Injury-induced gelatinase and thrombin-like activities in regenerating and nonregenerating nervous systems.
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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. (+info)
Prevention of the death of the rat axotomized hypoglossal nerve and promotion of its regeneration by bovine brain gangliosides.
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We have examined the time course of the neuronal death and regeneration of rat axotomized hypoglossal nerve with various conditions of the nerve resection, and established a useful system to measure neurotrophic activities of bioactive substances. In this system, neuronal death can be evaluated by counting surviving neurons in the nucleus of hypoglossal neuron at the brain stem, and the degree of the regeneration can be measured by counting horseradish peroxidase-positive cells at the same region after injection of horseradish peroxidase into tongue. Using this system, the effects of brain gangliosides on rat hypoglossal nerve regeneration following 5 mm transection were examined. The addition of a ganglioside mixture from bovine brain as well as the autograft strongly prevented the death of neurons and promoted the regeneration of the lesioned nerve at 10 weeks after the operation. Further analyses on the dose effects and injection sites of gangliosides were performed. Although the mechanisms of the neurotrophic effects of the gangliosides are unknown, the therapeutic application of gangliosides for neuronal degeneration is a promising approach. (+info)
Variance in transneuronal retrograde ganglion cell degeneration in monkeys after removal of striate cortex: effects of size of the cortical lesion.
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The extent of transneuronal retrograde degeneration of ganglion cells in the primate retina depends on the age at which striate cortex was damaged, the survival time, the species, and retinal eccentricity. We here report on the effect of lesion size beyond striate cortex, which we assessed along with retinal ganglion cell degeneration in three groups of macaque monkeys who, in each group, had undergone striate cortical ablation at similar ages and survived for similar periods, which ranged from 302 days to 8 years. Where possible, the number of surviving projection neurones in the degenerated dLGN and its volume were also estimated. Results confirm that both geniculate and retinal degeneration correlate significantly with survival time but that the differences within a group can exceed differences between groups and are best accounted for by the extent of the damage to extra-striate visual cortex and underlying white matter. (+info)
Acute direct adenoviral vector cytotoxicity and chronic, but not acute, inflammatory responses correlate with decreased vector-mediated transgene expression in the brain.
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The potential utility of adenoviruses for the treatment of chronic neurological disease is controversial due to reports of vector-associated toxicity, inflammation, and transient transgene expression. To focus upon the mechanism by which transgene expression is lost, we injected increasing doses [1 x 10(6) to 1 x 10(9) infectious units (iu)] of a first-generation adenovirus vector expressing beta-galactosidase into the brains of immune-competent adult rats. Transgene expression was evaluated simultaneously with acute neuronal and glial cell cytotoxicity, and acute and chronic inflammation using immunohistochemistry, at 3 and 30 days post-vector administration. Our results show a clear threshold effect of viral dose upon the amount of transgene expression persisting by 30 days after vector administration. Below 10(8) iu, transgene expression remained stable over the 30-day period. Following infection of more than 10(8) iu, the extent of transgene expression at 30 days was inversely correlated with increasing viral dose. The severity of acute inflammation increased proportionally with increasing vector dose from 10(6) to 10(9) infectious units. In contrast, acute vector-mediated cytotoxicity and chronic inflammation were observed only above the threshold level of vector dose. Above 10(8) iu both the extent of the acute toxicity and the severity of the chronic inflammation were inversely correlated with transgene expression at 30 days. Thus, our data suggest that both an acute loss of cells through direct vector-mediated toxicity and the elicitation of chronic inflammation (but not acute inflammation) may account for the decline in transduction persistence at high vector doses. (+info)
Increased expression and activation of poly(ADP-ribose) polymerase (PARP) contribute to retinal ganglion cell death following rat optic nerve transection.
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Excessive activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) by free-radical damaged DNA mediates necrotic cell death in injury models of cerebral ischemia-reperfusion and excitotoxicity. We recently reported that secondary retinal ganglion cell (RGC) death following rat optic nerve (ON) transection is mainly apoptotic and can significantly but not entirely be blocked by caspase inhibition. In the present study, we demonstrate transient, RGC-specific PARP activation and increased retinal PARP expression early after ON axotomy. In addition, intravitreal injections of 3-aminobenzamide blocked PARP activation in RGCs and resulted in an increased number of surviving RGCs when compared to control animals 14 days after ON transection. These data indicate that secondary degeneration of a subset of axotomized RGCs results from a necrotic-type cell death mediated by PARP activation and increased PARP expression. Furthermore, PARP inhibition may constitute a relevant strategy for clinical treatment of traumatic brain injury. (+info)
Traumatically induced axotomy adjacent to the soma does not result in acute neuronal death.
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Traumatic axonal injury (TAI), a consequence of traumatic brain injury (TBI), results from progressive pathologic processes initiated at the time of injury. Studies attempting to characterize the pathology associated with TAI have not succeeded in following damaged and/or disconnected axonal segments back to their individual neuronal somata to determine their fate. To address this issue, 71 adult male Sprague Dawley rats were subjected to moderate central fluid percussion injury and killed between 30 min and 7 d after injury. Antibodies to the C terminus of beta-amyloid precursor protein (APP) identified TAI in continuity with individual neuronal somata in the mediodorsal neocortex, the hilus of the dentate gyrus, and the dorsolateral thalamus. These somata were followed with immunocytochemical markers of neuronal injury targeting phosphorylated 200 kDa neurofilaments (RMO-24), altered protein translation (phosphorylated eukaryotic translation initiation factor 2 alpha), and cell death [terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)], with parallel electron microscopic (EM) assessment. Despite the finding of TAI within 20-50 micrometer of the soma, no evidence of cell death, long associated with proximal axotomy, was seen via TUNEL or routine light microscopy/electron microscopy. Rather, there was rapid onset (<6 hr after injury) subcellular change associated with impaired protein synthesis identified by EM, immunocytochemical, and Western blot analyses. When followed 7 d after injury, these abnormalities did not reveal dramatic progression. Rather, some somata showed evidence of potential reorganization and repair. This study demonstrates a novel somatic response to TAI in the perisomatic domain and also provides insight into the multifaceted pathology associated with TBI. (+info)
Methylmercury poisoning in common marmosets--MRI findings and peripheral nerve lesions.
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Common marmosets were used as model animals for methylmercury (MeHg) poisoning. Six marmosets were given MeHg of 5 ppm Hg in drinking water. The animals were divided into 3 groups of 2 each. The first group was examined for acute symptomatic MeHg poisoning. They were given MeHg for 70 and 90 days, respectively, to manifest severe symptoms. The second group was sacrificed after 38 days of MeHg exposure, when they had acute-subclinical MeHg poisoning. The third group of animals was exposed for 21 days, and then observed for 2.5 years without MeHg exposure. One of them showed typical symptoms of MeHg poisoning after MeHg exposure had ended, but the other one showed only slight symptoms without ataxia. This experiment demonstrated that MeHg causes pathological changes in neural tissues including the peripheral nerves in common marmosets. Furthermore, common marmosets were found to show MeHg-induced pathological changes similar to those in humans in the cerebrum and cerebellum. (+info)
Discrete gene loci regulate neurodegeneration, lymphocyte infiltration, and major histocompatibility complex class II expression in the CNS.
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Neurodegeneration and inflammation are fundamental aspects of many neurological diseases. A genome-wide scan of the response to ventral root avulsion (VRA) in a rat F2 cross discloses specific gene regions that regulate these processes. Two gene loci displayed linkage to neurodegeneration and T cell infiltration, respectively, and a single locus displayed extreme linkage to VRA-induced major histocompatibility complex class II expression on microglia. The demonstration that polymorphic genes in different loci control neurodegeneration and CNS inflammation has implications for various experimental rodent nervous system paradigms and potentially for genetically regulated susceptibility to a variety of human CNS diseases. (+info)