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Kunlin Jin

Publications and source records attributed to Kunlin Jin.

At least 19 recordsLinked to original sources
PubMed2004

Enhanced neurogenesis in Alzheimer's disease transgenic (PDGF-APPSw,Ind) mice.

Neurogenesis continues in the adult brain and is increased in certain pathological states. We reported recently that neurogenesis is enhanced in hippocampus of patients with Alzheimer's disease (AD). We now report that the effect of AD on neurogenesis can be reproduced in a transgenic mouse model. PDGF-APP(Sw,Ind) mice, which express the Swedish and Indiana amyloid precursor protein mutations, show increased incorporation of BrdUrd and expression of immature neuronal markers in two neuroproliferative regions: the dentate gyrus and subventricular zone. These changes, consisting of approximately 2-fold increases in the number of BrdUrd-labeled cells, were observed at age 3 months, when neuronal loss and amyloid deposition are not detected. Because enhanced neurogenesis occurs in both AD and an animal model of AD, it seems to be caused by the disease itself and not by confounding clinical factors. As neurogenesis is increased in PDGF-APP(Sw,Ind) mice in the absence of neuronal loss, it must be triggered by more subtle disease manifestations, such as impaired neurotransmission. Enhanced neurogenesis in AD and animal models of AD suggests that neurogenesis may be a compensatory response and that measures to enhance neurogenesis further could have therapeutic potential.

Alzheimer Disease↗
PubMed2004

Proteomic and immunochemical characterization of a role for stathmin in adult neurogenesis.

Stathmin is a developmentally regulated cytosolic protein expressed at high levels in the brain. Two-dimensional differential in-gel electrophoresis and mass spectroscopy of proteins expressed in immature and mature cultures from embryonic rat cerebral cortex identified stathmin among several differentially expressed proteins, consistent with a possible role in neurogenesis. Stathmin immunohistochemistry in adult rodent brain revealed prominent expression in neuroproliferative zones and neuronal migration pathways, a pattern that resembles the expression of doublecortin, which is implicated in neuronal migration. Stathmin immunoreactivity was also associated with neurons undergoing ectopic chain migration into the ischemic striatum and cerebral cortex following focal cerebral ischemia. Reducing the expression of stathmin or doublecortin with an antisense oligonucleotide inhibited the migration of new neurons from the subventricular zone to the olfactory bulb via the rostral migratory stream. These results suggest a role for stathmin in the migration of newborn neurons in the adult brain.

Aging↗
PubMed2004

Post-ischemic administration of heparin-binding epidermal growth factor-like growth factor (HB-EGF) reduces infarct size and modifies neurogenesis after focal cerebral ischemia in the rat.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a hypoxia-inducible, neuroprotective protein that also stimulates proliferation of neuronal precursor cells. Accordingly, HB-EGF may contribute to recovery from cerebral injury through direct neuroprotective effects, by enhancing neurogenesis, or both. When administered by the intracerebroventricular route 1-3 days after focal cerebral ischemia in adult rats, HB-EGF decreased the volume of the resulting infarcts and reduced post-ischemic neurological deficits. HB-EGF also increased the incorporation of bromodeoxyuridine into cells expressing the immature neuronal marker protein TUC-4 in the dentate subgranular and rostral subventricular zones, consistent with increased proliferation of neuronal precursors. However, HB-EGF decreased the number of newborn neurons that migrated into the ischemic striatum, perhaps partly because reduction of infarct size by HB-EGF also reduced the stimulus to migration. To determine if HB-EGF might also directly inhibit migration of neuronal precursors, we co-cultured subventricular zone (SVZ) explants treated with HB-EGF or vehicle together with hypoxic cerebral cortical explants, and measured cell migration from the former toward the latter. HB-EGF reduced directed migration of SVZ cells toward the cortical explants, possibly due to a local chemoattractant effect on neuronal precursor cells, which may be mediated through the HB-EGF-specific receptor, N-arginine dibasic convertase. The delayed neuroprotective effect of HB-EGF may have implications for efforts to prolong the therapeutic window for intervention in stroke.

Animals↗
PubMed2004

Defective adult neurogenesis in CB1 cannabinoid receptor knockout mice.

Pharmacological studies suggest a role for CB1 cannabinoid receptors (CB1R) in regulating neurogenesis in the adult brain. To investigate this possibility, we measured neurogenesis by intraperitoneal injection of bromodeoxyuridine (BrdU), which labels newborn neurons, in wild-type and CB1R-knockout (CB1R-KO) mice. CB1R-KO mice showed reductions in the number of BrdU-labeled cells to approximately 50% of wild-type (WT) levels in dentate gyrus and subventricular zone (SVZ), suggesting that CB1R activation promotes neurogenesis. To test this further, WT mice were given the CB1R antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716A) before measuring neurogenesis with BrdU. SR141716A paradoxically increased the number of BrdU-labeled cells by approximately 50% in SVZ; another CB1R antagonist, 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM251), had a similar effect. To investigate this discrepancy, SR141716A was given to CB1R-KO mice, in which it still stimulated neurogenesis, indicating involvement of a non-CB1 receptor. Action at one such non-CB1, SR141716A-sensitive site, the VR1 vanilloid receptor, was tested by administering SR141716A to VR1-KO mice, in which the ability of SR141716A to enhance neurogenesis was abolished. Thus, CB1 and VR1 receptors both seem to have roles in regulating adult neurogenesis.

Animals↗
PubMed2003

Increased hippocampal neurogenesis in Alzheimer's disease.

Neurogenesis, which persists in the adult mammalian brain, may provide a basis for neuronal replacement therapy in neurodegenerative diseases like Alzheimer's disease (AD). Neurogenesis is increased in certain acute neurological disorders, such as ischemia and epilepsy, but the effect of more chronic neurodegenerations is uncertain, and some animal models of AD show impaired neurogenesis. To determine how neurogenesis is affected in the brains of patients with AD, we investigated the expression of immature neuronal marker proteins that signal the birth of new neurons in the hippocampus of AD patients. Compared to controls, Alzheimer's brains showed increased expression of doublecortin, polysialylated nerve cell adhesion molecule, neurogenic differentiation factor and TUC-4. Expression of doublecortin and TUC-4 was associated with neurons in the neuroproliferative (subgranular) zone of the dentate gyrus, the physiological destination of these neurons (granule cell layer), and the CA1 region of Ammon's horn, which is the principal site of hippocampal pathology in AD. These findings suggest that neurogenesis is increased in AD hippocampus, where it may give rise to cells that replace neurons lost in the disease, and that stimulating hippocampal neurogenesis might provide a new treatment strategy.

Adolescent↗
PubMed2003

Hypoxic induction of endoglin via mitogen-activated protein kinases in mouse brain microvascular endothelial cells.

BACKGROUND AND PURPOSE: Endoglin (CD105) is a membrane glycoprotein that is mutated in hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease) and shows increased expression in proliferating endothelial cells during angiogenesis. METHODS: We investigated the effect of hypoxia on endoglin expression in murine cerebral microvascular endothelial (bEND.3) cells in vitro and the possible involvement of mitogen-activated protein kinase (MAPK) pathways. RESULTS: Hypoxia increased endoglin mRNA and protein expression in bEND.3 cells, which was associated with phosphoactivation of extracellular signal-related kinase (ERK), p38 MAPK, and Jun amino-terminal kinase (JNK). Inhibitors of p38 decreased hypoxic induction of endoglin expression, as did dominant negative MAPK kinase 3 (MKK3), which activates p38. In contrast, constitutively active MKK3 or JNK1 potentiated the hypoxic induction of endoglin. CONCLUSIONS: These results indicate that hypoxia induces the expression of endoglin at both the mRNA and protein levels and that induction is regulated by the p38 and perhaps also JNK pathways.

Animals↗
PubMed2003

Neuroglobin protects the brain from experimental stroke in vivo.

Neuroglobin (Ngb) is an O(2)-binding protein localized to cerebral neurons of vertebrates, including humans. Its physiological role is unknown but, like hemoglobin, myoglobin, and cytoglobin/histoglobin, it may transport O(2), detoxify reactive oxygen species, or serve as a hypoxia sensor. We reported recently that hypoxia stimulates transcriptional activation of Ngb in cultured cortical neurons and that antisense inhibition of Ngb expression increases hypoxic neuronal injury, whereas overexpression of Ngb confers resistance to hypoxia. These findings are consistent with a role for Ngb in promoting neuronal survival after hypoxic insults in vitro. Here we report that in rats, intracerebroventricular administration of an Ngb antisense, but not sense, oligodeoxynucleotide increases infarct volume and worsens functional neurological outcome, whereas intracerebral administration of a Ngb-expressing adeno-associated virus vector reduces infarct size and improves functional outcome, after focal cerebral ischemia induced by occlusion of the middle cerebral artery. We conclude that Ngb acts as an endogenous neuroprotective factor in focal cerebral ischemia and may therefore represent a target for the development of new treatments for stroke.

Amino Acid Sequence↗
PubMed2003

Cerebral neurogenesis is induced by intranasal administration of growth factors.

Neurogenesis persists in the adult brain, where it may contribute to repair and recovery after injury, but the lack of methods for noninvasive stimulation of cerebral neurogenesis limits its potential for clinical application. We report that intranasal administration of either fibroblast growth factor-2 or heparin-binding epidermal growth factor-like growth factor increases neurogenesis, measured by the incorporation of bromodeoxyuridine into cells that express the early neuronal marker protein doublecortin in the subventricular zone of mouse brain. These findings indicate that intranasal growth factors may have potential as neurogenesis-promoting therapeutic agents.

Administration, Intranasal↗
PubMed2003

Induction of neuronal markers in bone marrow cells: differential effects of growth factors and patterns of intracellular expression.

Bone marrow cells (BMC) can be induced to express neuronal phenotypic features in vitro, but the extent to which they can transdifferentiate to mature, functional neurons is uncertain. We examined the effects of different growth factors and combinations thereof on the expression of neuronal marker proteins in cultures of BMC enriched in marrow stromal cells. Patterns of neuronal marker expression varied depending on the growth factor or factors to which BMC cultures were exposed. Cultures treated for up to 5 weeks with epidermal growth factor, fibroblast growth factor-2, retinoic acid, and nerve growth factor displayed neuron-like cellular processes and expressed neuronal markers, including the neuronal nuclear antigen NeuN, microtubule-associated protein 2, tau, synaptophysin, alpha(1A) and alpha(1B) calcium channel subunits, NR2A glutamate receptor subunits, and gamma-aminobutyric acid. However, the intracellular distribution of these markers was distinct from their usual distribution in mature neurons. We conclude that a variety of growth factors can drive BMC toward a neuronal phenotype or phenotypes, but that morphological neuronal features and the ectopic expression of neuronal proteins and neurotransmitters may not equate with the ability to execute normal neuronal functions.

Animals↗
PubMed2003

Directed migration of neuronal precursors into the ischemic cerebral cortex and striatum.

Pathological processes, including cerebral ischemia, can enhance neurogenesis in the adult brain, but the fate of the newborn neurons that are produced and their role in brain repair are obscure. To determine if ischemia-induced neuronal proliferation is associated with migration of nascent neurons toward ischemic lesions, we mapped the migration of cells labeled by cell proliferation markers and antibodies against neuronal marker proteins, for up to 2 weeks after a 90-min episode of focal cerebral ischemia caused by occlusion of the middle cerebral artery. Doublecortin-immunoreactive cells in the rostral subventricular zone, but not the dentate gyrus, migrated into the ischemic penumbra of the adjacent striatum and, via the rostral migratory stream and lateral cortical stream, into the penumbra of ischemic cortex. These results indicate that after cerebral ischemia, new neurons are directed toward sites of brain injury, where they might be in a position to participate in brain repair and functional recovery.

Animals↗
PubMed2003

Ero1-L, an ischemia-inducible gene from rat brain with homology to global ischemia-induced gene 11 (Giig11), is localized to neuronal dendrites by a dispersed identifier (ID) element-dependent mechanism.

Many changes in neuronal gene expression occur in response to ischemia, and these may play a role in determining the fate of ischemic neurons. To identify genes induced in the rat brain following cerebral ischemia, a strategy was used that combines subtractive hybridization and differential screening. Among the genes identified was one referred to as global ischemia-inducible gene 11(Giig11). Sequence analysis indicated that Giig11 exhibited 97% and 91% identity to the known Ero1-L (S. cereviseae ero1-like oxidoreductase) of mouse and human origin, which is involved in oxidative endoplasmic reticulum protein folding. Rat Ero1-L/Giig11 also contains a l07-bp sequence that is nearly identical (> 95%) to the known dispersed repetitive identifier (ID), but which is lacking in mouse and human Ero1-L. Northern blotting showed that expression of the ID element and Ero1-L/Giig11 mRNA increased after global cerebral ischemia. In situ hybridization demonstrated increased expression of Ero1-L/Giig11 in the brain following ischemic injury, with the highest levels in the vulnerable hippocampal CA1 pyramidal neurons. Transfection of cultured primary hippocampal neurons with a plasmid containing green fluorescent protein (gfp) and Ero1-L/Giig11 cDNA (with and without the ID element) produced a gfp-Ero1-L/Giig11 fusion protein, and more fusion protein was localized into dendrites in the presence of the ID element, suggesting that the ID element promotes Ero1-L/Giig11 protein localization to dendrites. Therefore, Ero-1L/Giig11 may have a role in ischemia-induced neuronal repair or survival mechanisms directed at counteracting abnormalities in protein folding, maturation and distribution.

Amino Acid Sequence↗
PubMed2003

Neurogenesis and aging: FGF-2 and HB-EGF restore neurogenesis in hippocampus and subventricular zone of aged mice.

Neurogenesis, which may contribute to the ability of the adult brain to function normally and adapt to disease, nevertheless declines with advancing age. Adult neurogenesis can be enhanced by administration of growth factors, but whether the aged brain remains responsive to these factors is unknown. We compared the effects of intracerebroventricular fibroblast growth factor (FGF)-2 and heparin-binding epidermal growth factor-like growth factor (HB-EGF) on neurogenesis in the hippocampal dentate subgranular zone (SGZ) and the subventricular zone (SVZ) of young adult (3-month) and aged (20-month) mice. Neurogenesis, measured by labelling with bromodeoxyuridine (BrdU) and by expression of doublecortin, was reduced by approximately 90% in SGZ and by approximately 50% in SVZ of aged mice. HB-EGF increased BrdU labelling in SGZ at 3 months by approximately 60% and at 20 months by approximately 450%, which increased the number of BrdU-labelled cells in SGZ of aged mice to approximately 25% of that in young adults. FGF-2 also stimulated BrdU labelling in SGZ, by approximately 25% at 3 months and by approximately 250% at 20 months, increasing the number of newborn neurones in older mice to approximately 20% of that in younger mice. In SVZ, HB-EGF and FGF-2 increased BrdU incorporation by approximately 140% at 3 months and approximately 170% at 20 months, so the number of BrdU-labelled cells was comparable in untreated 3-month-old and growth factor-treated 20-month-old mice. These results demonstrate that the aged brain retains the capacity to respond to exogenous growth factors with increased neurogenesis, which may have implications for the therapeutic potential of neurogenesis enhancement in age-associated neurological disorders.

Aging↗
PubMed2003

Vascular endothelial growth factor promotes proliferation of cortical neuron precursors by regulating E2F expression.

Neurogenesis, or the production of new neurons, is regulated by physiological and pathological processes including aging, stress, and brain injury. Many mitogenic and trophic factors that regulate proliferation of nonneuronal cells are also involved in neurogenesis. These include vascular endothelial cell growth factor (VEGF), which stimulates the incorporation of bromodeoxyuridine (BrdU) into neuronal precursor cells in vitro and in the adult rat brain in vivo. Using BrdU labeling as an index of cell proliferation, we found that the in vitro neuroproliferative effect of VEGF was associated with up-regulation of E2F family transcription factors, cyclin D1, cyclin E, and cdc25. VEGF also increased nuclear expression of E2F1, E2F2, and E2F3, consistent with regulation of the G1/S phase transition of the cell cycle. The proliferative effect of VEGF was inhibited by the extracellular signal-regulated kinase kinase (MEK) inhibitor PD98059, the phospholipase C (PLC) inhibitor U73122, the protein kinase C (PKC) inhibitor GF102390X, and the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin, indicating involvement of multiple signaling pathways. These findings help to provide a molecular basis for some of the recently identified neuronal effects of VEGF.

Androstadienes↗
PubMed2003

VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia.

Vascular endothelial growth factor (VEGF) is an angiogenic protein with therapeutic potential in ischemic disorders, including stroke. VEGF confers neuroprotection and promotes neurogenesis and cerebral angiogenesis, but the manner in which these effects may interact in the ischemic brain is poorly understood. We produced focal cerebral ischemia by middle cerebral artery occlusion for 90 minutes in the adult rat brain and measured infarct size, neurological function, BrdU labeling of neuroproliferative zones, and vWF-immunoreactive vascular profiles, without and with intracerebroventricular administration of VEGF on days 1-3 of reperfusion. VEGF reduced infarct size, improved neurological performance, enhanced the delayed survival of newborn neurons in the dentate gyrus and subventricular zone, and stimulated angiogenesis in the striatal ischemic penumbra, but not the dentate gyrus. We conclude that in the ischemic brain VEGF exerts an acute neuroprotective effect, as well as longer latency effects on survival of new neurons and on angiogenesis, and that these effects appear to operate independently. VEGF may, therefore, improve histological and functional outcome from stroke through multiple mechanisms.

Animals↗
PubMed2002

Increased severity of stroke in CB1 cannabinoid receptor knock-out mice.

Endogenous cannabinoid signaling pathways have been implicated in protection of the brain from hypoxia, ischemia, and trauma, but the mechanism for these protective effects is uncertain. We found that in CB1 cannabinoid receptor knock-out mice, mortality from permanent focal cerebral ischemia was increased, infarct size and neurological deficits after transient focal cerebral ischemia were more severe, cerebral blood flow in the ischemic penumbra during reperfusion was reduced, and NMDA neurotoxicity was increased compared with wild-type littermates. These findings indicate that endogenous cannabinoid signaling pathways protect mice from ischemic stroke by a mechanism that involves CB1 receptors, and suggest that both blood vessels and neurons may be targets of this protective effect.

Animals↗