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Biomedical subjects

J A Zivin

Publications and source records attributed to J A Zivin.

At least 19 recordsLinked to original sources
PubMed2005

Prospective reliability of the STRokE DOC wireless/site independent telemedicine system.

The authors evaluated a site-independent telemedicine system. Telemedicine may be limited by the need for fixed connectivity. Wireless and site-independent technologies eliminate this limitation. Twenty-five stroke patients underwent evaluations by remote and bedside examiners. Ten of 15 (67%) NIH Stroke Scale and 9 of 11 (82%) Modified NIH Stroke Scale items showed excellent interrater reliability. Spearman correlations were > or =0.93. This Internet system is reliable and valid. Further studies should assess its use in acute stroke.

Adolescent↗
PubMed2001

Pharmacological effects of the spin trap agents N-t-butyl-phenylnitrone (PBN) and 2,2,6, 6-tetramethylpiperidine-N-oxyl (TEMPO) in a rabbit thromboembolic stroke model: combination studies with the thrombolytic tissue plasminogen activator.

BACKGROUND AND PURPOSE: It has been proposed that spin trap agents such as N:-t-butyl-phenylnitrone (PBN) may be useful as neuroprotective agents in the treatment of ischemia and stroke. However, to date, there is little information concerning the effectiveness of spin trap agents when administered in combination with the only Food and Drug Administration-approved pharmacological agent for the treatment of stroke, the thrombolytic tissue plasminogen activator (tPA). Thus, we determined the effects of PBN when administered before tPA on hemorrhage and infarct rate and volume. We also compared the effects of PBN with those of 2,2,6, 6-tetramethylpiperidine-N:-oxyl (TEMPO), another spin trap agent that has a different chemical structure and trapping profile, on the incidence of infarcts and hemorrhage. METHODS: One hundred sixty-five male New Zealand White rabbits were embolized by injecting a blood clot into the middle cerebral artery via a catheter. Five minutes after embolization, PBN or TEMPO (100 mg/kg) was infused intravenously. Control rabbits received saline, the vehicle required to solubilize the spin traps. In tPA studies, rabbits were given intravenous tPA starting 60 minutes after embolization. Postmortem analysis included assessment of hemorrhage, infarct size and location, and clot lysis. RESULTS: In the control group, the hemorrhage rate after a thromboembolic stroke was 24%. The amount of hemorrhage was significantly increased to 77% if the thrombolytic tPA was administered. The rabbits treated with PBN in the absence of tPA had a 91% incidence of hemorrhage compared with 33% for the TEMPO-treated group. In the combination drug-treated groups, the PBN/tPA group had a 44% incidence of hemorrhage, and the TEMPO/tPA group had a 42% incidence of hemorrhage. tPA, PBN/tPA, and TEMPO/tPA were similarly effective at lysing clots (49%, 44%, and 33%, respectively) compared with the 5% rate of lysis in the control group. There was no significant effect of drug combinations on the rate or volume of infarcts. CONCLUSIONS: This study suggests that certain spin trap agents may have deleterious effects when administered after an embolic stroke. However, spin trap agents such as PBN or TEMPO, when administered in combination with tPA, may improve the safety of tPA by reducing the incidence of tPA-induced hemorrhage. Overall, the therapeutic benefit of spin trap agents for the treatment of ischemic stroke requires additional scrutiny before they can be considered "safe" therapeutics.

Animals↗
PubMed2001

Neuroprotection by the selective cyclooxygenase-2 inhibitor SC-236 results in improvements in behavioral deficits induced by reversible spinal cord ischemia.

BACKGROUND AND PURPOSE: Cyclooxygenase-2 (COX-2), an enzyme that is induced in the central nervous system after various insults, has been localized to neurons and in cells associated with the cerebral vasculature, where it may be involved in the inflammatory component of the ischemic cascade. COX-2 is part of the initial reaction that involves the arachidonic acid cascade, which produces molecules that support an inflammatory response. The present study evaluated the pharmacological effects of a specific long-acting COX-2 inhibitor, SC-236, in a reversible rabbit spinal cord ischemia model using clinical rating scores (behavioral analysis) as the primary end point. METHODS: SC-236 was administered (10 to 100 mg/kg SC) 5 minutes after the start of occlusion to groups of rabbits exposed to ischemia induced by temporary (10 to 40 minutes) occlusion of the infrarenal aorta. Behavioral analysis, which allowed for the calculation of an ET(50) value representing the duration of ischemia (minutes) associated with a 50% probability of resultant permanent paraplegia, was conducted 18 and 48 hours later. A drug was determined to be neuroprotective if it prolonged the ET(50) significantly compared with the appropriate control group. RESULTS: Since SC-236 is not readily soluble in aqueous solutions, it was dissolved in 100% dimethyl sulfoxide (DMSO) for subcutaneous administration. Therefore, the vehicle-treated control group consisted of rabbits given an equal volume of DMSO without drug. In the DMSO-treated control group, the ET(50) assessed 18 hours after initiation of aortal occlusion was 18.84+/-3.19 minutes. In contrast, treatment with 100 mg/kg of SC-236 given 5 minutes after the start of occlusion prolonged the ET(50) of the group significantly to 30.04+/-3.55, an effect that was still evident 48 hours later. In addition, lower doses of the drug (10 and 50 mg/kg) also showed a trend for an increase in ET(50). SC-236 (100 mg/kg) did not significantly alter body temperature after a subcutaneous injection. CONCLUSIONS: The present study suggests that COX-2 plays an important role in the ischemic cascade of events that translate into ischemia-induced behavioral deficits and furthermore that selective COX-2 inhibitors may be useful in the treatment of ischemic stroke to improve behavioral functions.

Animals↗
PubMed2000

Continuous intrathecal fluid infusions elevate nerve growth factor levels and prevent functional deficits after spinal cord ischemia.

Continuous intracerebroventricular or intrathecal infusions of neurotrophic factors have been reported to prevent neuronal degeneration, stimulate axonal sprouting and ameliorate behavioral deficits in various models of CNS injury and aging. In the present study, the ability of intrathecal infusions of recombinant human nerve growth factor (NGF) to reduce functional deficits following spinal cord ischemia was investigated. Adult rabbits underwent intrathecal cannulation and continuous infusions of either 300 microg/ml recombinant human NGF or artificial CSF (vehicle) at a rate of 143 microl/day for 7 days prior to induction of spinal cord ischemia. Continuous infusions were maintained after induction of ischemia. Four days later, both NGF-treated and vehicle-infused subjects showed a significant amelioration of functional motor deficits compared to lesioned, non-infused subjects (P<0.05). The average duration of tolerated ischemia increased from 23.4+/-1.8 min in lesioned, non-infused subjects to 35.5+/-3.1 min in lesioned, artificial CSF-infused subjects and 35.6+/-4.7 min in NGF-infused subjects (mean+/-S.E.M.). Significantly elevated NGF protein levels were attained within the spinal cords of both NGF-treated subjects and artificial CSF-infused subjects, although levels were substantially higher in NGF-treated subjects (9.8+/-3.8 ng/g in NGF-infused vs. 2.0+/-0.4 ng/g in vehicle-infused and only 0.4+/-0.2 ng/g in lesioned, non-infused animals). These findings indicate that the process of intrathecal cannulation and fluid infusion elicits alterations in the spinal cord environment that are neuroprotective, including spontaneous elevations in NGF levels.

Animals↗
PubMed2000

Prosaptide exacerbates ischemia-induced behavioral deficits in vivo; an effect that does not involve mitogen-activated protein kinase activation.

Prosaposin is a 517 amino acid membrane component and secreted protein(5,7,9) that is proteolytically cleaved to generate the four small glycoproteins; saposins A, B, C and D.(9,13,19) Prosaposin's ability to promote neurite outgrowth(31) and to protect neurons from programmed cell death(28) in vitro, as well as to rescue neurons from ischemia and other damage in vivo(11,12,15,25) implied that prosaposin was neurotrophic/neuroprotectant.(1,7,24,31) The neurotrophic sequence of prosaposin was isolated to smaller peptide fragments termed prosaptides(15,31) within the amino terminal portion of saposin C.(1,6,8,10,17,20,21,28) The proposed use of synthetic prosaptides as peripherally administered neuroprotective and/or neurotrophic therapeutic agents has stemmed from their ability to cross the blood-brain barrier,(27) as well as their reported neurotrophic activity in vitro.(15,23,31) Few studies, however, have attempted to characterize these peptides, presumably due to their reported instability following peripheral administration.(27) With the recent design of a stable 11-mer retro-inverso prosaptide,(15,31) it has become feasible to investigate the pharmacological effects of a stable version of these peptides in the validated rabbit spinal cord ischemia model that has been used extensively in the development of therapeutics to treat ischemic stroke.(4,14,16,18) Our results show not only that prosaptide was not neurotrophic/neuroprotectant in vivo, but rather it worsened ischemia-induced behavioral deficits.

Animals↗
PubMed2000

Metalloproteinase inhibition reduces thrombolytic (tissue plasminogen activator)-induced hemorrhage after thromboembolic stroke.

BACKGROUND AND PURPOSE: A potentially dangerous side effect associated with tissue plasminogen activator (tPA) use is cerebral hemorrhage. We have focused on developing drugs that could be administered with tPA to reduce the rate of hemorrhage. Since recent studies suggest that various matrix metalloproteinases (MMPs) are important in tumor necrosis factor-alpha production and membrane and vessel remodeling after ischemia, we investigated whether MMP inhibition affected the rate of hemorrhage and infarct production in the absence or presence of tPA treatment. METHODS: We occluded the middle cerebral artery of New Zealand White rabbits with radiolabeled blood clots. Five minutes after embolization, we administered either the MMP inhibitor BB-94 (30 mg/kg SC) or its vehicle. Additional groups received BB-94 or vehicle in combination with tPA, administered 60 minutes after embolization (3.3 mg/kg tPA). After 48 hours, the rabbits were killed and brains were removed, immersion fixed for 1 week in 4% paraformaldehyde, and then cut into 5-mm coronal sections that were examined for the presence of hemorrhage, infarcts, and recanalization. RESULTS: Hemorrhage after embolic stroke was detected in 24% of the control group. tPA induced macroscopically visible hemorrhage in 77% of the tPA-treated group. The rabbits treated with BB-94 had an 18% incidence of hemorrhage (P:>0.05 compared with control). However, when the combination of BB-94 and tPA was administered to rabbits, there was only a 41% incidence of hemorrhage (compared with 77% in the tPA group; P:<0. 05). Both tPA and BB-94/tPA were similarly effective at lysing clots, at 49% and 35% (P:<0.05), respectively, compared with the 5% rate of lysis in the control group. There was a trend for a reduction in the number of infarcts, but it did not reach statistical significance. CONCLUSIONS: Our data suggest that MMP inhibition attenuates mechanisms involved in tPA-induced hemorrhage. This novel form of combination therapy may show promise as a treatment strategy for acute stroke.

Animals↗
PubMed2000

Dehydroepiandrosterone sulfate is neuroprotective in a reversible spinal cord ischemia model: possible involvement of GABA(A) receptors.

BACKGROUND AND PURPOSE: Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) may function as neurotrophic or neuroprotective factors to protect central nervous system (CNS) neurons against a variety of insults, including excitotoxicity. The present study evaluated the pharmacological effects of DHEAS in a reversible spinal cord ischemia model. METHODS: DHEAS was administered (50 mg/kg IV) 5 or 30 minutes after the start of occlusion to groups of rabbits exposed to ischemia induced by temporary (15 to 60 minutes) occlusion of the infrarenal aorta. The group P(50) represents the duration of ischemia (in minutes) associated with 50% probability of resultant permanent paraplegia. RESULTS: The P(50) of the vehicle-treated control group, when behavioral analysis was assessed 18 hours after aortal occlusion, was 28.8+/-2.0 minutes. Neuroprotection was demonstrated if a drug significantly prolonged the P(50) compared with the vehicle-treated control group. Treatment with DHEAS at 5 minutes significantly (P<0.05) prolonged the P(50) of the group to 36.8+/-3.9 minutes. In addition, the DHEAS effect appeared durable, because a significant difference between the control and DHEAS-treated groups was still measurable at the 4-day time point. At 4 days, the P(50) of the control group was 26.1+/-2.2 minutes, whereas the P(50) for the DHEAS-treated group was 38.6+/-5. 9 minutes. DHEAS was not neuroprotective if administered 30 minutes after occlusion. In addition, the GABA(A) antagonist bicuculline abolished the neuroprotective effect of DHEAS. CONCLUSIONS: The present study suggests that neurosteroids may have substantial therapeutic benefit for the treatment of ischemic stroke.

Animals↗
PubMed1999

Reduction of intracerebral hemorrhaging in a rabbit embolic stroke model.

OBJECTIVE: To study the effects of a spin trap agent and a CD18 antibody administered after stroke induction on intracerebral hemorrhaging. The drugs can prevent leukocyte adhesion. METHODS: A rabbit embolic stroke model that produces intracerebral hemorrhage was used. RESULTS: A time course study showed that hemorrhaging was grossly apparent in approximately 50% of the subjects at 5 hours and in 75% at 24 hours after embolization. MDL 101,002, a spin trap agent, administered IV 5 minutes after embolization, significantly decreased the volume of hemorrhage. It also improved the behavior score relative to vehicle-treated rabbits. The CD18 antibody tended to decrease hemorrhage volume. CONCLUSION: The beneficial effect of MDL 101,002 may be caused by inhibition of free radical injury to brain tissue, thereby protecting brain microvessel integrity. Acute therapy for intracerebral hemorrhage may be feasible.

Animals↗
PubMed1999

Thrombolytic stroke therapy: past, present, and future.

Until 1995, treatment of strokes consisted exclusively of efforts to prevent recurrence. Proof that tissue plasminogen activator is useful for acute management is changing the approach to stroke patients. The development process has been difficult and the current treatment recommendations have been controversial. Recent successful clinical trials lend additional credence to these concepts. Future treatment strategies will probably include combinations of thrombolytics and neuroprotectants of various types. However, the need to initiate treatment rapidly after stroke onset is likely to continue.

Animals↗
PubMed1999

Changes in expression of the DNA repair protein complex DNA-dependent protein kinase after ischemia and reperfusion.

Reperfusion of ischemic tissue causes an immediate increase in DNA damage, including base lesions and strand breaks. Damage is reversible in surviving regions indicating that repair mechanisms are operable. DNA strand breaks are repaired by nonhomologous end joining in mammalian cells. This process requires DNA-dependent protein kinase (DNA-PK), composed of heterodimeric Ku antigen and a 460,000 Da catalytic subunit (DNA-PKcs). In this study, a rabbit spinal cord model of reversible ischemia was used to demonstrate the effect of acute CNS injury on the activity and expression of DNA-dependent protein kinase. The DNA-binding activity of Ku antigen, analyzed by an electrophoretic mobility shift assay, increased during reperfusion after a short ischemic insult (15 min of occlusion), from which the animals recover neurological function. After severe ischemic injury (60 min of occlusion) and reperfusion that results in permanent paraplegia, Ku DNA binding was reduced. Protein levels of the DNA-PK components-Ku70, Ku80, and DNA-PKcs-were monitored by immunoblotting. After 60 min of occlusion, the amount of DNA-PKcs and the enzyme poly(ADP-ribose) polymerase (PARP) decreased with the same time course during reperfusion. Concurrently 150 and 120 kDa fragments were immunostained by an anti-DNA-PKcs monoclonal antibody. This antibody was shown to cross-react with alpha-fodrin breakdown products. The 120 kDa fodrin peptide is associated with caspase-3 activation during apoptosis. Both DNA-PKcs and PARP are also substrates for caspase-3-like activities. The results are consistent with a model in which after a short ischemic insult, DNA repair proteins such as DNA-PK are activated. After severe ischemic injury, DNA damage overwhelms repair capabilities, and cell death programs are initiated.

Animals↗
PubMed1999

Modification of postsynaptic densities after transient cerebral ischemia: a quantitative and three-dimensional ultrastructural study.

Abnormal synaptic transmission has been hypothesized to be a cause of neuronal death resulting from transient ischemia, although the mechanisms are not fully understood. Here, we present evidence that synapses are markedly modified in the hippocampus after transient cerebral ischemia. Using both conventional and high-voltage electron microscopy, we performed two- and three-dimensional analyses of synapses selectively stained with ethanolic phosphotungstic acid in the hippocampus of rats subjected to 15 min of ischemia followed by various periods of reperfusion. Postsynaptic densities (PSDs) from both area CA1 and the dentate gyrus were thicker and fluffier in postischemic hippocampus than in controls. Three-dimensional reconstructions of selectively stained PSDs created using electron tomography indicated that postsynaptic densities became more irregular and loosely configured in postischemic brains compared with those in controls. A quantitative study based on thin sections of the time course of PSD modification indicated that the increase in thickness was both greater and more long-lived in area CA1 than in dentate gyrus. Whereas the magnitude of morphological change in dentate gyrus peaked at 4 hr of reperfusion (140% of control values) and declined thereafter, changes in area CA1 persisted and increased at 24 hr of reperfusion (191% of control values). We hypothesize that the degenerative ultrastructural alteration of PSDs may produce a toxic signal such as a greater calcium influx, which is integrated from the thousands of excitatory synapses onto dendrites, and is propagated to the neuronal somata where it causes or contributes to neuronal damage during the postischemic phase.

Animals↗
PubMed1999

Persistent phosphorylation of cyclic AMP responsive element-binding protein and activating transcription factor-2 transcription factors following transient cerebral ischemia in rat brain.

The transcription factors cyclic AMP responsive element-binding protein (CREB) and activating transcription factor-2 were studied in rat brains subjected to 15 min ischemia followed by varied periods of reperfusion using western blot and immunocytochemical analyses. The total amounts of both CREB and activating transcription factor-2 were not altered in the hippocampus after ischemia. In contrast, levels of the phosphorylated forms of both transcription factors decreased during ischemia but rebounded following reperfusion. The phospho-forms of CREB and activating transcription factor-2 showed regional and temporal differences in their expression. Phospho-CREB was increased relative to control levels at 30 min, and continued to increase for at least three days postischemia, mainly in dentate granule cells. The level of phospho-activating transcription factor-2 appeared to be higher in CAI pyramidal cells than in dentate granule cells after ischemia. The present findings suggest that the signaling pathways for phosphorylation of CREB may be neuroprotective for dentate cells, which are relatively resistant to ischemic insults. The increased phospho-activating transcription factor-2 may reflect increased stresses in these neurons. The more modest activation of CREB pathways in CA1 neurons may not be enough to overcome the increased stresses in these neurons, contributing to delayed neuronal death.

Activating Transcription Factor 2↗
PubMed1999

Thrombolysis with tissue plasminogen activator alters adhesion molecule expression in the ischemic rat brain.

BACKGROUND AND PURPOSE: We tested the hypothesis that treatment of embolic stroke with recombinant human tissue plasminogen activator (rhtPA) alters cerebral expression of adhesion molecules. METHODS: Male Wistar rats were subjected to middle cerebral artery occlusion by a single fibrin-rich clot. P-selectin, E-selectin, and intercellular adhesion molecule-1 (ICAM-1) immunoreactivity was measured at 6 or 24 hours after embolic stroke in control rats and in rats treated with rhtPA at 1 or 4 hours after stroke. To examine the therapeutic efficacy of combined rhtPA and anti-ICAM-1 antibody treatment at 4 hours after embolization, ischemic lesion volumes were measured in rats treated with rhtPA alone, rats treated with rhtPA and anti-ICAM-1 antibody, and nontreated rats. RESULTS: Administration of rhtPA at 1 hour after embolization resulted in a significant reduction of adhesion molecule vascular immunoreactivity after embolization in the ipsilateral hemisphere compared with corresponding control rats. However, when rhtPA was administered to rats at 4 hours after embolization, significant increases of adhesion molecule immunoreactivity in the ipsilateral hemisphere were detected. A significant increase of ICAM-1 immunoreactivity was also detected in the contralateral hemisphere at 24 hours after ischemia. A significant reduction in lesion volume was found in rats treated with the combination of rhtPA and anti-ICAM-1 antibody compared with rats treated only with rhtPA. CONCLUSIONS: The present study suggests that the time of initiation of thrombolytic therapy alters vascular immunoreactivity of inflammatory adhesion molecules in the ischemic brain and that therapeutic benefit can be obtained by combining rhtPA and anti-ICAM-1 antibody treatment 4 hours after stroke.

Animals↗
PubMed1998

Activation of nuclear factor-kappaB in the rabbit spinal cord following ischemia and reperfusion.

The transcription factor NF-kappaB is a ubiquitously expressed inducible regulator of a broad range of genes. Recent studies have shown that activation of NF-kappaB predominantly is associated with protecting cells from apoptosis, but in some cell models, it is associated with promoting cell death. We used a rabbit spinal cord model of reversible ischemia to determine whether NF-kappaB was activated by ischemic and reperfusion injury. DNA binding activity of NF-kappaB was analyzed by an electrophoretic mobility shift assay in animals subjected to varying durations of ischemia and reperfusion. A low level of constitutive NF-kappaB DNA binding was detected in normal lumbar spinal cord extracts. Animals subjected to a short ischemic insult of 15 min, from which they usually recover neurologic function, had a significant increase in the amount of active NF-kappaB in nuclear extracts after 18 h reperfusion. There was no change in nuclear NF-kappaB DNA binding in animals occluded for 60 min that are permanently paraplegic and exhibit extensive neuropathological damage. The amount of deoxycholate-releasable NF-kappaB sequestered in the cytosol, however, decreased after 18 h reperfusion in rabbits occluded for 60 min. This correlated with a decrease in the amount of RelA(p65) NF-kappaB subunit. The results suggest that activation of NF-kappaB after a limited ischemic injury may participate in a neuroprotective response and not in cell death.

Animals↗
PubMed1998

Assembly of proteins to postsynaptic densities after transient cerebral ischemia.

Transient ischemia leads to changes in synaptic efficacy and results in selective neuronal damage during the postischemic phase, although the mechanisms are not fully understood. The protein composition and ultrastructure of postsynaptic densities (PSDs) were studied by using a rat transient ischemic model. We found that a brief ischemic episode induced a marked accumulation in PSDs of the protein assembly ATPases, N-ethylmaleimide-sensitive fusion protein, and heat-shock cognate protein-70 as well as the BDNF receptor (trkB) and protein kinases, as determined by protein microsequencing. The changes in PSD composition were accompanied by a 2.5-fold increase in the yield of PSD protein relative to controls. Biochemical modification of PSDs correlated well with an increase in PSD thickness observed in vivo by electron microscopy. We conclude that a brief ischemic episode modifies the molecular composition and ultrastructure of synapses by assembly of proteins to the postsynaptic density, which may underlie observed changes in synaptic function and selective neuronal damage.

Adenosine Triphosphatases↗