Reactivity of microglia and astrocytes after an excitotoxic injury induced by kainic acid in the rat spinal cord.

After injury of the nervous system glial cells react according to the stimuli by modifying their morphology and function. Glia activation was reported in different kainic acid (KA)-induced neurodegeneration models. Here, we describe glial morphometric changes occurring in an excitotoxic KA-induced cervical spinal cord injury model. Concomitant degenerative and apoptotic processes are also reported. Male rats injected at the spinal cord C5 segment either with KA or saline were euthanized at post-injection (PI) days 1, 2, 3 or 7. Anti-IBA-1 and anti-GFAP antibodies were used to identify microglia and activated astrocytes, respectively, and to morphometrically characterized them. Fluoro-Jade B staining and TUNEL reaction were used to determine neuronal and glial degeneration and apoptosis. KA-injected group showed a significant increase in microglia number at the ipsilateral side by PI day 3. Different microglia reactive phenotypes were observed. Reactive microglia was still present by PI day 7. Astrocytes in KA-injected group showed a biphasic increase in number at PI days 1 and 3. Degenerative and apoptotic events were only observed in KA-injected animals, increasing mainly by PI day 1. Understanding the compromise of glia in different neurodegenerative processes may help to define possible common or specific therapeutic approaches directed towards neurorestorative strategies.

Thalidomide alleviates bone cancer pain by down-regulating expressions of NF-κB and GFAP in spinal astrocytes in a mouse model.

Aim: Thalidomide is one of the first line therapies in cancer pain management. Previous study has shown that thalidomide decreases the expression of tumor necrosis factor alpha in the mouse spinal cord. However, the exact cellular and molecular mechanism underlying the effect of thalidomide remains unclear. Here, we investigated the effect of thalidomide on the expression level of NF-κB as well as glial fibrillary acidic protein (GFAP) in the spinal cord astrocyte in a mice model. Materials and methods: MC57G fibrosarcoma cells were intramedullary injected into the right femurs of C57/BL mice to induce behaviors related to bone cancer pain. Postoperative thalidomide was administered intraperitoneally to the mice at dose of 100 mg/kg/day for 7 days. The effect of thalidomide on pain hypersensitivity was checked by behavioral testing. The expression levels of NF-κB and GFAP in spinal cord were evaluated by using Western blotting and Immunohistochemistry. Results: Compared with the controls, the tumor-bearing mice showed substantial pain-related behaviors. Furthermore, the expression levels of both NF-κB and GFAP increased significantly in the spinal cord astrocytes of the tumor-bearing mice. Treating the tumor-bearing mice with thalidomide results in a dramatic reduction in pain behaviors and a significant decrease of NF-κB and GFAP expressions. Conclusions: Thalidomide alleviates the pain behaviors probably by down-regulating the expression of NF-κB and GFAP.

Astrocytic mobilization of glutathione peroxidase-1 contributes to the protective potential against cocaine kindling behaviors in mice via activation of JAK2/STAT3 signaling.

Compelling evidence indicates that oxidative stress contributes to cocaine neurotoxicity. The present study was performed to elucidate the role of the glutathione peroxidase-1 (GPx-1) in cocaine-induced kindling (convulsive) behaviors in mice. Cocaine-induced convulsive behaviors significantly increased GPx-1, p-IkB, and p-JAK2/STAT3 expression, and oxidative burdens in the hippocampus of mice. There was no significant difference in cocaine-induced p-IkB expression between non-transgenic (non-TG) and GPx-1 overexpressing transgenic (GPx-1 TG) mice, but significant differences were observed in cocaine-induced p-JAK2/STAT3 expression and oxidative stress between non-TG and GPx-1 TG mice. Cocaine-induced glial fibrillary acidic protein (GFAP)-labeled astrocytic level was significantly higher in the hippocampus of GPx-1 TG mice. Triple-labeling immunocytochemistry indicated that GPx-1-, p-STAT3-, and GFAP-immunoreactivities were co-localized in the same cells. AG490, a JAK2/STAT3 inhibitor, but not pyrrolidone dithiocarbamate, an NFκB inhibitor, significantly counteracted GPx-1-mediated protective potentials (i.e., anticonvulsant-, antioxidant-, antiapoptotic-effects). Genetic overexpression of GPx-1 significantly attenuated proliferation of Iba-1-labeled microglia induced by cocaine in mice. However, AG490 or astrocytic inhibition (by GFAP antisense oligonucleotide and α-aminoadipate) significantly increased Iba-1-labeled microglial activity and M1 phenotype microglial mRNA levels, reflecting that proinflammatory potentials were mediated by AG490 or astrocytic inhibition. This microglial activation was less pronounced in GPx-1 TG than in non-TG mice. Furthermore, either AG490 or astrocytic inhibition significantly counteracted GPx-1-mediated protective potentials. Therefore, our results suggest that astrocytic modulation between GPx-1 and JAK2/STAT3 might be one of the underlying mechanisms for protecting against convulsive neurotoxicity induced by cocaine.

Quercetin Attenuates Neuropathic Pain in Rats with Spared Nerve Injury.

Quercetin is a flavonoid widely found in plants and marketed to the public as a supplement. Several studies have reported its effect on glial cells. This study aimed to examine the effect of quercetin on the development of neuropathic pain and the underlying mechanism in a spared nerve injury (SNI) rat model. Male Sprague-Dawley rats randomly assigned to the control or the quercetin group were subjected to SNI of the sciatic nerve. We measured pain behaviors on the hind paw and glial fibrillary acidic protein (GFAP) in the dorsal root ganglion (DRG) and spinal cord. Oral administration of 1% quercetin, begun before surgery, attenuated mechanical allodynia compared to the control group at days 7 and 10 after SNI. On the other hand, established pain was not attenuated in a post-dose group in which quercetin was begun 7 days after SNI. Quercetin inhibited GFAP in the satellite glial cells of the ipsilateral L5 DRG on day 7 compared to the control group. Quercetin suppressed the development of neuropathic pain through a mechanism partly involving the inhibition of satellite glial cells. As its safety is well established, quercetin has great potential for clinical use in pain treatment.

Antisense suppression of glial fibrillary acidic protein as a treatment for Alexander disease.

OBJECTIVE: Alexander disease is a fatal leukodystrophy caused by autosomal dominant gain-of-function mutations in the gene for glial fibrillary acidic protein (GFAP), an intermediate filament protein primarily expressed in astrocytes of the central nervous system. A key feature of pathogenesis is overexpression and accumulation of GFAP, with formation of characteristic cytoplasmic aggregates known as Rosenthal fibers. Here we investigate whether suppressing GFAP with antisense oligonucleotides could provide a therapeutic strategy for treating Alexander disease. METHODS: In this study, we use GFAP mutant mouse models of Alexander disease to test the efficacy of antisense suppression and evaluate the effects on molecular and cellular phenotypes and non-cell-autonomous toxicity. Antisense oligonucleotides were designed to target the murine Gfap transcript, and screened using primary mouse cortical cultures. Lead oligonucleotides were then tested for their ability to reduce GFAP transcripts and protein, first in wild-type mice with normal levels of GFAP, and then in adult mutant mice with established pathology and elevated levels of GFAP. RESULTS: Nearly complete and long-lasting elimination of GFAP occurred in brain and spinal cord following single bolus intracerebroventricular injections, with a striking reversal of Rosenthal fibers and downstream markers of microglial and other stress-related responses. GFAP protein was also cleared from cerebrospinal fluid, demonstrating its potential utility as a biomarker in future clinical applications. Finally, treatment led to improved body condition and rescue of hippocampal neurogenesis. INTERPRETATION: These results demonstrate the efficacy of antisense suppression for an astrocyte target, and provide a compelling therapeutic approach for Alexander disease. Ann Neurol 2018;83:27-39.

Treatment with the KCa3.1 inhibitor TRAM-34 during diabetic ketoacidosis reduces inflammatory changes in the brain.

BACKGROUND: Diabetic ketoacidosis (DKA) causes brain injuries in children ranging from subtle to life-threatening. Previous studies suggest that DKA-related brain injury may involve both stimulation of Na-K-Cl cotransport and microglial activation. Other studies implicate the Na-K-Cl cotransporter and the Ca-activated K channel KCa3.1 in activation of microglia and ischemia-induced brain edema. In this study, we determined whether inhibiting cerebral Na-K-Cl cotransport or KCa3.1 could reduce microglial activation and decrease DKA-related inflammatory changes in the brain. METHODS: Using immunohistochemistry, we investigated cellular alterations in brain specimens from juvenile rats with DKA before, during and after insulin and saline treatment. We compared findings in rats treated with and without bumetanide (an inhibitor of Na-K-Cl cotransport) or the KCa3.1 inhibitor TRAM-34. RESULTS: Glial fibrillary acidic protein (GFAP) staining intensity was increased in the hippocampus during DKA, suggesting reactive astrogliosis. OX42 staining intensity was increased during DKA in the hippocampus, cortex and striatum, indicating microglial activation. Treatment with TRAM-34 decreased both OX42 and GFAP intensity suggesting a decreased inflammatory response to DKA. Treatment with bumetanide did not significantly alter OX42 or GFAP intensity. CONCLUSIONS: Inhibiting KCa3.1 activity with TRAM-34 during DKA treatment decreases microglial activation and reduces reactive astrogliosis, suggesting a decreased inflammatory response.

Scorpion Venom Heat-Resistant Peptide Attenuates Glial Fibrillary Acidic Protein Expression via c-Jun/AP-1.

Scorpion venom has been used in the Orient to treat central nervous system diseases for many years, and the protein/peptide toxins in Buthus martensii Karsch (BmK) venom are believed to be the effective components. Scorpion venom heat-resistant peptide (SVHRP) is an active component of the scorpion venom extracted from BmK. In a previous study, we found that SVHRP could inhibit the formation of a glial scar, which is characterized by enhanced glial fibrillary acidic protein (GFAP) expression, in the epileptic hippocampus. However, the cellular and molecular mechanisms underlying this process remain to be clarified. The results of the present study indicate that endogenous GFAP expression in primary rat astrocytes was attenuated by SVHRP. We further demonstrate that the suppression of GFAP was primarily mediated by inhibiting both c-Jun expression and its binding with AP-1 DNA binding site and other factors at the GFAP promoter. These results support that SVHRP contributes to reducing GFAP at least in part by decreasing the activity of the transcription factor AP-1. In conclusion, the effects of SVHRP on astrocytes with respect to the c-Jun/AP-1 signaling pathway in vitro provide a practical basis for studying astrocyte activation and inhibition and a scientific basis for further studies of traditional medicine.

Exendin-4 protects retinal cells from early diabetes in Goto-Kakizaki rats by increasing the Bcl-2/Bax and Bcl-xL/Bax ratios and reducing reactive gliosis.

PURPOSE: Exendin-4 (E4), a long-acting agonist of the hormone glucagon-like peptide 1 receptor (GLP-1R), is administered to treat type II diabetes in the clinical setting and also shows a neuroprotective effect. Our previous studies demonstrated its protective effect in early experimental diabetic retinopathy (DR), but the molecular and cellular mechanisms are largely unknown. This study aimed to investigate the protective mechanism of a GLP-1R agonist E4 against early DR in Goto-Kakizaki (GK) rats. METHODS: Diabetic GK rats and control animals were randomly assigned to receive E4 or vehicle by intravitreal injection. The retinal function and retinal cell counts were evaluated using an electroretinogram and light microscopy. The expressions of retinal GLP-1R, mitochondria-dependent apoptosis-associated genes, reactive gliosis markers, and endoplasmic reticulum stress-related pathway genes were studied by western blotting and immunohistochemistry in vivo and in vitro. RESULTS: E4 significantly prevented the reduction of the b-wave and oscillatory potential amplitudes and retinal cell loss and maintained the Bcl-2/Bax and Bcl-xL/Bax ratio balances in GK rats. It also downregulated the expression of glial fibrillary acidic protein and reduced retinal reactive gliosis. Similar results were found in primary rat Müller cells under high glucose culture in vitro. CONCLUSIONS: E4 may protect retinal cells from diabetic attacks by activating GLP-1R, decreasing retinal cell apoptosis, and reducing retinal reactive gliosis. Thus, E4 treatment may be a novel approach for early DR.

Structural and neurochemical plasticity in both supraoptic and paraventricular nuclei of hypothalamus of a desert rodent Meriones shawi after a severe dehydration versus opposite treatment by rehydration: GFAP and vasopressin immunohistochemical study.

Various lines of evidence indicate that astrocytes can undergo morphological changes that modify their relationship to adjacent neurons in response to physiological stimulation such as dehydration. Supraoptic (SON) and paraventricular (PVN) nuclei of hypothalamus represent obvious examples of activity-dependent neuro-astrocytic plasticity. In the present study, Meriones shawi is used as an animal model. Moreover, GFAP and vasopressin expressions are used as indicators successively of astrocytes and neuronal activations. In order to evaluate the reversibility of the neuro-astrocytic plasticity in SON and PVN, prolonged episode of water deprivation followed by episode of rehydration were examined. Hence, we studied the immunoreactivity in various hydration states: water ad libitum, dehydration, and rehydration of animals. Our results showed that dehydration of Meriones induced a significant decrease of GFAP immunoreactivity accompanied by a significant increase of AVP immunoreactivity, the latter concerns both cell bodies and fibers in the same hypothalamic nuclei SON and PVN. Conversely, rehydration of animals shows a reversible phenomenon leading a return of vasopressin and GFAP immunoreactivities to the control level. These results show that both astrocytes and vasopressin neurons display a remarkable structural and physiological plasticity, allowing to M. shawi, a great ability to support the hostile conditions in dry environment.

Drug screening to identify suppressors of GFAP expression.

Glial fibrillary acidic protein (GFAP) is the major intermediate filament protein of astrocytes in the vertebrate central nervous system. Increased levels of GFAP are the hallmark feature of gliosis, a non-specific response of astrocytes to a wide variety of injuries and disorders of the CNS, and also occur in Alexander disease where the initial insult is a mutation within the coding region of GFAP itself. In both settings, excess GFAP may cause or exacerbate astrocyte dysfunction. With the goal of finding drugs that reduce the expression of GFAP, we have devised screens to detect changes in GFAP promoter activity or protein levels in primary cultures of mouse astrocytes in a 96-well format. We have applied these screens to libraries enriched in compounds that are already approved for human use by the FDA. We report that several compounds are active at micromolar levels in suppressing the expression of GFAP. Treatment of mice for 3 weeks with one of these drugs, clomipramine, causes nearly 50% reduction in the levels of GFAP protein in brain.

Glial inhibitors influence the mRNA and protein levels of mGlu2/3, 5 and 7 receptors and potentiate the analgesic effects of their ligands in a mouse model of neuropathic pain.

Metabotropic glutamate (mGlu) receptors, which are present on neurons and glial cells, have been shown to play a role in neuropathic pain. The present study sought to investigate how the glial inhibitors minocycline and pentoxifylline alter the effect that chronic constriction injury (CCI) has on the expression of mGlu receptors and on their associated ligands. RT-PCR analysis revealed that seven days after CCI, the mRNA levels of glial markers C1q and GFAP, as well as those of mGlu5 and mGlu3, but not mGlu7, were elevated in the lumbar spinal cord - ipsilateral to the injury. The protein levels of the microglial marker OX42, the astroglial marker GFAP, and mGlu5 receptor protein were increased, whereas the levels of mGlu2/3 and mGlu7 receptor proteins were reduced. Preemptive and repeated intraperitoneal (i.p.) administration (16 and 1h before nerve injury and then twice daily for seven days) of minocycline (30mg/kg) and pentoxifylline (20mg/kg) prevented the injury-induced changes in the levels of mGlu3 and mGlu5 receptor mRNAs and the injury-induced changes in the protein levels of all the receptors. Repeated administration of minocycline and pentoxifylline significantly attenuated CCI-induced allodynia (von Frey test) and hyperalgesia (cold plate test) measured on day seven after injury and potentiated the antiallodynic and antihyperalgesic effects of single i.p. and intrathecal (i.t.) injections of mGlu receptor ligands: MPEP, LY379268 or AMN082. We conclude that attenuation of injury-induced glial activation can reduce glutamatergic activity, thereby contributing to regulation of pain sensation.

Methylprednisolone inhibits the expression of glial fibrillary acidic protein and chondroitin sulfate proteoglycans in reactivated astrocytes.

Reactive gliosis caused by post-traumatic injury often results in marked expression of chondroitin sulfate proteoglycan (CSPG), which inhibits neurite outgrowth and regeneration. Methylprednisolone (MP), a synthetic glucocorticoid, has been shown to have neuroprotective and anti-inflammatory effects for the treatment of acute spinal cord injury (SCI). However, the effect of MP on CSPG expression in reactive glial cells remains unclear. In our study, we induced astrocyte reactivation using alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and cyclothiazide to mimic the excitotoxic stimuli of SCI. The expression of glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivation, and CSPG neurocan and phosphacan were significantly elevated by AMPA treatment. The conditioned media from AMPA-treated astrocytes strongly inhibited neurite outgrowth of rat dorsal root ganglion neurons, and this effect was reversed by pretreatment with MP. Furthermore, MP downregulated GFAP and CSPG expression in adult rats with SCI. Additionally, both the glucocorticoid receptor (GR) antagonist RU486 and GR siRNA reversed the inhibitory effects of MP on GFAP and neurocan expression. Taken together, these results suggest that MP may improve neuronal repair and promote neurite outgrowth after excitotoxic insult via GR-mediated downregulation of astrocyte reactivation and inhibition of CSPG expression.

Protection against human immunodeficiency virus type 1 Tat neurotoxicity by Ginkgo biloba extract EGb 761 involving glial fibrillary acidic protein.

Human immunodeficiency virus (HIV)-1 Tat protein is an important pathogenic factor in HIV-associated neuropathogenesis. Despite recent progress, the molecular mechanisms underlying Tat neurotoxicity are still not completely understood. However, few therapeutics have been developed to specifically target HIV infection in the brain. Recent development of an inducible brain-specific Tat transgenic mouse model has made it possible to define the mechanisms of Tat neurotoxicity and evaluate anti-neuroAIDS therapeutic candidates in the context of a whole organism. Herein, we demonstrate that administration of EGb 761, a standardized formulation of Ginkgo biloba extract, markedly protected Tat transgenic mice from Tat-induced developmental retardation, inflammation, death, astrocytosis, and neuron loss. EGb 761 directly down-regulated glial fibrillary acidic protein (GFAP) expression at both protein and mRNA levels. This down-regulation was, at least in part, attributable to direct effects of EGb 761 on the interactions of the AP1 and NF-kappaB transcription factors with the GFAP promoter. Most strikingly, Tat-induced neuropathological phenotypes including macrophage/microglia activation, central nervous system infiltration of T lymphocytes, and oxidative stress were significantly alleviated in GFAP-null/Tat transgenic mice. Taken together, these results provide the first evidence to support the potential for clinical use of EGb 761 to treat HIV-associated neurological diseases. Moreover, these findings suggest for the first time that GFAP activation is directly involved in Tat neurotoxicity, supporting the notion that astrocyte activation or astrocytosis may directly contribute to HIV-associated neurological disorders.

Targeting malignant gliomas with a glial fibrillary acidic protein (GFAP)-selective oncolytic adenovirus.

Glial fibrillary acidic protein (GFAP) is an intermediate filament protein abundantly expressed in malignant gliomas. We have constructed a novel oncolytic adenovirus, Ad5-gfa2(B)3-E1, for treatment of these tumors. In this construct, the E1 region is under control of the tissue-specific GFAP promoter (gfa2) with three additional copies of the glial specific 'B' enhancer. Infection of a GFAP-positive cell line with Ad5-gfa2(B)3-E1 resulted in E1A and E1B expression at 75% and 30% of the levels obtained after wtAd5 infection. Q-PCR showed that Ad5-gfa2(B)3-E1 replicated 4.5 times more efficiently in the GFAP-positive than in the GFAP-negative cell lines. Cell viability assays showed efficient elimination of GFAP-positive cells by Ad5-gfa2(B)3-E1, in some cell lines as efficiently as wtAd5, while the elimination was attenuated in GFAP-negative cell lines. When tested in human tumor xenografts in nude mice, Ad5-gfa2(B)3-E1 effectively suppressed the growth of GFAP-positive SNB-19 glial tumors but not of GFAP-negative A549 lung tumors. In Ad5-gfa2(B)3-E1, the E3 region was deleted to create space for future insertion of heterologous therapeutic genes. Experiments with dl7001, an E3-deleted variant of wtAd5, confirmed that the specificity of Ad5-gfa2(B)3-E1 replication was based on the promoter driving E1 and not on the E3 deletion. Strategies to further improve the efficacy of Ad5-gfa2(B)3-E1 for the treatment of malignant gliomas include the insertion of therapeutic genes in E3 or retargeting to receptors that are more abundantly expressed on primary glioma cells than CAR.

The effect of insulin and glucose levels on retinal glial cell activation and pigment epithelium-derived fibroblast growth factor-2.

PURPOSE: The diabetic retina exhibits decreases in endogenous nonangiogenic neurotrophins. This study hypothesized that deficiencies in systemic and retinal pigment epithelium-derived (RPE) neurotrophic factors also influence retinal changes in diabetes. METHODS: Diabetes was established in Listar hooded rats with streptozotocin. Reverse transcriptase coupled polymerase chain reaction (RT-PCR) and immunoblotting were used to determine the expression of fibroblast growth factor-2 (FGF-2) in the retina and RPE, and glial fibrillary acid protein (GFAP) in the retina. In addition, primary human RPE cultures and a transformed Müller cell line were used to determine the effect of insulin, glucose, and insulin-like growth factor (IGF) on the expression of these substances. RESULTS: FGF-2 and GFAP were increased in retina, but FGF-2 was decreased in the RPE of diabetic animals. Retinal GFAP correlated with RPE FGF-2 expression in these animals. Insulin produced a dose-dependent increase in FGF-2 in RPE cells and decrease in GFAP in Müller cells grown in 15 mM glucose. In 5 mM glucose, insulin had no effect on expression of either protein. Physiological levels of insulin inhibited changes induced by 15 mM glucose. The effect of 9 nM insulin on each culture was mimicked by 1 nM IGF, and blocked with an IGFR-1 inhibitor. CONCLUSIONS: It is suggested that decreased systemic insulin and high glucose levels contribute to decreased FGF-2 production in the RPE and increased glial cell activation in the diabetic retina. Addition of insulin and IGF act to reverse this effect through the IGFR-1. These mechanisms may contribute to the development of diabetic retinopathy.

Suppression of glial fibrillary acidic protein expression in astrocytes of the superficial glial delimiting membrane in traumatic subarachnoid hemorrhage.

Astrocyte reactions to brain damage are usually accompanied by increases in glial fibrillary acidic protein (GFAP) expression, though it remains unclear whether this reaction is universal. The aim of the present work was to study the reactions of astrocytes in the superficial glial delimiting membrane of the human brain to traumatic subarachnoid hemorrhage. Light microscopy and immunocytochemical studies showed that GFAP expression is suppressed in astrocytes in the superficial glial delimiting membrane for periods of up to three days from the moment of craniocerebral trauma accompanied by subarachnoid hemorrhage. These data provide evidence for the existence of regional characteristics in the reactions of astrocytes.

Time course of response to estradiol replacement in ovariectomized mice: brain apolipoprotein E and synaptophysin transiently increase and glial fibrillary acidic protein is suppressed.

The current study examined the effect of long-term estradiol replacement in ovariectomized mice. Estradiol-17beta (E2) pellets or vehicle pellets were implanted at the time of ovariectomy (OVX) in young adult female mice. Five mice from each group were sacrificed at 5, 14, 28 and 49 days after OVX and pellet replacement. Western blotting of homogenates from somatosensory cortex, hippocampus, olfactory bulb and cerebellum was performed to obtain concentrations of glial fibrillary acidic protein (GFAP), apolipoprotein E (apoE) and synaptophysin (SYN). At 5 days after OVX, GFAP levels were not affected by E2 replacement. In contrast to GFAP, synaptophysin and apoE concentrations were significantly elevated by 15% and 25%, respectively, in the E2-replaced group compared to the vehicle-replaced group at 5 days but by 14 days concentrations were equivalent. Late in the time course of this study, at 49 days, GFAP concentrations were higher in the E2-deprived mice but did not increase in the E2-replaced group. Immunocytochemistry for GFAP confirmed this observation. Of note was that these effects occurred in all four brain regions measured. These observations suggest that estradiol is able to suppress reactive gliosis. In addition, E2 replacement in OVX mice is associated with transiently higher levels of apoE and synaptophysin.

[Suppression of glial fibrillary acidic protein expression in astrocytes of the superficial glial limiting membrane after traumatic subarachnoid hemorrhage].

Although typical astrocytic reaction to brain injury is accompanied by an increase of glial fibrillary acidic protein (GFAP) expression, to what degree this reaction is universal remains to be elucidated. The aim of the present study was to investigate the reaction of superficial glial limiting membrane of human brain to traumatic subarachnoid hemorrhage. Using light microscopy and immunocytochemistry, it was found that a suppresion of GFAP expression in astrocytes of superficial glial limiting membrane occurred up to 3 days following the brain trauma. The data obtained suggest the existence of regional peculiarities of astrocytic reaction.

Treatment with magnesium improves reference memory but not working memory while reducing GFAP expression following traumatic brain injury.

PURPOSE: Previous studies have shown that administration of MgCl2 in animal models of brain injury significantly improves functional recovery: however, few studies have examined cognitive recovery. The present study evaluated the effect of MgCl2 pharmacotherapy on recovery of function following medial frontal cortex contusion injury. METHODS: Groups of rats were assigned to either MgCl2 (1.0 mmol/kg) or saline treatment conditions and prepared with contusion injuries or shams. Drug treatment was administered 15 min and 24 hr following injury. Rats were examined on tests of sensorimotor performance (bilateral tactile adhesive removal) and cognitive ability (reference and working memory). RESULTS: Administration of MgCl2 following injury significantly reduced the behavioral impairments observed on the bilateral tactile removal test. The acquisition of reference memory was also significantly improved compared to saline-treated rats; however, treatment did not improve working memory performance. Lesion analysis revealed that administration of MgCl2 did not significantly reduce lesion size compared to saline-treatment. Examination of glial fibrillary acidic protein (GFAP) expression showed that MgCl2 did significantly reduce the number of GFAP+ cells. CONCLUSION: These results indicate that MgCl2 administration significantly improved behavioral outcome following injury in a task dependent manner and reduced GFAP expression.