Acute neuroprotective synergy of erythropoietin and insulin-like growth factor I

Digicaylioglu, Murat; Garden, Gwenn A.; Timberlake, S.; Fletcher, Lauren; Lipton, Stuart A.

doi:10.1073/pnas.0403172101

Cited by 123 publications

(93 citation statements)

References 61 publications

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“…The reason was that Akt was recently reported to protect against excitotoxic neuronal death, which is believed to contribute to HIV-1-induced neuronal injury. 18,[36][37][38] Thus, we infected cerebrocortical cultures with an adenovirus encoding a dominant-interfering form of Akt or WT Akt as control. After 2 days, the cultures were exposed to HIV/gp120 SF2 in the presence or absence of MIP-1b.…”

Section: Resultsmentioning

confidence: 99%

“…To infect cerebrocortical cultures with minimal toxicity, AdVs were used at a multiplicity of infection (MOI) of 10, as described recently. 38 Neurotoxicity experiments were performed 48 h after infection with AdVs, and the presence of transduced proteins was assessed by immunofluorescence. 38 Exposure to toxins.…”

Section: Methodsmentioning

confidence: 99%

“…38 Neurotoxicity experiments were performed 48 h after infection with AdVs, and the presence of transduced proteins was assessed by immunofluorescence. 38 Exposure to toxins. Recombinant gp120 from different HIV-1 strains, representing CCR5-preferring, CXCR4-preferring, or dual tropic viruses, were obtained from the NIH AIDS Research and Reference Reagent Program or kindly provided by Genentech.…”

Section: Methodsmentioning

confidence: 99%

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HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection

et al. 2006

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The chemokine receptors CCR5 and CXCR4 serve, in addition to CD4, as coreceptors for human immunodeficiency virus-1 (HIV-1), and infection with HIV-1 can cause dementia. In brain-derived cells, HIV-1 envelope glycoprotein gp120 initiates a signaling cascade that involves p38 mitogen-activated protein kinase and leads to neuronal cell death. Using mixed neuronal/glial cultures from rats and mice genetically deficient in one or both HIV coreceptors, we show here that CCR5, CXCR4 or both can mediate HIV/ gp120 neurotoxicity depending on the viral strain. Paradoxically, we also found evidence for a CCR5-mediated neuroprotective pathway. We identify protein kinase Akt/PKB as an essential component of this pathway, which can be triggered by the CCR5 agonists macrophage inflammatory protein-1b and regulated-and-normal-T-cell-expressed-and-secreted. Moreover, these CCR5 ligands prevent neuronal cell death induced by stromal cell-derived factor-1, a CXCR4 agonist. Both neurons and glia coexpress CXCR4 and CCR5. Ca 2 þ imaging experiments demonstrate that engagement of CCR5 prevents CXCR4-triggered increases in intracellular free Ca 2 þ . This finding suggests that CCR5 ligands can protect neurons at least, in part, by modulating CXCR4-mediated toxicity through heterologous desensitization.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection

et al. 2006

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“…For example, insulin-like growth factor I has been reported to mediate the protective effects of exercise against the progression of inherited Purkinje cell degeneration in the cerebellum (3). This growth factor helps the neural protection in culture or in vivo against proapoptotic insults (7,8). Thus insulin-like growth factor I, present in abundance in the plasma under exercised conditions, would exert a neuroprotective effect when it passes through the blood-brain barrier.…”

Section: Discussionmentioning

confidence: 99%

Chronic treadmill exercise in rats delicately alters the Purkinje cell structure to improve motor performance and toxin resistance in the cerebellum

Huang

Lin

Cho

et al. 2012

Journal of Applied Physiology

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CJ. Chronic treadmill exercise in rats delicately alters the Purkinje cell structure to improve motor performance and toxin resistance in the cerebellum. J Appl Physiol 113: 889-895, 2012. First published July 26, 2012 doi:10.1152/japplphysiol.01363.2011.-Although exercise usually improves motor performance, the underlying cellular changes in the cerebellum remain to be elucidated. This study aimed to investigate whether and how chronic treadmill exercise in young rats induced Purkinje cell changes to improve motor performance and rendered the cerebellum less vulnerable to toxin insults. After 1-wk familiarization of treadmill running, 6-wk-old male Wistar rats were divided into exercise and sedentary groups. The exercise group was then subjected to 8 wk of exercise training at moderate intensity. The rotarod test was carried out to evaluate motor performance. Purkinje cells in cerebellar slices were visualized by lucifer yellow labeling in single neurons and by calbindin immunostaining in groups of neurons. Compared with sedentary control rats, exercised rats not only performed better in the rotarod task, but also showed finer Purkinje cell structure (higher dendritic volume and spine density with the same dendritic field). The exercise-improved cerebellar functions were further evaluated by monitoring the long-lasting effects of intraventricular application of OX7-saporin. In the sedentary group, OX7-saporin treatment retarded the rotarod performance and induced ϳ60% Purkinje cell loss in 3 wk. As a comparison, the exercise group showed much milder injuries in the cerebellum by the same toxin treatment. In conclusion, exercise training in young rats increased the dendritic density of Purkinje cells, which might play an important role in improving the motor performance. Furthermore, as Purkinje cells in the exercise group were relatively toxin resistant, the exercised rats showed good motor performance, even under toxin-treated conditions. morphology; OX7-saporin; two-photon microscopy; running; motor function THE RELATIONSHIP BETWEEN PHYSICAL activity and brain functions has been widely investigated. In particular, physical activity in older subjects benefits their mental health by protecting the brain against age-related deterioration (6). Many exercise studies primarily focus on brain structural and functional changes related to cognitive improvements (15), with relatively few studies focusing on the motor performance. Consequently, although connections between cognitive deficits and age-associated brain differences have been elucidated, relationships with motor performance are less well understood. Interestingly, aging impacts brain structures and associated behaviors differentially, with the cerebellum showing earlier senescence than the hippocampus (31). As physically active older adults require less error monitoring and show improvements in motor performance (26), it is desirable to explore the beneficial effects of exercise on the cerebellum. Purkinje cells in aged rats show pronounced dendrite degener...

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“…It is the discovery of EPO and its receptor in the nervous and vascular systems that has resulted in great interest and enthusiasm for the potential clinical applications of EPO, such as in Alzheimer's disease, cardiac insufficiency (Assaraf, et al, 2007, Palazzuoli, et al, 2006, and cardiac transplantation (Gleissner, et al, 2006, Mocini, et al, 2007. In the nervous system, the major sites of EPO production and secretion are in the hippocampus, internal capsule, cortex, midbrain, cerebral ECs, and astrocytes (Digicaylioglu, et al, 2004, Genc, et al, 2004. Further work has revealed several other organs as secretory tissues for EPO that include peripheral ECs (Anagnostou, et al, 1994), myoblasts (Ogilvie, et al, 2000), insulin-producing cells (Fenjves, et al, 2003), and cardiac tissue Haller, 2007, Maiese, et al, 2005c).…”

Section: Epo Expression Structure and Receptor Role In Cells And Timentioning

confidence: 99%

Erythropoietin and Oxidative Stress

Maiese

Chong

Hou

et al. 2008

CNR

110

113

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Unmitigated oxidative stress can lead to diminished cellular longevity, accelerated aging, and accumulated toxic effects for an organism. Current investigations further suggest the significant disadvantages that can occur with cellular oxidative stress that can lead to clinical disability in a number of disorders, such as myocardial infarction, dementia, stroke, and diabetes. New therapeutic strategies are therefore sought that can be directed toward ameliorating the toxic effects of oxidative stress. Here we discuss the exciting potential of the growth factor and cytokine erythropoietin for the treatment of diseases such as cardiac ischemia, vascular injury, neurodegeneration, and diabetes through the modulation of cellular oxidative stress. Erythropoietin controls a variety of signal transduction pathways during oxidative stress that can involve Janus-tyrosine kinase 2, protein kinase B, signal transducer and activator of transcription pathways, Wnt proteins, mammalian forkhead transcription factors, caspases, and nuclear factor κB. Yet, the biological effects of erythropoietin may not always be beneficial and may be poor tolerated in a number of clinical scenarios, necessitating further basic and clinical investigations that emphasize the elucidation of the signal transduction pathways controlled by erythropoietin to direct both successful and safe clinical care. KeywordsAlzheimer's disease; Akt; angiogenesis; apoptosis; cancer; cardiac; caspases; diabetes; endothelial; erythropoietin; forkhead; FoxO; GSK-3β; inflammation; mitochondria; NF-κB; renal; STATs; Wnt OXIDATIVE STRESSInitial work in pathways that can lead to oxidative stress by early investigators observed that increased metabolic rates could be detrimental to animals in an elevated oxygen environment. More current studies point to the potential aging mechanisms and accumulated toxic effects for an organism that are tied to oxidative stress (Maiese, et al., 2008a NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript in organisms, or at least the rate of oxygen consumption in organisms, has intrigued several investigators. Pearl proposed that increased exposure to oxygen through an increased metabolic rate could lead to a shortened life span (Pearl, 1928). Subsequent work by multiple investigators has furthered this hypothesis by demonstrating that increased metabolic rates could be detrimental to animals in an elevated oxygen environment . When one moves to more current work, oxygen free radicals and mitochondrial DNA mutations have become associated with oxidative stress injury, aging mechanisms, and accumulated toxicity for an organism (Yui and Matsuura, 2006).Oxygen free radicals can be generated in elevated quantities during the reduction of oxygen and subsequently lead to cell injury and apoptosis. Oxidative stress occurs as a result of the development of reactive oxygen species that consist of oxygen free radicals and other chemical entities. These agents can involve superoxide free radicals, hydrogen peroxide, sin...

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Acute neuroprotective synergy of erythropoietin and insulin-like growth factor I

Cited by 123 publications

References 61 publications

HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection

HIV-1 coreceptors CCR5 and CXCR4 both mediate neuronal cell death but CCR5 paradoxically can also contribute to protection

Chronic treadmill exercise in rats delicately alters the Purkinje cell structure to improve motor performance and toxin resistance in the cerebellum

Erythropoietin and Oxidative Stress

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