Biomedical subjects

Daniel M Rosenbaum

Publications and source records attributed to Daniel M Rosenbaum.

12 recordsLinked to original sources

PubMed2006

EDG receptors as a potential therapeutic target in retinal ischemia-reperfusion injury.

LPA (lysophosphatidic acid) specific endothelial differentiation gene (EDG) receptors have been implicated in various anti-apoptotic pathways. Ischemia of the brain and retina causes neuronal apoptosis, which raises the possibility that EDG receptors participate in anti-apoptotic signaling in ischemic injury. We examined the expression of EDG receptors in a model of retinal ischemia-reperfusion injury and also tested LXR-1035, a novel analogue of LPA, in the rat following global retinal ischemic injury. Rats were subjected to 45 or 60 min of raised intraocular pressure. Animals were sacrificed at 24 h post-ischemia and retinal tissue was stained for EDG receptors. In separate experiments, animals were randomized to receive LXR or saline vehicle by intravitreal injection 24 h prior to ischemia. The degree of retinal damage was assessed morphologically by measuring the thickness of the inner retinal layers as well as functionally by electroretinography (ERG). We found that the normal retina has a baseline expression of the LPA receptors, EDG-2 and EDG-4, which are significantly upregulated in the inner layers in response to ischemia. Animals pretreated with LXR-1035 had dose-dependent, significant reductions in histopathologic damage and significant improvement in functional deficits compared with corresponding vehicle-controls, after 45 and 60 min of ischemia. These results suggest that LPA receptor signaling may play an important role in neuroprotection in retinal ischemia-reperfusion injury.

Animals↗

PubMed2006

Binding and stability determinants of the PPARgamma nuclear receptor-coactivator interface as revealed by shotgun alanine scanning and in vivo selection.

We modified an existing selection for protein-protein interactions based on the fragment complementation of the enzyme DHFR. Using shotgun alanine scanning in conjunction with this selection, we analyzed the interaction of the nuclear receptor PPARgamma with two peptides derived from nuclear receptor coactivators SRC1 and TRAP220. A large binding epitope stretching between and including the charge clamp residues K301 and E471 of PPARgamma was identified as necessary for PPARgamma-coactivator interaction. To decouple protein stability from the propensity to form a receptor-coactivator interface, libraries of PPARgamma variants generated by shotgun scanning were further processed using a high-throughput screen measuring their in vivo stabilities. Our findings demonstrate that many of the residues that make up the binding epitope of PPARgamma are also crucial for the stability of the PPARgamma.

Alanine↗

PubMed2006

Ischemic preconditioning is mediated by erythropoietin through PI-3 kinase signaling in an animal model of transient ischemic attack.

Ischemic preconditioning (IP) protects the brain from subsequent, prolonged, and lethal ischemia in experimental studies. Erythropoietin (EPO) participates in the brain's intrinsic response to injury and may play a role in preconditioning. By using a middle cerebral artery occlusion (MCAo) model of transient ischemic attack (TIA), we sought to determine whether EPO is required for IP in the protective response against focal ischemic stroke. Rats underwent three 10-min MCA occlusions or sham surgery. Three days later, animals underwent 2 hr of MCAo and 22 hr of reperfusion. Experimental TIAs reduced infarct volumes by 55% (P < 0.05), inhibited DNA fragmentation, and improved neurological outcome by 50% (P < 0.05) after ischemic stroke. EPO and its receptor were up-regulated by IP in the ipsilateral hemisphere by 24 hr after IP, before ischemic stroke and soluble EPO receptor attenuated neuroprotection by IP (88% reduction, P < 0.05). Pretreatment with the PI-3 kinase inhibitor wortmannin abolished the protective effect of IP against ischemic injury (P < 0.05). IP may be mediated in part by EPO through a PI-3 kinase pathway.

Animals↗

PubMed2006

Antithrombotic and thrombolytic therapy for ischemic stroke.

Thrombolytic and antithrombotic agents form the cornerstone of stroke treatment and prevention. Recombinant tissue plasminogen activator improves outcome in patients treated within 3 hours of stroke onset. Emerging trials are directed to extend the therapeutic window and identify agents that could provide better safety profiles. Large, randomized trials have also highlighted the effectiveness and safety of early and continuous antiplatelet therapy in reducing atherothrombotic stroke recurrence. Aspirin has become the antiplatelet treatment standard against which several other antiplatelet agents have been shown to be more effective. The prevention of cardioembolic stroke is best accomplished with oral anticoagulation, barring any contraindications.

Age Factors↗

PubMed2005

Effects of status epilepticus early in life on susceptibility to ischemic injury in adulthood.

PURPOSE: Status epilepticus (SE) commonly occurs in children, whereas ischemic stroke is the most frequent neurologic insult in adults. The purpose of this study was to determine the effect of SE induced in immature (15 days old; PN15) male rats, on susceptibility to subsequent transient focal cerebral ischemia induced in adulthood. METHODS: SE was induced by flurothyl ether (FE) or kainic acid (KA). Rats that did not develop seizures after FE or KA served as controls. Five weeks later, the now-adult rats were subjected to middle cerebral artery occlusion (MCAo) for 1 or 2 h by using the intraluminal filament technique. The extent of the infarct volume was evaluated 24 h later. RESULTS: In rats submitted to 1-h-long FE-SE, the volume of infarction was significantly reduced compared with that in rats exposed to FE without SE. Longer duration of FE-SE was acutely lethal. KA-SE induced prolonged behavioral SE (156 +/- 17.5 min). In these rats, the volume of infarction was significantly larger compared with that in rats that did not show any electrographic seizures after KA administration. Comparison of FE and KA groups revealed that differences in the size of infarction were confined into cortical areas served by the MCA. Neither type of SE induced any obvious histologic changes in these neocortical regions before stroke induction. CONCLUSIONS: Early in life, SE can influence the outcome of a subsequent focal ischemic insult in adulthood. The extent of the infarct is related to the duration and cause of SE. Prolonged SE induced by KA worsens the outcome, whereas FE-SE has a neuroprotective effect.

Age Factors↗

PubMed2004

Erythropoietin (epoetin) as a protective factor for the brain.

Erythropoietin (EPO) has been viewed traditionally as a hematopoietic cytokine. Emerging evidence now exists supporting a physiologic role for EPO within the nervous system. EPO is expressed in the developing central nervous system and is capable of regulating the production of neuronal progenitor cells. There are numerous preclinical studies demonstrating a neuroprotective potential for EPO in a variety of disorders of both the central and peripheral nervous systems. A small pilot study in patients with acute ischemic stroke has recently been completed and the results are encouraging. Its mechanism of action is multifactorial but probably related to its ability to act as an antiapoptotic agent. Its widespread use clinically for the treatment of anemias has given us the experience and knowledge of its safety and pharmacokinetics. EPO is thus an ideal compound to study for the potential treatment of a variety of neurologic disorders.

Animals↗

PubMed2004

Cell therapy for stroke.

Increasing experimental evidence suggests that cell transplantation can enhance recovery from stroke in animal models of focal cerebral ischemia. Clinical trials have been investigating the effects of a human immortalized neuronal cell line and porcine fetal neurons in stroke victims with persistent and stable deficits. Preclinical studies are focusing on the effects of human stem cells from various sources including brain, bone marrow, umbilical cord, and adipose tissue. This review presents an overview of preclinical and clinical studies on cell therapy for stroke. We emphasize the current, limited knowledge about the biology of implant sources and discuss special conditions in stroke that will impact the potential success of neurotransplantation in clinical trials.

Cell Transplantation↗

PubMed2003

Efficient and sequence-specific DNA-templated polymerization of peptide nucleic acid aldehydes.

On the basis of the distance-dependence of DNA-templated reductive amination reactions and of recent findings of D. Lynn and co-workers, we developed DNA-templated polymerizations of synthetic peptide nucleic acid (PNA) aldehydes. The coupling reactions proceed in a highly efficient and sequence-specific manner, even in the presence of mixtures of PNA aldehydes of different sequence. Synthetic peptide nucleic acid polymers containing as many as 40 PNA units (representing 10 consecutive coupling reactions) were formed efficiently. The ease of preparing PNAs containing tailor-made functional groups together with these findings raises the possibility of evolving synthetic sequence-defined polymers by iterated cycles of translation, selection, PCR amplification, and diversification previously available only to biological macromolecules.

Aldehydes↗

PubMed2002

Erythropoietin administration protects retinal neurons from acute ischemia-reperfusion injury.

Erythropoietin (EPO) plays an important role in the brain's response to neuronal injury. Systemic administration of recombinant human EPO (rhEPO) protects neurons from injury after middle cerebral artery occlusion, traumatic brain injury, neuroinflammation, and excitotoxicity. Protection is in part mediated by antiapoptotic mechanisms. We conducted parallel studies of rhEPO in a model of transient global retinal ischemia induced by raising intraocular pressure, which is a clinically relevant model for retinal diseases. We observed abundant expression of EPO receptor (EPO-R) throughout the ischemic retina. Neutralization of endogenous EPO with soluble EPO-R exacerbated ischemic injury, which supports a crucial role for an endogenous EPO/EPO-R system in the survival and recovery of neurons after an ischemic insult. Systemic administration of rhEPO before or immediately after retinal ischemia not only reduced histopathological damage but also promoted functional recovery as assessed by electroretinography. Exogenous EPO also significantly diminished terminal deoxynucleotidyltransferase-mediated dUTP end labeling labeling of neurons in the ischemic retina, implying an antiapoptotic mechanism of action. These results further establish EPO as a neuroprotective agent in acute neuronal ischemic injury.

Animals↗

PubMed2002

Cell transplantation for stroke.

Cell transplantation has emerged as an experimental approach to restore brain function after stroke. Various cell types including porcine fetal cells, stem cells, immortalized cell lines, and marrow stromal cells are under investigation in experimental and clinical stroke trials. This review discusses the unique advantages and limitations of the different graft sources and emphasizes the current, limited knowledge about their biology. The survival, integration, and efficacy of neural transplants in stroke patients will depend on the type, severity, chronicity, adequacy of circulation, and location of the stroke lesion.

Bone Marrow Transplantation↗

PubMed2002

Ischemic preconditioning attenuates apoptotic cell death in the rat retina.

PURPOSE: Ischemic preconditioning (IPC) protects the rat retina against the injury that ordinarily follows prolonged ischemia. It has been shown that release of adenosine, de novo protein synthesis, and mediators, such as protein kinase C and K(ATP) channels, is required for IPC protection. However, the molecular mechanisms of neuroprotection by IPC are unknown. Retinal cells die after ischemia by necrosis and apoptosis. This study was undertaken to investigate the effect of IPC on apoptosis after ischemia and some of the key proteins involved in the apoptotic cascade. METHODS: Retinal ischemia or IPC was produced in anesthetized Sprague-Dawley rats by increasing intraocular pressure above systolic arterial pressure. Retinal ischemia was induced 24 hours after either IPC or sham IPC. TUNEL staining was used to quantitate the number of cells with DNA fragmentation. The authors examined expression of cleaved forms of caspases-2 and -3, bax, and poly-adenosine diphosphate-ribose-polymerase (PARP) by Western blot analysis for evidence of apoptosis-related gene expression. To examine possible mechanisms of apoptosis after ischemia, the authors studied the expression of mitogen-activated protein kinases (MAP kinases). Functional recovery after ischemia was measured using electroretinography, and retinal histology was examined and quantitated by light microscopy. RESULTS: Positive TUNEL staining, increases in caspase-2 and -3 cleavage, expression of bax and PARP, and activation of MAP kinases were found with ischemia. IPC attenuated these changes, but paradoxically, IPC itself triggered increased expression of MAP kinases. CONCLUSIONS: IPC protects against ischemic injury, in part, by diminishing apoptosis-related gene expression and by altering protein phosphorylation.

Animals↗

PubMedDate not supplied

Cell transplants offer promise for stroke recovery.

Cell transplantation is an experimental approach to restore brain function in neurodegenerative disorders such as Parkinson's and Huntington's disease. Transplantation also represents a possible strategy to repair the brain after a stroke. Various cell types are under investigation in experimental stroke studies. This review discusses the different graft sources and presents preliminary data on the transplantation of neural progenitor cells after stroke in rats. Following transplantation, progenitor cells proliferated and differentiated into all the different brain cell types, including neurons, and they repopulated the ischemic infarct. These results suggest that cell transplantation may serve as a future restorative therapy for stroke and other neurologic disorders such as Parkinson's disease, Alzheimer's disease, trauma, and multiple sclerosis.

Animals↗