Hypoxia-Ischemia, Brain; Intermediate Filament Proteins; Intracellular Signaling Peptides and Proteins; Lateral Ventricles; Male; Mice; Mice, Transgenic; Myelin Basic Protein; Nerve Fibers, Myelinated; Nerve Tissue Proteins; Nestin; Neurogenesis; Neuroprotective Agents; Oligodendroglia; Platelet-Derived Growth Factor; Proteoglycans; SOXB1 Transcription Factors; Time Factors; Transferrin