Rodent models of stroke limitations. What can we learn from recent clinical trials of thrombolysis?
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Animals↗
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Pathogenesis of malformations in a rodent model for Smith-Lemli-Opitz syndrome.
The fact that Smith-Lemli-Opitz syndrome (SLOS), a syndrome comprising major malformations involving a number of organ systems, results from an abnormality in cholesterol biosynthesis, was discovered only recently. Utilizing a drug (BM 15.766) to inhibit the same step in cholesterol biosynthesis as is abnormal in those affected with SLOS, we have developed a rat model that presents with abnormalities observed as early as gestational day 12 that appear to be consistent with some of those subsequent malformations that comprise the human syndrome. Abnormalities of the brain and face include deficiency in the midline region of the upper face, narrowing of the forebrain hemispheres and of the cerebral aqueduct, and deficiency in the developing lower jaw. Associated pathogenesis, as observed on gestational day 11 in histological sections and with scanning electron microscopy, involves abnormal cell populations at the rim of the developing forebrain and in the alar plate of the lower midbrain and hind-brain. The affected cells appear abnormally rounded up, having apparently lost their normal cell contacts. The potential basis for the selective vulnerability of this cell population and the impact of its vulnerability relative to subsequent dysmorphogenesis is discussed.
Animals↗
Workgroup I: rodent models of prostate cancer.
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Androgens↗
Beneficial effects of tempol, a membrane-permeable radical scavenger, in a rodent model of collagen-induced arthritis.
OBJECTIVE: To investigate the effects of tempol, a membrane-permeable radical scavenger, in rats with collagen-induced arthritis (CIA). METHODS: CIA was induced in Lewis rats by intradermal injection of 100 microl of an emulsion of 100 microg of bovine type II collagen (CII) in complete Freund's adjuvant (FCA) at the base of the tail. On day 21, a second injection of CII in FCA was administered. RESULTS: Lewis rats developed an erosive arthritis of the hind paws when immunized with CII in FCA. Macroscopic evidence of CIA first appeared as periarticular erythema and edema in the hind paws. The incidence of CIA was 100% by day 27 in the CII-challenged rats, and the severity of CIA progressed over a 35-day period. Radiographs revealed focal resorption of bone, with osteophyte formation in the tibiotarsal joint, and soft tissue swelling. The histopathologic features included erosion of the cartilage at the joint margins. Treatment of rats with tempol (10 mg/kg/day intraperitoneally) starting at the onset of arthritis (day 23) delayed the development of the clinical signs on days 24-35 and improved the histologic status of the knee and paw. Immunohistochemical analysis for nitrotyrosine and poly(ADP-ribose) synthetase (PARS) revealed positive staining in the inflamed joints of CII-treated rats. The degree of nitrotyrosine and PARS staining was markedly reduced in tissue sections obtained from CII-treated rats that had received tempol. Furthermore, radiographs revealed protection against bone resorption and osteophyte formation in the joints of tempol-treated rats. CONCLUSION: This study is the first to provide evidence that tempol, a small molecule that permeates biologic membranes and scavenges reactive oxygen species, attenuates the degree of chronic inflammation and tissue damage associated with CIA in the rat.
Animals↗
Protective effects of ginseng components in a rodent model of neurodegeneration.
To test the proposed neuroprotective activity of whole ginseng extract and its components, we used 3-nitropropionic acid (3-NP), an inhibitor of succinate dehydrogenase, to produce neurodegeneration. Treatment with 3-nitropropionic acid (90 mg/kg) over a 5-day period resulted in severe impairment of movement and loss of neurons in the striatum. Pretreatment with a preparation from the whole root of American ginseng had no protective effects. Pretreatment with a preparation of ground leaves and stems, which contains greater levels of ginsenosides than ground root, improved the behavioral score and reduced the volume of the striatal lesion. A partial purification of American ginseng was performed to concentrate the putative protective components: Rb1, Rb3, and Rd (termed Rb extract). Pretreatment with the Rb extract significantly reduced the 3-nitropropionic acid-induced motor impairment and cell loss in the striatum, and it completely prevented any mortality. Significant effects on motor function, mortality, and the striatal lesion volume also were measured in animals pretreated with the individual ginsenosides, Rb1, Rb3, or Rd. The results demonstrate that some of the ginsenosides have neuroprotective activity, and that a partial purification of whole ginseng to concentrate the neuroprotective components may have utility as a neuroprotective agent.
Animals↗
Embryonic and early postnatal abnormalities contributing to the development of hippocampal malformations in a rodent model of dysplasia.
While there are many recent examples of single gene deletions that lead to defects in cortical development, most human cases of cortical disorganization can be attributed to a combination of environmental and genetic factors. Elucidating the cellular or developmental basis of teratogenic exposures in experimental animals is an important approach to understanding how environmental insults at particular developmental junctures can lead to complex brain malformations. Rats with prenatal exposure to methylazoxymethanol (MAM) reproduce many anatomical features seen in epilepsy patients. Previous studies have shown that heterotopic clusters of neocortically derived neurons exhibit hyperexcitable firing activity and may be a source of heightened seizure susceptibility; however, the events that lead to the formation of these abnormal cell clusters is unclear. Here we used a panel of molecular markers and birthdating studies to show that in MAM-exposed rats the abnormal cell clusters (heterotopia) first appear postnatally in the hippocampus (P1-2) and that their appearance is preceded by a distinct sequence of perturbations in neocortical development: 1) disruption of the radial glial scaffolding with premature astroglial differentiation, and 2) thickening of the marginal zone with redistribution of Cajal-Retzius neurons to deeper layers. These initial events are followed by disruption of the cortical plate and appearance of subventricular zone nodules. Finally, we observed the erosion of neocortical subventricular zone nodules into the hippocampus around parturition followed by migration of nodules to hippocampus. We conclude that prenatal MAM exposure disrupts critical developmental processes and prenatal neocortical structures, ultimately resulting in neocortical disorganization and hippocampal malformations.
Animals↗
The role of oil and agalactosyl IgG in the induction of arthritis in rodent models.
The proportion of agalactosyl IgG [Gal(O)] is raised in human rheumatoid arthritis and tuberculosis. We report here that injection of pristane into the peritoneal cavities of mice on days 0 and 50, which is known to induce plasmacytomas and arthritis, also induced a rise in the proportion of Gal(O), correlating with a simultaneous rise in the level of IgG antibody binding to the 65-kDa heat-shock protein of Mycobacterium bovis (hsp65). Arthritis developed in a proportion of those CBA/Igb mice with the highest percentage of Gal(O). Pretreatment with 50 micrograms of recombinant mycobacterial hsp65 intraperitoneal (i.p.) on day -10, or with 500 rad irradiation on day -2 before the first of the two injections of pristane reduced the incidence of arthritis from 24% in control animals, to 5.3% and 0.4%, respectively. The reduced incidence of disease correlated with smaller rises in the % Gal(O) at 50-75 days, although levels at 150-200 days were not affected. The arthritogenic effect of oil was not confined to the pristane model, since a single i.p. injection of oil 21 days before immunizing DBA/1 mice with type II collagen reduced the mean day of onset of this arthritis, [which we have previously shown to correlate with raised % Gal(O)], from 38 to 15 days (p less than 0.001). One interpretation is that an autoimmunogenic stimulus, given when % Gal(O) is raised, is more likely to evoke disease. Since oil granulomata are known to secrete interleukin 6, which has B cell-regulatory properties and is secreted by rheumatoid synovial cells, we tested sera from interleukin 6-transgenic mice, and found a strikingly raised percentage of Gal(O). We suggest, therefore, that the role of oil in the induction of arthritis is the dysregulation of cytokine release of which a raised percentage of Gal(O) may be a direct or indirect consequence, associated with an increased susceptibility to autoimmunogenic stimuli.
Animals↗
On the various manifestations of spontaneous autoimmune diabetes in rodent models.
Autoimmune (type 1) diabetes mellitus in mouse, rat, and humans shares several features, including T lymphocyte infiltration into pancreatic islets and a dependence on permissive class II major histocompatibility complex (MHC) alleles. We report here on an experimental model involving mice that express influenza hemagglutinin (HA) under the control of the insulin promoter and, at the same time, a transgenic class II MHC-restricted T cell receptor (TcR) specific for an HA peptide. These mice spontaneously develop islet infiltrates resembling those found in NOD mice and most animals become diabetic within 8 weeks of age. Because of the availability of a clonotypic TcR antibody, we can be confident that the Ins-HA transgene does not induce any measurable alterations in the vast majority of T cells with the transgenic TcR in primary and secondary lymphoid organs. Continuous export of large numbers of HA-specific lymphocytes from the thymus was not required for the manifestation of the disease since mice thymectomized at 3 days after birth still developed the disease albeit with smaller infiltrates.
Animals↗
Enhanced hepatic collagen type I mRNA expression into fat-storing cells in a rodent model of hemochromatosis.
In recent years, identifying the hepatic cell type responsible for collagen synthesis in experimental models of postnecrotic or inflammatory fibrosis has been the subject of active investigation. In primary iron overload states, however, hepatic fibrosis and cirrhosis occur without accompanying necroinflammatory phenomena. In this study, we combined morphological, immunological, cell isolation and purification and molecular biological techniques to identify the hepatic cell responsible for enhanced collagen type I gene expression during chronic enteral iron overload in the rat. Ultrastructural analysis of liver tissue sections from iron-loaded rats specifically revealed an altered appearance of fat-storing cells, which showed few if any fat droplets left and increased rough endoplasmic reticulum. In situ hybridization analysis with specific complementary RNA probes identified enhanced signal for collagen type I into nonparenchymal cells in zones 1 and 2, without signal over the background onto iron-laden hepatocytes. Immunocytochemistry with desmin antibodies combined with in situ hybridization on the same tissue sections identified the cells expressing high level of collagen type I transcripts as fat-storing cells. Northern-blot analysis on RNA extracted from various purified cell isolates, confirmed the presence of collagen type I mRNA signal only into the fat-storing cells isolate. Our study shows that in an experimental model of metabolic fibrosis in which the hepatotoxin selectively accumulates into parenchymal cells, fat-storing cells are the main source of enhanced collagen type I gene expression.
Animals↗
Subiculum network excitability is increased in a rodent model of temporal lobe epilepsy.
In this study, we used in vitro electrophysiology along with immunohistochemistry and molecular techniques to study the subiculum--a limbic structure that gates the information flow from and to the hippocampus--in pilocarpine-treated epileptic rats. Comparative data were obtained from age-matched nonepileptic controls (NEC). Subicular neurons in hippocampal-entorhinal cortex (EC) slices of epileptic rats were: (i) hyperexcitable when activated by CA1 or EC inputs; and (ii) generated spontaneous postsynaptic potentials at higher frequencies than NEC cells. Analysis of pharmacologically isolated, GABA(A) receptor-mediated inhibitory postsynaptic potentials revealed more positive reversal potentials in epileptic tissue (-67.8 +/- 6.3 mV, n = 16 vs. -74.8 +/- 3.6 mV in NEC, n = 13; P < 0.001) combined with a reduction in peak conductance (17.6 +/- 11.3 nS vs. 41.1 +/- 26.7 nS in NEC; P < 0.003). These electrophysiological data correlated in the epileptic subiculum with (i) reduced levels of mRNA expression and immunoreactivity of the neuron-specific potassium-chloride cotransporter 2; (ii) decreased number of parvalbumin-positive cells; and (iii) increased synaptophysin (a putative marker of sprouting) immunoreactivity. These findings identify an increase in network excitability within the subiculum of pilocarpine-treated, epileptic rats and point at a reduction in inhibition as an underlying mechanism.
Action Potentials↗
Use of a rodent model to show that varicella-zoster virus ORF61 is dispensable for establishment of latency.
Varicella-zoster virus (VZV) results in a latent infection in humans after primary infection. Latency has also been established in guinea pigs and rats after inoculation with the virus. It was found that infection of cotton rats with the Oka vaccine strain of VZV results in a latent infection. To begin to identify which genes are required for latency, we infected cotton rats with VZV strain Oka that is deleted for ORF61. ORF61 protein transactivates certain VZV promoters and enhances the infectivity of viral DNA in transient transfections. Deletion of ORF61 results in abnormal syncytia and impairs the growth of VZV in vitro. Inoculation of cotton rats with ORF61-deleted Oka virus resulted in latent VZV infection in the nervous system similar to that seen for animals infected with parental virus. Thus, the cotton rat can be used to study the ability of mutants in the Oka vaccine strain of VZV to establish latent infection.
Animals↗
Intravenous versus intrastriatal cord blood administration in a rodent model of stroke.
Human umbilical cord blood (hUCB) is a rich source of hematopoietic stem cells that have been used to reconstitute immune cells and blood lineages. Cells from another hematopoietic source, bone marrow, have been found to differentiate into neural cells and are effective in the treatment of stroke. In this study, we administered hUCB cells intravenously into the femoral vein or directly into the striatum and assessed which route of cell administration produced the greatest behavioral recovery in rats with permanent middle cerebral artery occlusion (MCAO). All animals were immunosuppressed with cyclosporine (CSA). When spontaneous activity was measured using the Digiscan automated system, it was found to be significantly less when hUCB was transplanted 24 hr after stroke compared with nontransplanted, stroked animals (P < 0.01). Furthermore, behavioral recovery was similar with both striatal and femoral hUCB delivery. This is in contrast to the step test, in which significant improvements were found only after femoral delivery of the hUCB cells. In the passive avoidance test, transplanted animals learned the task faster than nontransplanted animals (P < 0.05). Together, these results suggest that hUCB transplantation may be an effective treatment for brain injuries, such as stroke, or neurodegenerative disorders. In addition, intravenous delivery may be more effective than striatal delivery in producing long-term functional benefits to the stroked animal.
Animals↗
Consequences of nitric oxide generation in epileptic-seizure rodent models as studied by in vivo EPR.
The role of nitric oxide (NO) in epileptogenesis was studied in pentylenetetrazole (PTZ)-treated animals using in vivo and ex vivo EPR spectroscopy. NO generation was measured directly in the brain of a PTZ-induced mouse in vivo by an L-band EPR spectrometer. An elevation in NO production in the brain was observed during convulsions, and more NO was generated in the tonic seizure vs. the clonic seizure. NO content in several brain tissues (including the cerebral cortex (CR), cerebellum (CL), olfactory bulb (OB), hippocampus (HI), and hypothalamus (HT)) of PTZ-doped rats was analyzed quantitatively ex vivo by X-band EPR. To test the involvement of NO in seizure development, pharmacological analyses were performed using the NO synthase (NOS) inhibitors N(G)-nitro-L-arginine (L-NNA), N(G)-monomethyl-L-arginine (L-NMMA), and 3-bromo-7-nitroindazole (3Br-7NI). All of these inhibitors suppressed the convulsions, holding them at the clonic level, and prevented development of a tonic convulsion in rats doped with up to 80 mg/kg PTZ. 3Br-7NI completely inhibited NO production, but L-NNA and L-NMMA showed only 70% inhibition of NO production in PTZ-doped rats. In order to examine the contributions of NO in convulsions, rats were treated with anticonvulsants (phenytoin and diazepam) before PTZ treatment. Both drugs completely suppressed tonic convulsion in PTZ-doped rats at doses up to 80 mg/kg, but NO levels were similar to those detected in a clonic convulsion. These results support the notion that NO does not directly induce a clonic convulsion, but may be generated as a consequence of onset of seizure.
Analysis of Variance↗
L-DOPA-induced modulation of GABA and glutamate release in substantia nigra pars reticulata in a rodent model of Parkinson's disease.
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Animals↗
Interhemispheric modulation of dopamine receptor interactions in unilateral 6-OHDA rodent model.
A critical assumption in the unilateral 6-hydroxydopamine (6-OHDA) model is that interactions between the intact and denervated hemispheres do not influence the response to insult. The present study examined this issue by assessing the effects of unilateral substantia nigra 6-OHDA lesions in rats that previously had received corpus callosum transections, a treatment designed to minimize interhemispheric influences. Quantitative autoradiography in the caudate-putamen ipsilateral to the lesion revealed that corpus callosum transection did not alter the increase in D2-like receptors ([125I]-epidepride-labeled sites) that is induced by unilateral 6-OHDA lesion. There were no effects of either 6-OHDA lesion or transection on D1 receptor density ([125I]-SCH23982 autoradiography). As a functional endpoint, dopamine-stimulated cAMP efflux was measured in superfused striatal slices. In this paradigm, the net effect of dopamine (DA) represents a combination of D1 receptor-mediated stimulation and D2 receptor-mediated inhibition. 6-OHDA lesion increased cAMP efflux induced by exposure to 100 microM DA alone; corpus callosum transection did not alter this effect. An interaction between 6-OHDA lesion and transection status was revealed, however, by comparison of results obtained with DA alone vs. DA plus the D2 antagonist sulpiride (to block the D2 inhibitory effects of 100 microM DA). This comparison revealed two important effects of 6-OHDA lesion in rats with an intact corpus callosum: 1) a moderate decrease in dopamine D1 receptor-mediated stimulation; and 2) a dramatic decrease in the ability of D2 receptors to inhibit this stimulation. Corpus callosum transection prevented these effects of 6-OHDA. These results provide a biochemical demonstration of D1:D2 receptor uncoupling in unilateral 6-OHDA lesioned rats, and suggest that interhemispheric influences (e.g., contralateral cortico-striatal glutamatergic projections) may contribute to lesion-induced alterations in D1:D2 receptor interactions.
Animals↗
Alterations in CNS gene expression in a rodent model of moderate traumatic brain injury complicated by acute alcohol intoxication.
The combined effects of acute alcoholic intoxication and moderate traumatic brain injury (TBI) on zif/268, glial fibrillary acidic protein (GFAP), and preproenkephalin (PPE) mRNA expression were examined. Adult male Wistar rats received ip injections of a 5% alcohol solution (2.4 g/kg in a final volume of 20 ml isotonic saline) 10 min prior to fixed-head, mechanical injury. Using Northern analysis, a transient three- to fourfold induction of zif/268 mRNA levels was observed 45 min after injury in both TBI and alcohol-treated rats. This induction occurred in regions close to the impact site, namely, the olfactory bulb (OB) and frontal cortex (FTCTX) but not in the more distal piriform/amygdala cortex (P/A). No PPE mRNA changes were observed at 45 min for any experimental group. By 6 h, zif/268 transcript levels returned to or fell below basal levels in the OB and FTCTX while GFAP mRNA levels began to increase in TBI rats. At 24 h, GFAP mRNA levels were greatly increased in all three brain regions of TBI rats. However, alcohol inhibited the temporal induction of GFAP mRNA in the FTCTX and P/A triggered by TBI at 6 and 24 h. These results suggest that although acute alcohol intoxication prior to TBI does not influence gene expression patterns immediately after injury, it may minimize the transcriptional activation of astrocytes particularly in more distant brain regions that were influenced by the impact in nonintoxicated rats.
Alcoholic Intoxication↗
Photoreceptor layer reconstruction in a rodent model of retinal degeneration.
We have examined the potential of retinal cell transplantation to dystrophic retinal degeneration mice as a way of replacing photoreceptors lost because of an intrinsic genetic defect. Early postnatal retinae which had been gently dissociated survived for at least 6 weeks after transplantation to the subretinal space. Over a significant area of distribution, transplanted cells formed outer segments which lay in close apposition to the host retinal pigment epithelial cell layer. The grafts integrated with the remaining host retina, sufficient at least to mediate a simple light-dark preference. A new synaptic layer was seen at the graft-host interface, which contained substantial numbers of photoreceptor synapses. This and the fact that the behavior could be elicited at low luminance levels argue for functional circuit reconstruction between grafted cells and host retina.
3',5'-Cyclic-GMP Phosphodiesterases↗