Journal of Neuroscience Research
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Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat Abstract The present study investigates the induction of neurogenesis, reduction of apoptosis, and promotion of basic fibroblast growth factor (bFGF) expression as possible mechanisms by which treatment of stroke with bone marrow stromal cells (MSCs) improves neurological functional recovery. Additionally, for the first time, we treated cerebral ischemia in female rats with intraveneous administration of MSCs. Female rats were subjected to 2 hr of middle cerebral artery occlusion (MCAo), followed by an injection of 3 × 106 male (for Y chromosome labeling) rat MSCs or phosphate‐buffered saline (PBS) into the tail vein 24 hr after MCAo. All animals received daily injection of bromodeoxyuridine (BrdU; 50 mg/kg, i.p.) for 13 days after treatment for identification of newly synthesized DNA. Animals were sacrificed at 14 days after MCAo. Behavioral tests (rotarod and adhesive‐removal tests) were performed. In situ hybridization, immunohistochemistry, and terminal deoxynucleotidyltransferase (TdT)‐mediated dUTP‐biotin nick‐end labeling (TUNEL) were performed to identify transplanted MSCs (Y chromosome), BrdU, bFGF, and apoptotic cells in the brain. Significant recovery of behavior was found in MSC‐treated rats at 7 days in the somatosensory test and at 14 days in the motor test after MCAo compared with control, PBS‐treated animals (P < .05). MSCs were found to survive and preferentially localize to the ipsilateral ischemic hemisphere. Significantly more BrdU‐positive cells were located in the subventricular zone (P < .05), and significantly fewer apoptotic cells and more bFGF immunoreactive cell were found in the ischemic boundary area (P < .05) of MSC‐treated rats than in PBS‐treated animals. Here we demonstrate that intravenously administered male MSCs increase bFGF expression, reduce apoptosis, promote endogenous cellular proliferation, and improve functional recovery after stroke in female rats. © 2003 Wiley‐Liss, Inc.
Journal of Neuroscience Research - Tập 73 Số 6 - Trang 778-786 - 2003
The interaction of circRNAs and RNA binding proteins: An important part of circRNA maintenance and function Abstract The widespread expression of circular RNAs (circRNAs) is regarded as a feature of gene expression in highly diverged eukaryotes. Recent studies have shown that circRNAs can act as a miRNA sponge to repress miRNA function, participate in splicing of target genes, translate genes into protein and interact with RNA binding proteins (RBPs). RBPs are a broad class of proteins involved in gene transcription and translation, and interaction with RBPs is considered an important part of circRNA function, which can serve as an essential element underlying the functions of circRNAs, including genesis, translation, transcriptional regulation of target genes, and extracellular transport. In this mini‐review, we attempt to explore in detail the relationship between circRNAs and RBPs, and the interactions between the two factors. The goal of this review is to investigate the emerging studies of RBPs and circRNAs to better understand how their interaction alters cellular function.
Journal of Neuroscience Research - Tập 98 Số 1 - Trang 87-97 - 2020
Hippocampal brain‐derived neurotrophic factor gene regulation by exercise and the medial septum Abstract Brain‐derived neurotrophic factor (BDNF) enhances synaptic plasticity and neuron function. We have reported that voluntary exercise increases BDNF mRNA levels in the hippocampus; however, mechanisms underlying this regulation have not been defined. We hypothesized that medial septal cholinergic and/or gamma amino butyric acid (GABA)ergic neurons, which provide a major input to the hippocampus, may regulate the baseline gene expression and exercise‐dependent gene upregulation of this neurotrophin. Focal lesions were produced by medial septal infusion of the saporin‐linked immunotoxins 192‐IgG‐saporin or OX7‐saporin. 192‐IgG‐saporin produced a selective and complete loss of medial septal cholinergic neurons with no accompanying GABA loss. Baseline BDNF mRNA was reduced in the hippocampus of sedentary animals, but exercise‐induced gene upregulation was not impaired, despite complete loss of septo‐hippocampal cholinergic afferents. OX7‐saporin produced a graded lesion of the medial septum characterized by predominant GABA neuron loss with less reduction in the number of cholinergic cells. OX7‐saporin lesion reduced baseline hippocampal BDNF mRNA and attenuated exercise‐induced gene upregulation, in a dose‐dependent manner. These results suggest that combined loss of septal GABAergic and cholinergic input to the hippocampus may be important for exercise‐dependent BDNF gene regulation, while cholinergic activity on its own is not sufficient. These results are discussed in relation to their implications for aging and Alzheimer's disease. © 2002 Wiley‐Liss, Inc.
Journal of Neuroscience Research - Tập 68 Số 5 - Trang 511-521 - 2002
Establishment of an astrocyte progenitor cell line: Induction of glial fibrillary acidic protein and fibronectin by transforming growth factor‐β1 Abstract An immortalized clonal cell line (AP‐16) has been established from glial cultures obtained from neonatal mouse cerebra by multipassages under serum‐free conditions. Immunofluorescent experiments showed that AP‐16 cells expressed a marker for glial progenitors (A2B5) and did not express markers for oligodendrocytes (galactocerebroside) or mature astrocytes (glial fibrillary acidic protein: GFAP). Treatment with transforming growth factor‐β1 (TGF‐β1) or fetal calf serum (FCS) for 2 days induced AP‐16 cells to differentiate into A2B5‐negative, GFAP‐positive, phenotypically mature astrocytes. AP‐16 cells depended on epidermal growth factor for survival, and their growth was inhibited by FCS. These results indicate that AP‐16 cells retained the properties of astrocyte progenitors. An enzyme‐linked immunosorbent assay showed that AP‐16 cells synthesized fibronectin and laminin, and that the expression of fibronectin was increased by TGF‐β1. AP‐16 cells should be useful for studying the roles of TGF‐β1 in the differentiation of astrocyte progenitors. © 1993 Wiley‐Liss, Inc.
Journal of Neuroscience Research - Tập 35 Số 2 - Trang 129-137 - 1993
Isolation, characterization, and expression of cDNA clones that encode rat UDP‐galactose: Ceramide galactosyltransferase Abstract UDP‐galactose:ceramide galactosyltransferase (CGT) (EC. 2.4.1.62) catalyzes the final step in the synthesis of galactocerebroside (GalC), a glycosphingolipid found in high amounts in the myelin sheath. Here, the isolation of rat CGT specific cDNA clones is reported. The CGT sequence contains an open reading frame of 1,623 bp which predicts a protein of Mr 61,126 Da. In transfection experiments the cDNA was found to confer CGT activity of Chinese hamster ovary cells. In rat brain the developmental expression pattern of CGT mRNA was similar to the myelination profile, whereas the sciatic nerve contained high amounts of CGT message over a long developmental period. CGT mRNA expression in the sciatic nerve was found to drop substantially following nerve injury and recover slowly when compared to the expression of mRNAs specific for the predominant myelin‐specific proteins. The absolute amounts of CGT message in sciatic nerve and brain were found to be comparable to those that encode the structural proteins of myelin. Except for low amounts in the kidney, the CGT mRNA was not detected in other tissues examined. Southern blot analysis revealed that the CGT protein is likely encoded by a single, relatively large gene. © 1994 Wiley‐Liss, Inc.
Journal of Neuroscience Research - Tập 38 Số 2 - Trang 234-242 - 1994
Huperzine A attenuates mitochondrial dysfunction after middle cerebral artery occlusion in rats Abstract Mitochondrial dysfunction has been proved to contribute to ischemia‐induced brain damage. In this study, which used a rat middle cerebral artery occlusion (MCAO) model, the protective effects of huperzine A (HupA) against mitochondrial dysfunction and brain damage were investigated. MCAO for 45 min followed by 4 hr of reperfusion significantly impaired the activities of mitochondrial respiratory chain enzymes (complex I, complex II–III, and complex IV) and α‐ketoglutarate dehydrogenase, increased the production of reactive oxygen species (ROS), and induced mitochondrial swelling. Pretreatment of HupA at 0.1 mg/kg significantly preserved respiratory chain enzyme activities, decreased ROS production, and attenuated mitochondrial swelling. It could also significantly attenuate the neurological deficits (after 4 or 24 hr reperfusion) and reduce infarct volumes (after 24 hr reperfusion). Moreover, HupA protected isolated nonsynaptosomal mitochondria from calcium‐induced damage in vitro by preserving mitochondrial membrane potential and decreasing ROS production. Overall, the present study indicates that HupA can ameliorate MCAO‐induced mitochondrial dysfunction, and this might partially contribute to its protective effect on brain damage after 24 hr of reperfusion. © 2008 Wiley‐Liss, Inc.
Journal of Neuroscience Research - Tập 86 Số 11 - Trang 2432-2440 - 2008
Unconjugated bilirubin activates and damages microglia Abstract Microglia are the resident immune cells of the brain and are the principal source of cytokines produced during central nervous system inflammation. We have previously shown that increased levels of unconjugated bilirubin (UCB), which can be detrimental to the central nervous system during neonatal life, induce the secretion of inflammatory cytokines and glutamate by astrocytes. Nevertheless, the effect of UCB on microglia has never been investigated. Hence, the main goal of the present study was to evaluate whether UCB leads to microglial activation and to the release of the cytokines tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β, and IL‐6. Additionally, we investigated the effects of UCB on glutamate efflux and cell death. The results showed that UCB induces morphological changes characteristic of activated microglia and the release of high levels of TNF‐α, IL‐1β, and IL‐6 in a concentration‐dependent manner. In addition, UCB triggered extracellular accumulation of glutamate and an increased cell death by apoptosis and necrosis. These results demonstrate, for the first time, that UCB is toxic to microglial cells and point to microglia as an important target of UCB in the central nervous system. Moreover, they suggest that UCB‐induced cytokine production, by mediating cell injury, can further contribute to exacerbate neurototoxicity. Interestingly, microglia cells are much more responsive to UCB than astrocytes. Collectively, these data indicate that microglia may play an important role in the pathogenesis of encephalopathy during severe hyperbilirubinemia. © 2006 Wiley‐Liss, Inc.
Journal of Neuroscience Research - Tập 84 Số 1 - Trang 194-201 - 2006
Mature myelin basic protein‐expressing oligodendrocytes are insensitive to kainate toxicity Abstract We examined the vulnerability to excitotoxicity of rat oligodendrocytes in dissociated cell culture at different developmental stages. Mature oligodendrocytes that express myelin basic protein were resistant to excitotoxic injury produced by kainate, whereas earlier stages in the oligodendrocyte lineage were vulnerable to this insult. To test the hypothesis that the sensitivity of immature oligodendrocytes and the resistance of mature oligodendrocytes to kainate toxicity were due to differences in membrane responsiveness to kainate, we used whole‐cell patch‐clamp recording. Oligodendrocyte precursors in cultures vulnerable to kainate toxicity responded to 500 μM kainate with large inward currents, whereas mature myelin basic protein‐expressing oligodendrocytes in cultures resistant to kainate toxicity showed no clear response to application of this agonist. We assayed expression of glutamate receptor subunits (GluR) ‐2, ‐4, ‐6, ‐7, and KA2 using immunoblot analysis and found that expression of all of these glutamate receptors was significantly down‐regulated in mature oligodendrocytes. These results suggest a striking developmental regulation of glutamate receptors in oligodendrocytes and suggest that the vulnerability of oligodendrocytes to non‐ N‐methyl‐D‐aspartate receptor‐mediated excitotoxicity might be much greater in developing oligodendrocytes than after the completion of myelination. © 2002 Wiley‐Liss, Inc.
Journal of Neuroscience Research - Tập 71 Số 2 - Trang 237-245 - 2003
Microglia in health and disease Abstract Microglia, one of three glial cell types in the central nervous system (CNS), play an important role as resident immunocompetent and phagocytic cells in the CNS in the event of injury and disease. It was del Rio Hortega in 1927 who determined that microglia belong a distinct glial cell type apart from astrocytes and oligodendrocytes, and since 1970s there has been wide recognition that microglia are immune effectors in the CNS that respond to pathological conditions and participate in initiation and progression of neurological disorders including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and acquired immune deficiency syndrome dementia complex by releasing potentially cytotoxic molecules such as proinflammatory cytokines, reactive oxygen intermediates, proteinases and complement proteins. There is also evidence to suggest that microglia are capable of secreting neurotrophic or neuron survival factors upon activation via inflammation or injury. It is thus timely to review current status of knowledge on biology and immunology of microglia, and consider new directions of investigation on microglia in health and disease. © 2005 Wiley‐Liss, Inc.
Journal of Neuroscience Research - Tập 81 Số 3 - Trang 302-313 - 2005
Where is the blood–brain barrier … really? Abstract Few terms in the biomedical lexicon are as widely recognized as the phrase blood–brain barrier (BBB). Indeed, it immediately conjures up a “barricade” between the blood and the brain, a feature often considered more obstacle than safeguard. In truth, the BBB performs in both capacities, and it is precisely this duality that imparts such a vital role to the BBB in influencing physiological and pathophysiological processes in the CNS. Although the concept is more than a century old, the BBB continues to remain enigmatic in both substance and idea, with seemingly resolved issues once again beckoning for clarification. In this regard, recent technological advancements, such as sequencing of the human genome and development of microarray analysis, have illuminated novel aspects of vascular gene expression and provoked reconsideration of the cellular and biochemical makeup of the BBB. In light of the critical impact of the BBB in the realms of science and medicine, this Mini‐Review will revisit the topic of the composition of the BBB, specifically highlighting how recent developments in endothelial biology have prompted a reevaluation of its precise vascular location. We have intentionally avoided discussing generalized features of the BBB, as these have been skillfully described elsewhere as noted. © 2005 Wiley‐Liss, Inc.
Journal of Neuroscience Research - Tập 79 Số 4 - Trang 421-427 - 2005
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