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Biomedical subjects

E Yoles

Publications and source records attributed to E Yoles.

At least 37 records · Page 2Linked to original sources
PubMed2000

Metabolic and ionic responses to global brain ischemia in the newborn dog in vivo: II. Post-natal age aspects.

The main difference between newborn and adult brains is expressed in the relative resistance of the newborn brain to oxygen deprivation. The aim of the present study was to examine the effect of global ischemia in canine puppies of three different ages on the metabolic, ionic and electrical activity of the brain and to study the basic mechanisms underlying the relative resistance of the newborn brain in ischemic episode. The puppies were divided into three age groups. The young group included 0-6-day-old puppies (n = 16), the intermediate group included 7-19-day-old puppies (n = 21), and the 'adult' group included puppies aged 20 days or more (n = 17). Statistical analysis of the results led to the following conclusions: The younger the puppy, the longer is the time until the occurrence of the secondary reflectance increase SRI (13.0 +/- 1.9 min vs. 5.3 +/- 0.5 min). The younger the puppy, the longer the time until onset of potassium leakage from the cells (0.9 +/- 0.1 min vs. 0.35 +/- 0.05 min) and the lower the amount of potassium leakage (9.6 +/- 2.8 mM vs. 21.7 +/- 4.8 mM). The rate of pumping of the potassium ions into the cells during the recovery stage was higher in the oldest group (1.2 +/- 0.2 mM min-1 vs. 0.38 +/- 0.1 mM min-1). It was possible to speculate that in the young puppies there is uncoupling of the oxidative phosphorylation from respiration and as a result, there is a lower, if any, rate of ATP synthesis. It seems that the newborn brain is able to cope with a decrease in available energy for a longer period of time. This is apparently due to differences in membrane characteristics and an improved ability to retain ionic equilibrium across both sides of the membrane.

Aging↗
PubMed2000

Neuroprotection: a new treatment modality for glaucoma?

It is now commonly accepted that glaucoma is a neurodegenerative disease of the optic nerve. Thus, at any given time, there are neurons that, though still viable, are vulnerable to the hostile extracellular milieu and are therefore amenable to neuroprotective therapy. Neuroprotection refers to any intervention, either external to the optic nerve or internally, that will lead to an intracellular change in the balance between survival and death signals in favor of survival. Several potential sites and modalities for such intervention may exist. When designing neuroprotective therapy, ways must be sought to recruit the physiologic self-repair mechanisms awakened by the primary or secondary risk factors. These mechanisms appear to be insufficiently effective when in their natural state, but they may be simulated or boosted by appropriate therapeutic compounds or cells.

Animals↗
PubMed2000

RGC death in mice after optic nerve crush injury: oxidative stress and neuroprotection.

PURPOSE: To establish a method for morphometric analysis of retrogradely labeled retinal ganglion cells (RGCs) of the mouse retina, to be used for the study of molecular aspects of RGC survival and neuroprotection in this model; to evaluate the effect of overexpression of Cu-Zn-superoxide dismutase (CuZnSOD) on RGC survival after severe crush injury to the optic nerve, and to assess the effect of the alpha2-adrenoreceptor agonist brimonidine, recently shown to be neuroprotective, on RGC survival. METHODS: A severe crush injury was inflicted unilaterally in the orbital portion of the optic nerves of wild-type and transgenic (Tg-SOD) mice expressing three to four times more human CuZnSOD than the wild type. In each mouse all RGCs were labeled 72 hours before crush injury by stereotactic injection of the neurotracer dye FluoroGold (Fluorochrome, Denver, CO) into the superior colliculus. Survival of RGCs was then assessed morphometrically, with and without systemic injection of brimonidine. RESULTS: Two weeks after crush injury, the number of surviving RGCs was significantly lower in the Tg-SOD mice (596.6 +/- 71.9 cells/mm(2)) than in the wild-type control mice (863. 5 +/- 68 cells/mm(2)). There was no difference between the numbers of surviving RGCs in the uninjured retinas of the two strains (3708 +/- 231.3 cells/mm(2) and 3904 +/- 120 cells/mm(2), respectively). Systemic injections of brimonidine significantly reduced cell death in the Tg-SOD mice, but not in the wild type. CONCLUSIONS: Overexpression of CuZnSOD accelerates RGC death after optic nerve injury in mice. Activation of the alpha2-adrenoreceptor pathway by brimonidine enhances survival of RGCs in an in vivo transgenic model of excessive oxidative stress.

Adrenergic alpha-Agonists↗
PubMed1999

The remedy may lie in ourselves: prospects for immune cell therapy in central nervous system protection and repair.

The irreversible loss of function after axonal injury in the central nervous system (CNS) is a result of the lack of neurogenesis, poor regeneration, and the spread of damage caused by toxicity emanating from the degenerating axons to uninjured neurons in the vicinity. Now, 100 years after Ramon y Cajal's discovery that CNS neurons--unlike neurons of the peripheral nervous system--fail to regenerate, it has become evident that (a) CNS tissue is indeed capable of regenerating, at.least in part, provided that it acquires the appropriate conditions for growth support, and (b) that the spread of damage can be stopped and the postinjury rescue of neurons thus achieved, if ways are found to neutralize the mediators of toxicity, either by inhibiting their action or by increasing tissue resistance to them. In most physiological systems the processes of tissue maintenance and repair depend on the active assistance of immune cells. In the CNS, however, communication with the immune system is restricted. The accumulated evidence from our previous studies suggests that the poor posttraumatic repair and maintenance in the CNS is due at least in part to this restriction. Key factors in the recovery of injured tissues, but missing or deficient in the CNS, are the processes of recruitment and activation of immune cells. We therefore propose the development of immune cell therapies in which the injured CNS is exogenously provided with an adequate number of appropriately activated immune cells (macrophages for regrowth and autoimmune T cells for maintenance), controlled in such a way as to derive maximal benefit with minimal risk of disease. It is expected that these self-adjusting cells will communicate with the damaged tissue, monitor tissue needs, and control the dynamic course of CNS healing.

Autoimmunity↗
PubMed1999

'Axogenic' and 'somagenic' neurodegenerative diseases: definitions and therapeutic implications.

Neurodegenerative diseases are characterized by a relentless loss of specific groups of neuronal subtypes. Many of these diseases share similar molecular mechanisms and extracellular mediators of neuronal loss. We now suggest that neurodegeneration originating in the neuronal cell bodies (e.g. in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis) should be distinguished from that originating in the axons (e.g. in glaucoma, certain peripheral neuropathies and spinal stenosis). We propose that the former group of diseases be defined as 'somagenic' and the latter as 'axogenic'. Although axogenic disorders may share common symptoms and mediators of toxicity with somagenic disorders, they have distinct temporal, subcellular and signal-transduction features. We further suggest that, by adopting this classification of disorders based on pathophysiological processes, we will come to recognize additional diseases (in particular, those defined as axogenic) as being neurodegenerative and therefore possibly amenable to neuroprotective therapy.

Axonal Transport↗
PubMed1999

Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy.

Autoimmunity to antigens of the central nervous system is usually considered detrimental. T cells specific to a central nervous system self antigen, such as myelin basic protein, can indeed induce experimental autoimmune encephalomyelitis, but such T cells may nevertheless appear in the blood of healthy individuals. We show here that autoimmune T cells specific to myelin basic protein can protect injured central nervous system neurons from secondary degeneration. After a partial crush injury of the optic nerve, rats injected with activated anti-myelin basic protein T cells retained approximately 300% more retinal ganglion cells with functionally intact axons than did rats injected with activated T cells specific for other antigens. Electrophysiological analysis confirmed this finding and suggested that the neuroprotection could result from a transient reduction in energy requirements owing to a transient reduction in nerve activity. These findings indicate that T-cell autoimmunity in the central nervous system, under certain circumstances, can exert a beneficial effect by protecting injured neurons from the spread of damage.

Amino Acid Sequence↗
PubMed1999

Brain metabolic and ionic responses to systemic hypoxia in the newborn dog in vivo.

Newborns are less sensitive than adults to hypoxic/ischemic injury. However, research into the mechanism of the newborn's relative resistance to reduced brain oxygen levels is relatively scarce, and the time-scale for the disappearance of resistance is not known. The multiprobe assembly (MPA) has enabled us to examine the resistance of puppies at various ages to hypoxia via continuous, simultaneous, on-line measurement of various ionic, metabolic and electrical parameters from the cerebral cortex. The parameters measured included electrocorticogram (ECoG), direct current (DC) steady state potential, extracellular potassium (Ke+) and calcium ion concentrations and intra-mitochondrial Nicotine amide adenine dinucleotide NADH redox levels. These parameters were measured under various degrees of hypoxia (fraction of inspiration oxygen was between 0-10%) in 6-h-old to 24-week-old puppies (n = 44). Sensitivity to hypoxia increased with age, being expressed in the leakage of potassium ions out of the cells (0.3 +/- 0.07 mM in the younger puppies and 3.0 +/- 1.3 mM in the older puppies) following an increase in intra-mitochondrial NADH redox levels. Potassium ion (Ke+) leakage was apparently due to depleted energy stores resulting from an impairment in the balance between oxygen supply and demand. Although the overall effect was similar, the kinetics of these changes were much faster in the older puppies. The time to initial increase of extracellular K+ was 2.5 +/- 0.1 min in the younger puppies and 0.9 +/- 0.1 min in the older puppies. The time to maximum increase of NADH was 3.2 +/- 0.2 min in the younger puppies and 1.4 +/- 0.1 min in the older puppies. Our results indicate that the older puppies utilize the existing oxygen faster than the younger puppies. It is concluded that the increased resistance of newborn puppies to hypoxia is due to intrinsic properties of the brain itself, like the ability of the membrane to maintain ionic homeostasis.

Age Factors↗
PubMed1999

Injury-induced gelatinase and thrombin-like activities in regenerating and nonregenerating nervous systems.

It is now widely accepted that injured nerves, like any other injured tissue, need assistance from their extracellular milieu in order to heal. We compared the postinjury activities of thrombin and gelatinases, two types of proteolytic activities known to be critically involved in tissue healing, in nonregenerative (rat optic nerve) and regenerative (fish optic nerve and rat sciatic nerve) neural tissue. Unlike gelatinases, whose induction pattern was comparable in all three nerves, thrombin-like activity differed clearly between regenerating and nonregenerating nervous systems. Postinjury levels of this latter activity seem to dictate whether it will display beneficial or detrimental effects on the capacity of the tissue for repair. The results of this study further highlight the fact that tissue repair and nerve regeneration are closely linked and that substances that are not unique to the nervous system, but participate in wound healing in general, are also crucial for regeneration or its failure in the nervous system.

Animals↗
PubMed1999

Alpha2-adrenoreceptor agonists are neuroprotective in a rat model of optic nerve degeneration.

PURPOSE: The neurodegenerative progression of glaucoma is considered to be related not only to primary risk factors such as the elevation of intraocular pressure, but also to mediators of secondary neuronal degeneration. In the present study, the neuroprotective activity of the alpha2-adrenoreceptor agonists brimonidine, AGN 191103, and clonidine were examined in an animal model that simulates secondary neuronal degeneration of the optic nerve in a way thought to be independent of elevation of intraocular pressure. The beta-blocker timolol, currently used clinically to decrease intraocular pressure, was also examined for neuroprotective activity at dosages corresponding to the effective antihypertensive dosage. METHODS: A single dose of each of the tested compounds was administered intraperitoneally immediately after partial crush injury of the rat optic nerve. Secondary degeneration was measured by determining injury-induced deficits with and without the drug. This was achieved electrophysiologically by measurement of compound action potential amplitude, and morphometrically by counting the retrogradely labeled retinal ganglion cells, representing viable optic nerve axons, in wholemounted retinas. RESULTS: All three alpha2-adrenoreceptor agonists, but not timolol, exhibited neuroprotective effects. Treatment immediately after injury with each of these agonists resulted in a dose-dependent attenuation of the injury-induced decrease in compound action potential amplitude. Moreover, after treatment with 100 microg/kg brimonidine administered intraperitoneally, the loss of retinal ganglion cells 2 weeks after injury was three times lower than in saline-treated animals. CONCLUSIONS: In addition to their known effect of lowering intraocular pressure, alpha2-adrenoreceptor agonists, unlike timolol, exert a neuroprotective effect. Use of the rat optic nerve model of partial crush injury can serve as a method of screening compounds that are potentially capable of alleviating the progression of secondary neuronal degeneration.

Action Potentials↗
PubMed1998

Elevation of intraocular glutamate levels in rats with partial lesion of the optic nerve.

BACKGROUND: Acute partial lesion of the rat optic nerve, although not a model for glaucoma, mimics some of the features of the disease. OBJECTIVE: To learn whether degeneration of rat optic nerve fibers and death of their retinal ganglion cells induced by an acute partial lesion are associated with elevated levels of glutamate, known to occur in the eyes of humans and monkeys with glaucoma. MATERIALS AND METHODS: Rat optic nerve was subjected to a partial crush injury. Aqueous humor samples were aspirated from the anterior and posterior aqueous chambers at specified times and their amino acid contents were determined by means of high-performance liquid chromatography. RESULTS: Three and 7 days after injury, intraocular glutamate and aspartate levels were found to be significantly higher than in normal or sham-operated-on eyes, and returned to normal by day 14. CONCLUSIONS: Degeneration of the optic nerve, induced by a mechanical injury of the axons, leads to intraocular elevation of glutamate and aspartate levels. These results illustrate that the model of the partial optic nerve lesion exhibits another feature typical of a long-term optic neuropathy, such as glaucoma.

Animals↗
PubMed1998

Degeneration of spared axons following partial white matter lesion: implications for optic nerve neuropathies.

Neuroprotective therapy is a relatively new development in the approach to the treatment of acute and chronic brain damage. Though initially viewed in the framework of acute CNS injuries, the concept was recently extended to include chronic injuries, in which at any given time there are some neurons in an acute phase of degeneration coexisting with others that are healthy, marginally damaged, or dead. The healthy neurons and those that are only marginally damaged are the potential targets for neuroprotection. For the development of neuroprotective therapies, it is essential to employ an animal model in which the damage resulting from secondary degeneration can be quantitatively distinguished from primary degeneration. This is of particular relevance when the site of the damage is in the white matter (nerve fibers) rather than in the gray matter (cell bodies). In the present work we reexamine the concepts of secondary degeneration and neuroprotection in white matter lesions. Using a partial crush injury of the adult rat optic nerve as a model, we were able to assess both primary and secondary nerve damage. We show that neurons whose axons were not damaged or only marginally damaged after an acute insult will eventually degenerate as a consequence of their existence in the degenerative environment produced by the injury. This secondary degeneration does not occur in all of the neurons at once, but affects them in a stepwise fashion related to the severity of the damage inflicted. These findings, which may be applicable to the progression of acute or chronic neuropathy, imply that neuroprotective therapy may have a beneficial effect even if there is a time lag between injury and treatment.

Animals↗
PubMed1998

Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats.

Postinjury recovery in most tissues requires an effective dialog with macrophages; however, in the mammalian central nervous system, this dialog may be restricted (possibly due to its immune-privileged status), which probably contributes to its regeneration failure. We circumvented this by implanting macrophages, pre-exposed ex vivo to peripheral nerve segments, into transected rat spinal cord. This stimulated tissue repair and partial recovery of motor function, manifested behaviorally by movement of hind limbs, plantar placement of the paws and weight support, and electrophysiologically by cortically evoked hind-limb muscle response. We substantiated these findings immunohistochemically by demonstrating continuity of labeled nerve fibers across the transected site, and by tracing descending fibers distally to it by anterograde labeling. In recovered rats, retransection of the cord above the primary transection site led to loss of recovery, indicating the involvement of long descending spinal tracts. Injection of macrophages into the site of injury is relatively non-invasive and, as the cells are autologous, it may be developed into a clinical therapy.

Animals↗
PubMed1997

NMDA-receptor antagonist protects neurons from secondary degeneration after partial optic nerve crush.

Damage resulting from a partial acute lesion of white matter in the central nervous system (CNS) gradually spreads also to neurons that escaped the primary injury, resulting in their degeneration. Such spreading has been referred to as secondary degeneration. In order to demonstrate that this degeneration is indeed secondary to that caused by the acute insult, as well as to investigate the mechanism underlying the spread of damage and ways in which to protect neurons from such damage, we have proposed the use of partial lesion of the rodent optic nerve as a model. In this model we examined whether an antagonist of a receptor-mediated channel, shown to be beneficial in gray matter lesions, can protect neurons from undergoing secondary degeneration following white matter lesion. A well-calibrated partial crush lesion inflicted on the optic nerve of adult rats was immediately followed by a single intraperitoneal injection of the N-methyl-D-aspartate receptor antagonist, MK-801 (1 mg/kg). Protection of neurons from secondary degeneration was assessed by retrograde labeling and by measurement of the visual evoked potential (VEP) response to light. Two weeks after the injury, the mean number of neurons that were still intact was about threefold higher in the MK-801-treated group than in the saline-treated control group, indicating a treatment-induced protection of neurons that had escaped primary injury. A positive VEP response to light was obtained in 90% of the MK-801 treated animals and in only 50% of injured controls. The questions regarding whether the secondary degeneration of initially spared neurons starts in their cell bodies or in their axons, and consequently the identity of the primary site of their protection by MK-801, are discussed in relation to the absence of N-methyl-D-aspartate receptors on nerve fibers. The present findings may have implications for both acute and chronic injuries of the CNS.

Analysis of Variance↗
PubMed1996

Complete transection of rat optic nerve while sparing the meninges and the vasculature: an experimental model for optic nerve neuropathy and trauma.

In this study we present a method to achieve a complete transection of optic nerve axons in adult rat, while preserving the vasculature and retaining the continuity of the meninges. Under deep anesthesia, the optic nerve of adult rat is exposed. Using specially designed instruments built from disposable glass microsampling pipettes, a small opening is created in the meninges of the optic nerve, 2-3 mm behind the eye globe. A glass dissector is introduced through the opening and is used to cut all the axons through the whole width of the nerve. Complete transection of the optic nerve axons was achieved, while retaining the continuity of the meninges and avoiding damage to the nerve's vascular supply. Transection was confirmed by transillumination showing a complete gap in the continuity of the nerve axons, and by both morphological and electrophysiological criteria. Nerve transection performed by the conventional technique leads to neuroma formation and hampers regeneration. Crush injury may cause nerve ischemia, which is detrimental to axonal recovery. Both of these disadvantages are avoided by the method of transection presented here. The opening created in the 'meningeal tube' can be used to inject substances that may be of benefit in recovery, rescue and/or regeneration of the injured axons. The model is particularly suitable for in vivo studies on nerve regeneration, and especially for screening of putative therapeutic agents.

Animals↗
PubMed1996

HU-211, a nonpsychotropic cannabinoid, produces short- and long-term neuroprotection after optic nerve axotomy.

HU-211 is a novel synthetic analog of tetrahydrocannabinol that was recently shown in animal models to be nonpsychotropic. In this study we show that HU-211 can potentially be used as a neuroprotective compound in the CNS. Using a calibrated crush injury of adult rat optic nerve, we show that HU-211 can reduce injury-induced metabolic and electrophysiological deficits. Energy metabolism was monitored by measuring the intramitochondrial nicotine-amine adenine dinucleotide redox state hourly for 6 h after injury and treatment. Electrophysiological activity was assessed by compound action potential and visual evoked potential response. Beneficial effects were dose-dependent, being optimal at 7 mg/kg, administered intraperitoneally. The time window during which treatment was effective was found to be from the time of injury for at least 5 h, with treatment most effective at the time of injury. These results strongly suggest that HU-211, given immediately after CNS injury at the optimal dosage, may possess neuroprotective activities.

Action Potentials↗
PubMed1996

Potential treatment modalities for glaucomatous neuropathy: neuroprotection and neuroregeneration.

PURPOSE: This article presents the rationale and an experimental strategy for the development of new treatment modalities for glaucomatous neuropathy. Accumulating evidence suggests that regardless of the primary trigger of the retinal and optic nerve damage in glaucoma, the disease will continue to progress even when the cause is removed. The resulting damage can be mimicked by the progression of damage secondary to an acute partial crush injury at the optic nerve head. Such secondary damage includes degeneration of the directly injured optic nerve fibers culminating in death of their cell bodies, as well as degeneration of nerve fibers that escaped acute injury but nevertheless deteriorate as a result of their exposure to injury-induced mediators of secondary degeneration released by the directly affected neurons. CONCLUSION: We therefore propose that substances found to be effective in rescuing fibers from secondary degeneration and in increasing the survival rate or prolonging survival of retinal ganglion cells in the partially lesioned optic nerve may be useful for the treatment of glaucoma. The new approach does not replace hypotensive therapy, but addresses the glaucoma-induced damage by promoting nerve protection and neuroregeneration.

Animals↗
PubMed1994

Recovery of visual response of injured adult rat optic nerves treated with transglutaminase.

Failure of axons of the central nervous system in adult mammals to regenerate spontaneously after injury is attributed in part to inhibitory molecules associated with oligodendrocytes. Regeneration of central nervous system axons in fish is correlated with the presence of a transglutaminase. This enzyme dimerizes interleukin-2, and the product is cytotoxic to oligodendrocytes in vitro. Application of this nerve-derived transglutaminase to rat optic nerves, in which the injury had caused the loss of visual evoked potential response to light, promoted the recovery of that response within 6 weeks after injury. Transmission electron microscopy analysis revealed the concomitant appearance of axons in the distal stump of the optic nerve.

Animals↗