Biomedical subjects

A M Planas

Publications and source records attributed to A M Planas.

At least 37 records · Page 2Linked to original sources

PubMed1999

Activation of nuclear factor-kappaB in the rat brain after transient focal ischemia.

Nuclear factor-kappaB (NF-kappaB) becomes activated under inflammatory conditions and triggers induction of gene expression. Here, activation of NF-kappaB was studied after transient middle cerebral artery occlusion in the rat. Expression of p65 and p50, protein subunits of NF-kappaB, was examined by Western blotting, and immunohistochemistry for p65 was carried out. Double-labelling with specific markers for astroglia and microglia was used for cell type identification. Neurons located within and surrounding the ischemic core were identified during the first 24 h post-ischemia by using an antibody against 72-kDa heat shock protein. NF-kappaB binding activity was evaluated at different times post-ischemia with electrophoretic mobility gel shift assays. The results showed constitutive expression of p65 and p50, and NF-kappaB binding activity. Basal p65 was seen in certain neurons and resting astrocytes. Constitutive NF-kappaB binding activity was attributable to one main protein complex possibly formed in neurons and astrocytes, although two minor complexes were also detected. At 1 day post-ischemia selective induction of p65 was seen in neurons located in a penumbra-like area. At this time, however, no disturbances of basal NF-kappaB binding activity were found. Western blotting showed delayed induction of p65 several days after ischemia, whereas no changes were detected for p50. From 4 days post-ischemia, a substantial increase in the amount of p65 was detected due to induction in reactive astrocytes and microglia/macrophages. This was correlated with a robust enhancement of NF-kappaB binding activity with formation of three major specific complexes binding DNA. It is proposed that the highly inducible NF-kappaB complexes resulted from induction of p65 and activation of NF-kappaB in post-ischemic reactive glia.

Animals↗

PubMed1999

Transforming growth factor-alpha acting at the epidermal growth factor receptor reduces infarct volume after permanent middle cerebral artery occlusion in rats.

Transforming growth factor-alpha (TGF-alpha) is a ligand for the epidermal growth factor (EGF) receptor (EGFR), and is more abundant than EGF in the brain. The authors studied whether administration of exogenous TGF-alpha into the brain can protect neurons against ischemia in a model of permanent middle cerebral artery (MCA) occlusion in the rat, and whether any effect of TGF-alpha was mediated by EGFR by administering 4,5-dianilinophthalimide (DAPH), a protein-tyrosine kinase inhibitor with high selectivity for EGFR. Rats received either TGF-alpha (10 or 25 ng), DAPH (100 ng), DAPH plus TGF-alpha (25 ng), or vehicle in the ipsilateral first ventricle. Drugs were administered twice: 30 minutes before and 30 minutes after MCA occlusion, and infarct volume was evaluated 24 hours later. Transforming growth factor-alpha at the dose of 25 ng caused a statistically significant reduction of infarct volume (60%) in relation to ischemic rats administered vehicle. This reduction was no longer seen when TGF-alpha was administered in combination with DAPH. The present results show that TGF-alpha can protect neurons from ischemic damage, and that this effect is mediated by EGFR. It is suggested that activation of EGFR-mediated intracellular signalling pathways contributes to the survival of neural cells susceptible to ischemic injury.

Animals↗

PubMed1998

Epidermal growth factor receptor in proliferating reactive glia following transient focal ischemia in the rat brain.

Severe transient focal cerebral ischemia causes brain infarction with a strong glial reaction. We have studied whether postischemic reactive glial cells express epidermal growth factor receptor (EGFR) following middle cerebral artery occlusion in the rat. We have also looked for signs of proliferating activity, as EGFR is known to be involved in cell growth and proliferation in certain non-neural cells. EGFR was studied using three different antibodies which were found to stain for a tyrosine-phosphorylated protein (p170) corresponding to the membrane-anchored EGFR. Neurons of the control brain were strongly immunoreactive to EGFR, but a decrease of EGFR-immunoreactivity was seen in the ipsilateral brain side from 24 h postischemia due to neuronal loss. However, the presence of abundant glial cells strongly immunoreactive to EGFR became apparent in this area from 4 days postischemia onward. The use of microglial (lectin or OX-42) and astroglial (GFAP) markers showed that these postischemic EGFR-stained cells were reactive microglia/macrophages and astroglia. The subcellular localization of EGFR in reactive microglia/macrophages was compatible with the network of the Golgi apparatus, as revealed with an antibody against a peripheral membrane-bound protein of the Golgi. The presence of abundant proliferating cells in the ischemic brain was detected from 4 days postischemia with an antibody against proliferating cell nuclear antigen. Proliferating reactive microglia/macrophages were abundant within the infarcted brain side, whereas proliferating astrocytes were found mainly in the immediate periphery of the infarct limiting the necrotic area from the undamaged tissue. These proliferating cells were immunoreactive to EGFR. The results show the presence of EGFR in postischemic reactive glial cells and suggest that EGFR-dependent pathways mediate signal transduction in reactive glia following transient focal cerebral ischemia.

Animals↗

PubMed1997

Stat1 in developing and adult rat brain. Induction after transient focal ischemia.

Stat1 has a dual function as signal transducer and activator of transcription, and is activated in response to growth factors and cytokines. We examined Stat1 in the rat brain during development and following transient focal ischemia, using Western immunoblotting. Two bands of 91 and 84 kDa, corresponding to Stat1 alpha and Stat1 beta forms, were found with an intensity that increased from postnatal day 0 to adulthood in cerebellum and cerebral cortex. Ischemia caused a strong induction of Stat1 in the ipsilateral cortex after 4, 7 and 15 days, but not at 6 or 24 h. These results show that Stat1 is normally expressed in the postnatal and adult rat brain and is induced under brain infarction.

Animals↗

PubMed1997

bFGF and FGFR-3 immunoreactivity in the rat brain following systemic kainic acid administration at convulsant doses: localization of bFGF and FGFR-3 in reactive astrocytes, and FGFR-3 in reactive microglia.

Strong bFGF immunoreactivity was observed in reactive astrocytes, as shown by double-labeling immunohistochemistry of bFGF and GFAP, from days 7 up to 30 (last time point examined) following kainic acid (KA) injection at convulsant doses in the adult rat. bFGF was not found in OX-42-positive reactive microglia. A few reactive glia co-localized FGFR-3 and GFAP, whereas the majority of cells expressing FGFR-3 were OX-42-immunoreactive. This was further supported by the observation that only approximately 10% of reactive glia co-localized bFGF and FGFR-3. These results show that reactive astrocytes are a major source of bFGF during the subacute stages of tissue damage following KA injection and that reactive astrocytes and, most particularly, reactive microglia are putative targets of bFGF through FGFR-3.

Animals↗

PubMed1997

Cortical infarct volume is dependent on the ischemic reduction of perifocal cerebral blood flow in a three-vessel intraluminal MCA occlusion/reperfusion model in the rat.

Occlusion of the middle cerebral artery (MCA) causes a reduction of cerebral blood flow (CBF), which shows a progressive decrease from the periphery to the core of the MCA territory. The severity of ischemia is dependent on the duration of the ischemic episode and degree of CBF reduction. Fixing the ischemic episode to 1 h, we have examined whether or not cortical infarct size was related to the degree of CBF reduction in a perifocal cortical area in rats. One-hour intraluminal MCA occlusion accompanied with bilateral common carotid artery (CCA) occlusion (three-vessel occlusion/reperfusion model) was carried out in Sprague-Dawley rats and CBF was monitored with laser-Doppler flowmetry in the fronto-parietal cortex, an area which is perifocal to the core of the MCA territory. Finally, infarct size was measured 7 days later and was related to the corresponding CBF decrease. Sequential ipsilateral CCA, MCA and contralateral CCA occlusions produced reductions of CBF to 96%, 52% and 33% of baseline, respectively. Cortical infarct volume was found to be dependent on the corresponding reduction of perifocal cortical CBF during the ischemic episode. These results show that the reduction of CBF in the periphery of the MCA territory during 1-h focal ischemia determines infarct size in a three-vessel occlusion/reperfusion model.

Animals↗

PubMed1997

Striatal infarction in the rat causes a transient reduction of tyrosine hydroxylase immunoreactivity in the ipsilateral substantia nigra.

Dopaminergic neurons of the substantia nigra pars compacta were examined in the rat brain following striatal infarction subsequent to transient focal cerebral ischemia. Rats had the middle cerebral artery occluded for 2 h or were sham-operated, and tyrosine hydroxylase immunoreactivity was evaluated by Western blot and immunohistochemistry at different times ranging from 1 to 60 days after ischemia. The number of tyrosine hydroxylase-immunoreactive cells in the substantia nigra pars compacta was counted under the light microscope and compared to that in the contralateral side and controls. No changes of tyrosine hydroxylase immunoreactivity were detected in the ipsilateral versus the contralateral substantia nigra of sham-operated rats or 1 day after ischemia. However, a statistically significant reduction of tyrosine hydroxylase-immunoreactive cells became apparent in the ipsilateral compared with the contralateral substantia nigra at 7 and 14 days after ischemia. This reduction showed a clear recovery at 30 days after ischemia, and no signs of difference between the ipsilateral and the contralateral side were apparent by 60 days. Therefore, the reduction of tyrosine hydroxylase immunoreactivity in the ipsilateral substantia nigra was only transiently seen from 1 to 2 weeks following ischemia. The observed loss of tyrosine hydroxylase was not accompanied by signs of cell death or gliosis in the ipsilateral pars compacta. The present results show a transitory reduction of tyrosine hydroxylase immunoreactivity in the ipsilateral substantia nigra pars compacta after focal ischemia and suggest that striatal infarction causes a transient deficit of dopaminergic function.

Animals↗

PubMed1997

Ubiquitination of apoptotic cells in the developing cerebellum of the rat following ionizing radiation or methylazoxymethanol injection.

Previous studies have shown ubiquitin mRNA induction and protein expression associated with regressive phenomena in some cases of developmentally programmed cell death and experimentally induced apoptosis. Ubiquitin immunoreactivity was examined in the developing cerebellum of the rat following ionizing radiation or methylazoxymethanol (MAM) injection. In irradiated rats, apoptotic cells in the external granule cell layer appeared at 3 h, peaked at 6 h, and decreased thereafter to reach nearly normal values at 48 h. In MAM-treated rats, apoptotic cells in the external granule cell layer were seen at 24 h, peaked at 48 h, and decreased at 72 h. Strong ubiquitin expression was observed in about 15% of apoptotic cells at later stages of apoptosis in both experimental models of induced cell death. In irradiated rats, strong ubiquitin immunoreactivity in apoptotic cells and cellular debris was observed 12 h after irradiation, peaking at 24 h, and decreasing at 48 h. In MAM-treated rats, strong ubiquitin immunoreactivity was found in apoptotic cells and cellular debris at 48 h and decreased at 72 h. Results suggest that activation of the ubiquitin pathway is not a signal that triggers apoptosis but rather a final step in the apoptotic process.

Alkylating Agents↗

PubMed1997

Strong c-Jun/AP-1 immunoreactivity is restricted to apoptotic cells following intracerebral ibotenic acid injection in developing rats.

Strong c-Jun immunoreactivity, as revealed with the antibody c-Jun/activator protein 1 (AP-1) which is raised against the amino acids 91-105 mapping with the amino terminal domain of mouse c-Jun p39, is observed in apoptotic cells, but not in necrotic cells, following intracerebral injection of ibotenic acid in the developing rat brain processed for immunohistochemistry. Immunostaining occurs in the cytoplasm and dendrites, thus suggesting impaired nuclear translocation of c-Jun in apoptotic cells. Western blotting of total brain homogenates, using the same antibody, shows a band at p39 which is more marked in treated animals than in age-matched controls. In addition, increased c-Jun N-terminal kinase 1 (JNK-1) expression, as revealed on Western blots, is found in rats treated with ibotenic acid when compared with controls. In contrast, apoptotic cells are not stained with antibodies to Jun B and Jun D. These results give further support to previous studies showing strong c-Jun expression in apoptotic cells at determinate stages of development, and emphasize that intracellular distribution of c-Jun, possible post-translational modifications of c-Jun due to phosphorylation at specific transactivation sites, and lack of associated Jun B and Jun D expression may differentiate the Jun response in apoptotic cells from other forms of cellular response involving c-Jun which are not associated with cell death.

Animals↗

PubMed1997

The heat shock stress response after brain lesions: induction of 72 kDa heat shock protein (cell types involved, axonal transport, transcriptional regulation) and protein synthesis inhibition.

The cerebral stress response is examined following a variety of pathological conditions such as focal and global ischemia, administration of excitotoxins, and hyperthermia. Expression of 72 kDa heat shock protein (Hsp70) and hsp70 mRNA, the mechanism underlying induction of hsp70 mRNA involving activation of heat shock factor 1, and inhibition of cerebral protein synthesis are different aspects of the stress response considered here. The results are compared with those in the literature on induction, transcriptional regulation, expression, and cellular location of Hsp70, with a view to getting more insight into the function of the stress response in the injured brain. The present results illustrate that Hsp70 can be expressed in cells affected at various degrees following an insult that will either survive or dic as the brain lesion develops, depending on the severity of cell injury. This indicates that, under certain circumstances, synthesized Hsp70 might be necessary but not sufficient to ensure cell survival. Other situations involve uncoupling between synthesis of hsp70 mRNA and protein, probably due to very strict protein synthesis blockade, and often result in cell loss. Cells eventually will die if protein synthesis rates do not go back to normal after a period of protein synthesis inhibition. The stress response is a dynamic event that is switched on in neural cells sensitive to a brain insult. The stress response is, however, tricky, as affected cells seem to need it, have to deal transiently with it, but eventually be able to get rid of it, in order to survive. Putative therapeutic treatments can act either selectively, potentiating the synthesis of Hsp70 protein and recovery of protein synthesis, or preventing the stress response by deadening the insult severity.

Animals↗

PubMed1997

Differential cellular distribution and dynamics of HSP70, cyclooxygenase-2, and c-Fos in the rat brain after transient focal ischemia or kainic acid.

Cerebral ischemia and also excitotoxicity induce the expression of 72,000 mol. wt heat shock protein (Hsp70), c-Fos, and cyclooxygenase-2. In the present work we have examined whether Hsp70, c-Fos and cyclooxygenase-2 are expressed by the same cells in the rat brain at 6, 12 and 24 h following transient focal ischemia or kainic acid administration, by means of single and double immunohistochemistry. At 6 h after kainic acid, some co-localization of Hsp70 with c-Fos and cyclooxygenase-2 was seen in pyramidal hippocampal neurons and superficial cortical layers, however by 24 h such colocalization became rare within the cortex but was partially maintained in the hippocampus. Cyclooxygenase-2 was seen in many neurons that were also immunoreactive for c-Fos in superficial cortical layers, dentate gyrus and pyramidal cell layer of the hippocampus from 6 h after kainic acid. Co-localization of cyclooxygenase-2 and c-Fos was also observed in superficial cortical layers within the ipsilateral hemisphere at 6 h following focal ischemia. Also, some co-localization of Hsp70 with c-Fos and cyclooxygenase-2 was seen at this time. However, by 24 h cyclooxygenase-2 and c-Fos-immunoreactive cells were restricted to perifocal regions, and only a very limited co-localization with Hsp70 was seen in perifocal neurons located in the border of the penumbra-like area that surrounds the ischemic core and is strongly immunoreactive for Hsp70. This study shows a selective and dynamic cellular expression of inducible proteins following either ischemia or kainic acid, with a remarkable neuronal co-localization of c-Fos and cyclooxygenase-2. The results suggest that, first, stimuli underlying neuronal c-Fos expression can also lead to the induction of cyclooxygenase-2; second, transient co-localization of Hsp70 and c-Fos can take place in non-vulnerable neurons; and finally, expression of c-Fos, cyclooxygenase-2, and/or Hsp70 at a given time-point is part of the response to altered environmental conditions and can be related to the particular cellular sensitivity rather than the pathological outcome.

Animals↗

PubMed1997

Radiation-induced apoptosis in developing rats and kainic acid-induced excitotoxicity in adult rats are associated with distinctive morphological and biochemical c-Jun/AP-1 (N) expression.

Ionizing radiation produces apoptosis in the developing rat brain. Strong c-Jun immunoreactivity, as revealed with the antibody c-Jun/AP-1 (N) which is raised against the amino acids 91-105 mapping with the amino terminal domain of mouse c-Jun p39, is simultaneously observed in the nucleus and cytoplasm of apoptotic cells. Western blotting of total brain homogenates, using the same antibody, shows a p39 band in control rats which is accompanied by a strong, phosphorylated p62 double-band in irradiated animals. In addition, increased c-Jun N-terminal kinase 1 expression, as found on western blots, is found in irradiated rats when compared with controls. Intraperitoneal injection of kainic acid at convulsant doses to the adult rat produces cell death with morphological features of necrosis, together with the appearance of cells with fine granular chromatin degeneration and small numbers of apoptotic-like cells, in the entorhinal and piriform cortices, basal amygdala, certain thalamic nuclei, and CA1 region of the hippocampus. c-Jun expression in kainic acid-treated rats, as revealed with the c-Jun/AP-1 (N) antibody, is found in the nuclei of a minority of cells in the same areas. The vast majority of c-Jun-immunoreactive cells have normal nuclear morphology, whereas necrotic cells are negative and only a few cells with fine granular chromatin condensation and apoptotic cells following kainic acid injection are stained with c-Jun antibodies. Western blotting, using the same antibody, shows a p39 band in control rats, which is accompanied by a band at about p26 from 6 h onwards following kainic acid injection. Decreased c-Jun N-terminal kinase 1 expression, as revealed on western blots, is observed in kainic acid-treated rats. These results show that the antibody c-Jun/AP-1 (N) recognizes three different forms of c-Jun-related immunoreactivity in normal and pathological states, which are associated with the different outcome of cells. These results stress the necessity of examining in detail the composition of c-Jun-immunoreactive bands and the metabolic state of c-Jun(s) in different paradigms of cell death and survival.

Animals↗

PubMed1997

Stat3 is present in the developing and adult rat cerebellum and participates in the formation of transcription complexes binding DNA at the sis-inducible element.

Stat3 is a member of a recently identified family of proteins named STATs for their ability to act as signal transducers and activators of transcription. Stimulation of epidermal growth factor or cytokine receptors can cause activation of Stat3 and transduction of specific responses to the nucleus. Here the presence of Stat3 has been examined in the rat cerebellum at different times during postnatal development and adulthood by means of immunohistochemistry and western blotting. In addition, DNA binding activity at the sis-inducible element that is present in the promoter of the c-fos gene has been studied by electrophoretic mobility shift assay. The results have shown that Stat3 p92 is abundant in the rat cerebellum. Stat3 was found in the external granule cell layer and also within the molecular layer from postnatal day (P) 0 to P7. From P15 to the adult, the internal granule cell layer and Purkinje cells were also stained for Stat3. Nuclear extracts were found to contain DNA binding activity to the sis-inducible element during development and adulthood. Supershift assays demonstrated that Stat3 mediates the formation of one protein-DNA complex. The present results suggest that Stat3 participates in intracellular signaling and is involved in maintaining basal c-fos expression in the cerebellum of the developing and adult rat under physiological conditions.

Acute-Phase Proteins↗

PubMed1997

Methylazoxymethanol acetate-induced apoptosis in the external granule cell layer of the developing cerebellum of the rat is associated with strong c-Jun expression and formation of high molecular weight c-Jun complexes.

Intraperitoneal administration of methylazoxymethanol (MAM) acetate (0.05 microl/g of body weight) in male Sprague-Dawley rats aged 3 days produced cell death in the external granule layer of the cerebellum which peaked at 48 hours (h) and was followed by removal of cellular debris at 72 h. Dying cells had the morphological features of apoptosis and were stained with the method of in situ labeling of nuclear DNA fragmentation. Strong c-Jun immunoreactivity was observed in apoptotic cells during the whole process of MAM-induced apoptosis. No differences of c-Fos immunoreactivity were observed between control and MAM-treated rats throughout the period studied. Western blotting of cerebellar homogenates in control rats disclosed two bands which reacted with both c-Jun antibodies, one located at p39 that corresponds to the molecular weight of c-Jun, and the other at about p62. MAM-treated rats showed a robust band at p62, together with a thinner band located immediately above it, which was accompanied by a reduction of the p39 band. The specificity of the immunoreaction was tested by incubating the antibodies with the appropriate control peptides. No difference between control and MAM-treatad rats was observed in Western blots processed with antibodies to c-Fos during this study. These results show that MAM-induced apoptosis in the external granule cell layer of the rat is associated with strong c-Jun expression, which is restricted to apoptotic cells, and with the formation of high-molecular-weight c-Jun complexes. Taken together, the present observations suggest that c-Jun may participate in the genetic cascade of events leading to apoptotic cell death in the developing cerebellum.

Alkylating Agents↗

PubMed1997

BDNF and TrkB co-localize in CA1 neurons resistant to transient forebrain ischemia in the adult gerbil.

Delayed cell death of projection cells in the CA1 area of the hippocampus is produced in the adult gerbil following 5 minutes (min) of transient forebrain ischemia. Parvalbumin-immunoreactive local-circuit neurons are resistant to the ischemic insult. Brain-Derived Neurotrophic Factor (BDNF) immunoreactivity is localized in all neurons of the CA1 area in control gerbils. However, TrkB immunoreactivity is observed in a minority of BDNF-immunoreactive neurons in the CA1 area. The number of BDNF-immunoreactive cells in CA1 is dramatically reduced in ischemic gerbils as early as 24 h after ischemia, but the number of TrkB-immunoreactive cells in the CA1 area is maintained following ischemia. Moreover, about 90% of BDNF-immunoreactive cells and about 85% of TrkB-immunoreactive cells in ischemic gerbils co-localize the calcium-binding protein parvalbumin. Finally, BDNF and TrkB are coexpressed in about 95% of CA1 neurons surviving the ischemic insult. These results indicate that a subpopulation of CA1 hippocampal neurons coexpressing TrkB, parvalbumin and BDNF is resistant to transient forebrain ischemia in the gerbil. These results also suggest that a subpopulation of CA1 hippocampal neurons in the gerbil hippocampus is endowed with a putative BDNF/TrkB autocrine regulatory loop that may be involved in both cell survival and synaptic remodeling of the damaged gerbil hippocampus following transient forebrain ischemia.

Animals↗

PubMed1997

Kainic acid-induced excitotoxicity is associated with a complex c-Fos and c-Jun response which does not preclude either cell death or survival.

c-fos and c-jun mRNA induction and c-Fos and c-Jun protein expression were examined in the brains of adult rats subjected to systemic kainic acid (KA) injection at convulsant doses. Induction of c-fos and c-jun mRNA, as seen with in situ hybridization, occurred in the piriform and entorhinal cortices, neocortex, amygdala, hippocampus, dentate gyrus, and discrete thalamic nuclei. This was followed by c-Fos protein expression, as revealed with immunohistochemistry, in the same regions. However, the distribution of c-Jun protein expression differed depending on the antibody used. The distribution of cells immunostained with the antibody c-Jun (AB-1) was similar to that of c-jun mRNA, but the distribution of cells immunostained with the antibody c-Jun/AP1 (N) was restricted to a few neurons in the pyramidal cell layer of CA1 and CA3, layer II of the piriform and entorhinal cortices, basal amygdala, and discrete thalamic nuclei. Although the regional distribution of c-Fos- and c-Jun-immunoreactive cells in the hippocampus, layer II of the entorhinal and piriform cortices, basal amygdala, and discrete thalamic nuclei matched the distribution of cells committed to dying, c-Fos- and c-Jun-immunoreactive cells in the neocortex and dentate gyrus survived. Therefore, the present data show that c-fos and c-jun are not predictors of either cell death or survival, but rather, markers of cells sensitive to KA excitotoxicity. Western blots to c-Fos showed a double band at p62 in samples containing the hippocampus and entorhinal and piriform cortices (hip samples) and in samples containing the neocortex (cortex samples). The upper band was abolished following preincubation of the samples with alkaline phosphatase, thus suggesting c-Fos phosphorylation. Western blots to c-Jun (AB-1) showed a single band at about p39 in hip and cortex. However, Western blots to c-Jun/AP1 (N) identified two bands. One band at about p39 was seen in control rats and the cortex of KA-treated rats. Another band at p26 was observed only in hip samples of KA-treated rats. In addition, decreased c-Jun N-terminal kinase 1 (JNK-1) expression, as revealed on Western blots, was coincidental with the appearance of the p26 c-Jun-immunoreactive band in KA-treated rats. These results show that c-Fos and different Jun-related antigens are expressed following KA excitotoxicity, and that posttranslational modifications involving phosphorylation of c-Fos and Jun(s) may occur following KA injection. These results also stress the necessity of examining the composition of Fos and Jun-related antigens and the metabolic state of Fos and Jun(s) in different experimental models of nervous system injury.

Animals↗

PubMed1997

[Cell membrane alterations and protein synthesis in experimental models of cerebral ischemia: pharmacological implications in the treatment of ischemic disease].

Brain ischemia causes a large variety of cellular and tissular disturbances that can lead to cerebral infarction. A lack of glucose and oxygen supply that is constantly needed for normal brain function produces a lesion becoming more severe as the duration of the ischemic period increases. Experimental models allow to examine the effect of permanent versus transient ischemia with reperfusion. Cellular and tissular ischemic disturbances can, to a certain extent, be separated from those occurring at reperfusion. Ischemia causes severe and at times non-recoverable alterations, suggesting that minimizing the duration of ischemia by favoring recanalization would be clinically desirable. However, many alterations occurring at reperfusion time do also favor lesion progression. Certain surviving neurons at the penumbra region can become affected during reperfusion as the infarct progresses. Reperfusion injury seems to offer a comparatively larger window for therapeutical intervention aimed to protect cells from death. Several postischemic changes such as alteration of cell membranes, induction of heat shock protein (Hsp70) and protein synthesis inhibition are considered here, together with putative pharmacological treatments directed to reduce or arrest postischemic lesion progression.

Animals↗

PubMed1996

Jun expression is found in neurons located in the vicinity of subacute plaques in patients with multiple sclerosis.

The expression of members of the Fos and Jun families is examined by immunohistochemistry in the brains of two patients with multiple sclerosis (MS). Strong c-Jun immunoreactivity is observed in the cytoplasm of neurons located in the vicinity of subacute plaques, but not in neurons of brain compartments not compromised by MS and in the neighborhood of chronic plaques. Strong c-Jun immunoreactivity also contrast with weak c-Jun immunoreactivity of corresponding neurons in control brains. In addition, punctate Jun D immunoreactivity is observed in the neuropil of the same areas that express c-Jun. No immunoreaction is found to c-Fos, Fos-related antigens and Jun B in these areas. The present results suggest that selective Jun neuronal expression in the vicinity of subacute plaques is a consistent reaction to demyelination and axonal damage.

Adult↗