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PubMed2002

The precrystalline cytoplasmic granules of alveolar soft part sarcoma contain monocarboxylate transporter 1 and CD147.

Alveolar soft part sarcoma (ASPS) is an unusual tumor of young adults with the characteristic presence on ultrastructural analysis of rhomboid or rectangular cytoplasmic crystals. These membrane-bound crystals are known to form within specific PAS-diastase-resistant electron-dense cytoplasmic granules. The composition of these crystals and the dense granules from which they are derived has remained elusive. After the detection of strong discrete granular cytoplasmic immunoreactivity in ASPS for monocarboxylate transporter 1 (MCT1) in the course of a broad immunohistochemical characterization of an MCT1 antibody, we studied the expression of MCT1 and its interacting partner, CD147, in a panel of 10 ASPS cases using appropriate antibodies. MCT1 is one of a family of widely expressed proton-linked transporters for monocarboxylates such as lactate and pyruvate. In all normal and neoplastic tissues studied to date, MCT1 immunoreactivity is limited to the cell surface. We find that the periodic acid-Schiff-diastase-resistant cytoplasmic granules of ASPS are strongly immunoreactive for MCT1 and CD147. Specifically, intense cytoplasmic granular positivity for MCT1 and CD147 was found in 7 of 10 and 8 of 10 ASPSs, respectively. Ultrastructural immunohistochemistry with immunogold labeling confirmed that the MCT1 immunoreactivity localized to the cytoplasmic electron-dense granules in ASPS. Western blot analysis of several ASPS cases confirmed that the protein reactive with the MCT1 antibody and that reactive with the CD147 antibody both migrated at the size expected for MCT1 and CD147, respectively. Thus, ASPS cells seem to accumulate MCT1-CD147 complexes in the specific cytoplasmic granules known to undergo crystallization. The possible basis for the overproduction or impaired surface localization of these proteins in ASPS remains unclear.

Adult↗
PubMed2001

Tumorigenic potential of extracellular matrix metalloproteinase inducer.

Extracellular matrix metalloproteinase inducer (EMMPRIN), a glycoprotein present on the cancer cell plasma membrane, enhances fibroblast synthesis of matrix metalloproteinases (MMPs). The demonstration that peritumoral fibroblasts synthesize most of the MMPs in human tumors rather than the cancer cells themselves has ignited interest in the role of EMMPRIN in tumor dissemination. In this report we have demonstrated a role for EMMPRIN in cancer progression. Human MDA-MB-436 breast cancer cells, which are tumorigenic but slow growing in vivo, were transfected with EMMPRIN cDNA and injected orthotopically into mammary tissue of female NCr nu/nu mice. Green fluorescent protein was used to visualize metastases. In three experiments, breast cancer cell clones transfected with EMMPRIN cDNA were considerably more tumorigenic and invasive than plasmid-transfected cancer cells. Increased gelatinase A and gelatinase B expression (demonstrated by in situ hybridization and gelatin substrate zymography) was demonstrated in EMMPRIN-enhanced tumors. In contrast to de novo breast cancers in humans, human tumors transplanted into mice elicited minimal stromal or inflammatory cell reactions. Based on these experimental studies and our previous demonstration that EMMPRIN is prominently displayed in human cancer tissue, we propose that EMMPRIN plays an important role in cancer progression by increasing synthesis of MMPs.

Animals↗
PubMed2002

Insights into the pathobiology of hepatitis C virus-associated cirrhosis: analysis of intrahepatic differential gene expression.

The pathogenesis of hepatitis C virus (HCV)-associated liver injury involves many genes from multiple pathogenic pathways. cDNA array analysis, which examines the expression of many genes simultaneously, was used to achieve new insights into HCV liver injury. Membrane-based cDNA arrays of 874 genes compared HCV-associated cirrhosis with autoimmune hepatitis-associated cirrhosis as an inflammatory and cirrhotic control, and with nondiseased liver tissue. Array analysis identified many differentially expressed genes that are important in inflammation, fibrosis, proliferation, signaling, apoptosis, and oxidative stress. Genes up-regulated in HCV-associated cirrhosis were predominantly associated with a Th1 immune response, fibrosis, cellular proliferation, and apoptosis. Novel observations of differential gene expression included increased expression of secreted apoptosis-related protein 3, a Wnt pathway gene possibly involved in cellular apoptosis. EMMPRIN (CD147) and discoidin domain receptor 1 (CD167) were also shown to be increased and are likely to play a role in liver fibrosis. Real-time quantitative reverse transcriptase-polymerase chain reaction confirmed the increased expression of 15 genes. The comparison of HCV cirrhosis with autoimmune hepatitis cirrhosis showed a marked difference in the apoptosis-associated gene profile with HCV cirrhosis characterized by increased proapoptotic gene expression whereas autoimmune hepatitis was characterized by increased expression of both antiapoptotic and proapoptotic genes. Furthermore, expression of beta-catenin and the fibrosis-associated protein EMMPRIN were localized by immunohistochemistry to the plasma membranes of hepatocytes and biliary epithelium. In conclusion, HCV-associated cirrhosis was characterized by a proinflammatory, profibrotic, and proapoptotic gene expression profile.

Adult↗
PubMed2003

Electroconvulsive seizures induce proliferation of NG2-expressing glial cells in adult rat hippocampus.

BACKGROUND: Analysis of postmortem tissue from patients with major depression and bipolar disorder has revealed structural changes in several brain regions. We have shown that electroconvulsive seizure (ECS), used for the treatment of severe depression, induces proliferation of both neuronal and nonneuronal cells in the adult rat hippocampus. METHODS: Male Wistar rats were subjected to one or several ECS treatments, then injected with bromodeoxyuridine (BrdU) to detect cell proliferation. Animals were perfused either 1 day or 3 weeks following the last BrdU injection. Cells were double stained for BrdU and the cell type markers chondroitin sulfate proteoglycan (NG2), complement 3-receptor OX-42, 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNPase), Ca(+) binding protein S100-beta, or neuron-specific nuclear protein (NeuN). RESULTS: We identified NG2-expressing cells as a major cell type proliferating in the rat dentate gyrus in response to ECS. A sharp increase in NG2-positive cell proliferation was seen 2 days after ECS, and a large number of NG2-expressing cells persisted at 3 weeks. CONCLUSIONS: Our results show that antidepressant treatment can induce a strong proliferation of glial progenitor cells in the adult rat hippocampus. We propose that this may counteract degenerative changes found in depression and be an important neurobiological event underlying the clinical effect of electroconvulsive seizures.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed2000

Early microglial reaction following mild forebrain ischemia induced by common carotid artery occlusion in rats.

Early microglial reaction following mild ischemic injury caused by bilateral common carotid artery occlusion has been investigated in rats. The ischemic insults lasted for 10, 15 and 20 min without recirculation, and with several reperfusion intervals from 1 h to 3 days. The resting and activated microglial cells were visualized with immunohistochemistry using monoclonal antibodies raised against the CR3 complement receptor, the MHC class I and class II antigens, the macrophage common antigen and with Bandeiiraea simplicifolia lectin-histochemistry. The neuroprotective effect of hypothermia on the early microglial activation was also studied. Ten minutes bilateral common carotid artery occlusion in hypothermic rats without reperfusion caused a mild microglial reaction in the hippocampus. Strong reaction was seen following 20 min insult without reperfusion. Ischemia followed by recirculation caused milder reaction than without reperfusion. Our results suggest that the microglial cells are very sensitive indicators of a mild, transient ischemic insult that does not result in neuronal cell death.

Animals↗
PubMed2000

Acute inflammatory reaction following experimental intracerebral hemorrhage in rat.

Previous studies on intracerebral hemorrhage (ICH) indicate that brain edema increases progressively in the first 24 h and remains elevated for several days. The cause of secondary brain injury and edema formation is uncertain. We hypothesized that inflammatory mediators released from the blood after cerebral hemorrhage might cause secondary brain injury and edema formation. This study investigates if, when and where inflammation occurs after ICH in rat. Immunocytochemistry for polymorphonuclear leukocyte marker (myeloperoxidase, MPO), microglia marker (OX42) and intracellular adhesion molecule-1 (ICAM-1) was performed in control, and 1, 3, 7 and 10 days after the injection of 100 microliter autologous blood in the right basal ganglia. Double labeling immunohistochemistry was used to identify ICAM-1 positive cells. The results show that an inflammatory response occurred in and around the blood clot after ICH, characterized by the infiltration of neutrophils and macrophages as well as activation of microglia. ICAM-1 immunoreactivity was observed in blood vessels adjacent to the clot, as well as in activated microglia and neurons in the ipsilateral hemisphere. The present study demonstrates there is an inflammatory response in the brain after ICH. Infiltrating leukocytes and activated microglia may release cytotoxic mediators contributing to secondary brain injury.

Animals↗
PubMed2001

Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain: activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures.

Reperfusion damages the blood-brain barrier (BBB). Matrix metalloproteinases (MMPs) are associated with the opening of the BBB, but their cellular localization and activation mechanisms are uncertain. We used immunohistochemistry to determine the cellular localization of the MMPs in reperfused rat brain, and cell cultures to study their activation. Spontaneously hypertensive rats (SHR) had a 90 min middle cerebral artery occlusion (MCAO) followed by reperfusion for times from 3 h to 21 days. Frozen sections were immunostained with antibodies to gelatinase A (MMP-2), stromelysin-1 (MMP-3), and gelatinase B (MMP-9). Sham-operated control rats showed MMP-2 immunostaining in astrocytic processes next to blood vessels. After 3 h of the onset of reperfusion MMP-2 immunostaining increased in astrocytes. At 24 h immunoreactivity for MMP-3 and MMP-9 appeared. MMP-3 co-localized with activated microglia (Ox-42+) and ischemic neurons (NeuN+). MMP-9 immunostaining was seen at 48 h in endothelial cells, neutrophils, and neurons. At 5 and 21 days intense MMP-2 staining was seen in reactive astrocytes around the ischemic core. Studies of activation of the MMP were done in lipopolysaccharide (LPS)-stimulated astrocyte and microglia cultures. Stimulated astrocytes produced an activated form of MMP-2. When microglia were stimulated, they activated MMP-9. Immunostaining showed MMP-3 in cultures of enriched microglial cells. The hydroxymate-type, MMP inhibitor, BB-1101, blocked the activation of MMP-2 and MMP-9 by LPS in mixed glial cultures. We propose that MMP-2 is normally present in astrocytic end feet, and that during ischemia MMP-9 and MMP-3 are produced. MMP-3 in microglia/macrophages may be activating proMMP-9. Our results show that a differential expression of MMPs by astrocytes, microglia, and endothelial cells at the blood vessels is involved in the proteolytic disruption of the BBB.

Animals↗
PubMed2001

Involvement of enhanced sensitivity of N-methyl-D-aspartate receptors in vulnerability of developing cortical neurons to methylmercury neurotoxicity.

The developing cortical neurons have been well documented to be extremely vulnerable to the toxic effect of methylmercury (MeHg). In the present study, a possible involvement of N-methyl-D-aspartate (NMDA) receptors in MeHg neurotoxicity was examined because the sensitivity of cortical neurons to NMDA neurotoxicity has a similar developmental profile. Rats on postnatal day 2 (P2), P16, and P60 were orally administered MeHg (10 mg/kg) for 7 consecutive days. The most severe neuronal damage was observed in the occipital cortex of P16 rats. When MK-801 (0.1 mg/kg), a non-competitive antagonist of NMDA, was administered intraperitoneally with MeHg, MeHg-induced neurodegeneration was markedly ameliorated. Furthermore, there was a marked accumulation of nitrotyrosine, a reaction product of peroxynitrite and L-tyrosine, after chronic treatment of MeHg in the occipital cortex of P16 rats. The accumulation of nitrotyrosine was also significantly suppressed by MK-801. In the present electrophysiological study, the amplitude of synaptic responses mediated by NMDA receptors recorded in cortical neurons of P16 rats was significantly larger than those from P2 and P60 rats. These observations strongly suggest that a generation of peroxynitrite through activation of NMDA receptors is a major causal factor for MeHg neurotoxicity in the developing cortical neurons. Furthermore, enhanced sensitivity of NMDA receptors may make the cortical neurons of P16 rats most susceptible to MeHg neurotoxicity.

Age Factors↗
PubMed2001

Rapid activation of microglial cells by hypoxia, kainic acid, and potassium ions in slice preparations of the rat hippocampus.

Microglial activation induced by hypoxia, kainic acid and elevated potassium concentration, all of which alter neuronal function, was studied in hippocampal slices. The activation of microglia was detected by immunostaining with a monoclonal antibody (OX-42) raised against a type 3 complement receptor (CD11b). During activation the phenotype of microglia changes and the intensity of staining of individual cells increases. Oxygen deprivation depressed the focal responses of CA1 neurons to stratum radiatum volleys. Microglial activation was time dependent. Ten minute hypoxia caused mild activation, and after 20 min, a strong microglial reaction could be observed. Although neuronal function returned during reoxygenation, the morphological signs of microglial activation remained. Epileptiform activity of hippocampal neurons, followed by depression, was induced by application of 0.5 mM kainic acid, in a time and dose dependent manner. Washing out kainic acid did not alter microglial reaction. Elevated concentrations of potassium ions induced microglial changes similar to those induced by hypoxia and kainic acid. It is therefore suggested that an elevated extracellular potassium ion concentration may be the common factor in microglial activation observed in these experiments since this is raised both in hypoxia and under the effect of excitotoxins.

Action Potentials↗
PubMed2002

Volumetric structural magnetic resonance imaging (MRI) of the rat hippocampus following kainic acid (KA) treatment.

An in vivo MRI study employing a high field (7T) magnet and a T1- and T2-weighted imaging sequence with subsequent histopathological evaluations was undertaken to develop and evaluate MRI-based volumetric measurements in the rat. The brain structures considered were the hippocampus, the cingulate cortex, the retrosplenial granular cortex and the ventricles. Control (n=3) and kainic acid (KA; n=4) treated rats were scanned 10 days following the manifestation of stage four seizures. The MRI images exhibited anatomical details (125 microm in-plane resolution) that enabled volumetric analysis with high intra-rater reliability. Volumetric analysis revealed that KA-treated rats had significantly smaller hippocampi, and a significant increase in ventricular size. The cingulate cortex and the retrosplenial granular cortex did not differ in volume between the two groups. The histological observations supported the MRI data showing neuronal loss and neuronal degeneration in CA1 and CA3 of the hippocampus, which was accompanied by strong microglia activation. These data demonstrate a reliable and valid method for the measurement of the rat hippocampus in vivo using MRI with a high field magnet, thereby providing a useful tool for future studies of rodent models of neuro-degenerative diseases.

Animals↗
PubMed2003

Identification of cerebral neurons and glial cell types inducing heat shock protein Hsp70 following heat stress in the rat.

Heat shock proteins were recently recognized as molecular chaperones that besides their chaperoning function were also involved in processes of cell death and survival. Many types of neural cells were reportedly capable of expressing heat shock protein Hsp70 following heat stress in vitro. However, identification of cell types inducing Hsp70 protein in the hyperthermic brain is not clear. In this study, cerebral Hsp70 distribution was evaluated in anesthetized adult rats (urethane, 1.5 g/kg, i.p.) subjected to short-term hyperthermia (41.5 degrees C for 30 min). Detection of Hsp70 was achieved by an ABC technique in vibratome or paraffin sections combined with specific markers of glial cell types. Hsp70 appeared by 90 min, mainly in glial and vascular cells, with enhanced immunostaining by 4 h following hyperthermia. Higher numbers of Hsp70-positive cells were detected in the white matter and diencephalic region than in the cerebral cortex, especially over the shorter interval. Hsp70 was localized in many oligodendrocytes, double-labeled with lectin GSII, and some vessels. Microglia showed apparently less Hsp70/OX-42 double-labeled cells than the previous two cell types. In contrast, only a few Hsp70-stained cells were positive for astrocyte marker GFAP. In addition to glial/vascular Hsp70 staining, neuronal Hsp70 induction was observed only in discrete regions including the paraventricular, supraoptic, suprachiasmatic and other hypothalamic nuclei, and in amygdala. Prevailing heat-stress expression of Hsp70 in oligodendrocytes and vascular cells might render them less susceptible to the consequences of other types of cell stress and could be exploited to increase selectively their survival in pathological situations.

Amygdala↗
PubMed2003

Temporal relationships between HIV-1 Tat-induced neuronal degeneration, OX-42 immunoreactivity, reactive astrocytosis, and protein oxidation in the rat striatum.

HIV-1 transactivating protein Tat is neurotoxic and is believed to play a role in the development of AIDS-associated dementia complex. Neurotoxicity of Tat may be associated with oxidative stress. In this study we examined temporal progression of histopathological changes induced by a single microinjection of Tat 1-72 into the rat striatum. Degenerating neural cells, detected by Fluoro-Jade B staining and increased protein oxidation, determined by protein carbonyl immunostaining, were observed in the striatum as soon as 2 h following the microinjection. Further progression of neuronal degeneration was associated with pronounced infiltration of the area surrounding Tat 1-72 injection site by OX-42 positive macrophages/microglia, which was evident at the 24 h time point. Signs of reactive astrocytosis were found in the striatum of Tat 1-72 injected animals as late as 7 days following the single microinjection. Increased GFAP immunoreactivity and changes in the morphology of astrocytes coincided with a second phase of increased protein carbonyl formation, but not with neuronal degeneration. Control polypeptide, nontoxic Tat delta 31-61, did not cause any cell death, inflammatory reaction or oxidative damage. Results of our study support the hypothesis that oxidative stress may be an early step in the mechanism of Tat neurotoxicity.

Acetyltransferases↗
PubMed1998

Induction of microglial reaction and expression of nitric oxide synthase I in the nucleus dorsalis and red nucleus following lower thoracic spinal cord hemisection.

In the present study, immunohistochemical stainings for OX-6, OX-42, nitric oxide synthase I and II as well as nitrotyrosine were used to investigate possible correlation among microglial reactivity, nitric oxide synthase upregulation, peroxynitrite involvement and neuronal death in the nucleus dorsalis and red nucleus following lower thoracic spinal cord hemisection. Significant neuronal loss was found in the ipsilateral nucleus dorsalis and contralateral red nucleus after cord hemisection. A distinctive microglial reaction for OX-42 could be observed from one to four weeks post axotomy in the ipsilateral nucleus dorsalis; by contrast, it was observed on both sides of the red nucleus from one to three weeks following cord hemisection. The activated microglial cells showed some degree of hypertrophy. From the microglial immunoreactivity as well as their appearance, it was speculated that microglial activation might be beneficial or protective to the axotomized neurons. In normal and sham-operated rats, neurons of the nucleus dorsalis were not nitric oxide synthase I reactive. Three weeks after cord hemisection, neurons in the ipsilateral nucleus dorsalis below the lesion showed strong immunoreactivity. Neurons in the red nucleus that normally displayed weak nitric oxide synthase I immunoreactivity showed an increase on both sides of the nucleus. These results suggested that nitric oxide synthase I expression in the nucleus dorsalis following axotomy was synthesized de novo and might act as a neurotoxic agent. However, the bilateral increase in expression of nitric oxide synthase I in the red nucleus after lower thoracic cord hemisection was due to up-regulation of the constitutive enzyme and might have some neuroprotective function. Our results also suggested that peroxynitrite played no or little role in the neurodegeneration in the nucleus dorsalis and red nucleus following axotomy.

Animals↗
PubMed2003

Neurotrophins regulate proliferation and survival of two microglial cell lines in vitro.

Microglia are thought to play a key role in the development and regeneration of the central nervous system although the mechanisms regulating their presence and activity are not fully understood. Substantial evidence suggests that members of the neurotrophin family such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 and -4 (NT-3/4) have a dramatic effect on both neurons and perineuronal cells. This study employed two murine microglial lines, BV-2 and N9, to examine the action of these neurotrophins on the mitotic activity and survival of microglia in vitro. Neurotrophins were incorporated into the media at the time of plating and cell number and levels of mitochondrial dehydrogenase activity (MTT) were determined at various time points in vitro. NGF increased cell number and MTT levels of both cell lines in a dose-dependent manner. BV-2 was more sensitive to NGF than N9. Similar responses were elicited by BDNF, although the sensitivity of each cell line was different than that found for NGF. NT-3 and NT-4 had no effect on cell proliferation. However, NT-4 had an effect on the survival of BV-2 and N9 cells. The response of these cells to neurotrophins was blocked by K252a, a tyrosine kinase inhibitor, suggesting that actions of neurotrophins were mediated by high-affinity tyrosine kinase receptors (Trk). Immunolocalization studies revealed positive Trk (pan) reactivity in the above cell lines and in primary microglia, but an absence of the low-affinity p75 neurotrophin receptor. Western blot analysis supported the above observations. These studies suggest that in addition to their neurotrophic actions, NGF and BDNF may also regulate microglial dynamics, thereby influencing the surrounding milieu during neuronal regeneration.

Animals↗
PubMed1998

Tumor-derived EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates collagenase transcription through MAPK p38.

EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates fibroblast metalloproteinases (MMP) 1, 2 and 3 (Kataoka et al. (1993) Cancer Res. 53, 3154-3158). Here we focus on MMP-1, showing that in lung tumors, MMP-1's cognate mRNA is strongly expressed in stromal fibroblasts adjacent to EMMPRIN-expressing tumor cells. In vitro, EMMPRIN upregulates MMP-1 mRNA expression in a concentration-dependent manner, with a peak accumulation at 24 h. The response is genistein-sensitive, suggesting it is dependent on tyrosine kinase activity. Analysis of tyrosine phosphorylation-dependent MAP kinases ERK 1/2, SAPK/JNK, and p38 showed that the activity of p38 but not that of the other 2 kinases was elevated in response to EMMPRIN. That p38 activity was required for EMMPRIN stimulation of MMP-1 was evident from results showing that the p38 inhibitor SB203580 blocked this response. This is the first available information regarding the mechanism by which tumor-associated molecules upregulate MMP synthesis in stromal fibroblasts.

Antigens, CD↗
PubMed2003

Displaying and epitope mapping of CD147 on VCSM13 phages: influence of Escherichia coli strains.

The external domain of a human leukocyte surface molecule, CD147 was displayed on the surface of phage. Two Escherichia coli laboratory strains, XL-1 Blue and TG-1, were chosen to separately propagate the recombinant phages. By sandwich enzyme linked immunosorbent assay (ELISA), CD147 on phage particles were individually captured by six CD147 mAbs and subsequently detected by anti-M13 conjugated HRP. All mAbs specifically bound the CD147 on phage particles derived from TG-1. On the contrary, only four of them could recognize the CD147 on phages produced by XL-1 Blue. The results indicate that the environment in the TG-1 periplasm is more appropriate than that of XL-1 Blue for promoting the suitable folding of CD147. This finding emphasizes the importance of selecting the appropriate E. coli host for display of a complex protein. The epitopes of CD147 displayed on the phage were further mapped by competitive inhibition ELISA, which is a reliable and economical method. Certain clusters of mAb recognition areas were identified and will provide valuable information for the discovery of the ligand for CD147.

Antigens, CD↗
PubMedDate not supplied

Safety aspects of chronic low-frequency transcranial magnetic stimulation based on localized proton magnetic resonance spectroscopy and histology of the rat brain.

Because repetitive transcranial magnetic stimulation (rTMS) is capable of inducing lasting alterations of cortical excitability, it represents a promising therapeutic tool in several neuropsychiatric disorders. However, rTMS, especially when applied chronically, may cause harmful effects in the stimulated tissue. To study the safety of chronic rTMS we used a novel small stimulation coil, which was specially designed to treat rats, and investigated brain tissue using in vivo localized proton magnetic resonance spectroscopy (MRS) and post mortem histological analysis. Histology was based on a modified stereology method in combination with immunohistochemistry applying antibodies against OX-6, OX-42, ED, and GFAP to detect any microglial and/or astrocytic activation 48 h after the last TMS session. Conscious rats were treated with a daily suprathreshold rTMS regimen of 1000 stimuli applied on 5 consecutive days at a frequency of 1 Hz. In comparison with control animals receiving magnetic stimulation over the lumbar spine, quantitative evaluations of cerebral metabolite concentrations by proton MRS revealed no significant alterations of N-acetyl-aspartate, creatine and phosphocreatine, choline-containing compounds, myo-inositol, glucose and lactate after chronic rTMS. Similarly to the in vivo results, post mortem histology revealed no changes in microglial and astrocytic activation after rTMS. In conclusion, these data provide support for the safety of chronic rTMS. However, they do not exclude acute changes on neurotransmitters systems or other physiologic responses during or directly after the rTMS treatment.

Animals↗
PubMed2003

Neuroprotection by aminoguanidine after lateral fluid-percussive brain injury in rats: a combined magnetic resonance imaging, histopathologic and functional study.

The present study examined the effects of a selective inducible nitric oxide synthase (iNOS) inhibitor, aminoguanidine (AG), on neuronal cell survival and post-traumatic recovery in rats following a lateral fluid percussive brain injury. Daily treatment of AG at the dosage of 100 mg/kg or normal saline was given intraperitoneally into rats starting 2 h before or 30 min after brain injury. Treatment with AG significantly reduced lesion volumes in the brains of rats after injury, as evaluated by high-resolution magnetic resonance imaging (MRI). Immunohistochemical analysis showed a marked induction of iNOS expression in brain macrophages ipsilateral to the injury. Apoptotic neurons were observed in the ipsilateral cerebral cortex by in situ terminal transferase d-UTP nick-end labelling (TUNEL) and caspase-3 immunohistochemistry. In rats receiving prophylactic or post-injury treatment of AG, the number of degenerating neurons was markedly reduced in the cerebrum compared to those receiving saline injection. The location and extent of these pathologic changes correlated with MRI findings. Neurobehavioral studies showed that rotametric performance, grip-strength score, total and ambulatory locomotor responses and acoustic startle response were reduced in rats subjected to the injury but were significantly improved in AG-treated rats. It is suggested that inhibition of iNOS by AG may represent a potential therapeutic strategy for the treatment of traumatic brain injury.

Animals↗