Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Seizures are known to induce dramatic alterations in neuronal gene expression. These changes may play a role in the genesis of an epileptic state. The present report describes another consequence of seizures-a dramatic induction of glial fibrillary acidic protein (GFAP) expression in astrocytes. Using a hippocampal kindling model, we demonstrate that kindled seizures lead to many fold increases in mRNA for GFAP in structures which experience electrographic seizures. The increases can be detected 1 day following a single seizure. If seizures are induced repetitively (every other day for many days), levels of GFAP mRNA remain elevated. However, when kindled seizures are not induced, levels of GFAP mRNA return to near control levels within a few days. The increases in GFAP mRNA levels are not in response to decreases in neuronal activity (as a result of postictal depression), because GFAP mRNA levels are unaffected when neuronal activity is decreased by blocking afferent drive (with tetrodotoxin). The induction of GFAP expression by seizures may reflect the first step in a process in which seizures induce astrocytic hypertrophy. The changes in astrocytes could in turn modify the way in which astrocytes maintain homeostasis in the extracellular microenvironment in ways that could contribute to the development of an epileptic state.
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PMID:Seizures and the regulation of astroglial gene expression. 133 63

Exposure of a limited brain surface to a high potassium (K+) concentration produces an injury limited to the underlying cortex, without apparently affecting other brain areas. Such a treatment produces an increased expression of glial fibrillary acidic protein (GFAP) in astrocytes, as assessed by immunohistochemical techniques, throughout the cortex ipsilateral to K+ exposure. This effect is evident 2 days after treatment and persists up to, at least, day 7. Thirty days after K+ exposure GFAP immunostaining is similar in both hemispheres. Administration of the non-competitive NMDA antagonist MK-801 (4 mg/kg i.p.) prior to the injury prevented the rise in GFAP immunoreactivity (IR) at 2 but not 7 days after the treatment. Administration of MK-801 after the injury appeared to have no effect on GFAP expression. This work confirms that brain injury, associated with spreading depression, can induce a glial response far from the lesion site. Furthermore, the fact that this phenomenon can be modified by an NMDA receptor antagonist suggests that glutamate may play a role, in vivo, in the regulation of astrocytic response to injury and introduces the possibility that brain injury-induced gliosis may be pharmacologically manipulated.
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PMID:MK-801 affects the potassium-induced increase of glial fibrillary acidic protein immunoreactivity in rat brain. 136 21

Reactive astrocytosis is a process by which astrocytes respond to brain injury by showing an increase in glial fibrillary acidic protein (GFAP) staining that is associated with hypertrophy and/or hyperplasia of these cells. Because spreading depression (SD) is a perturbation uncomplicated by neuronal necrosis and is seen in both in vivo and in vitro neural structures, we sought to determine whether SD was a sufficient stimulus to induce enhanced GFAP staining. SD was elicited in anesthetized rats by application of KCI to parietal cortex for 3 hr; equimolar NaCI was applied to contralateral cortex. SD was confirmed by monitoring DC potentials in frontal neocortices. Animals were allowed to recover for 48 hr, and their brains were processed for semiquantitative and computer-based analyses of GFAP staining intensity. Experimental GFAP staining was referenced to contralateral control levels. Neocortical SD (13-37 SDs) was associated with a significant (p less than 10(-4)), 43% increase in GFAP staining intensity, which remained statistically greater than normal for more than 2 weeks. If SD was inhibited by combined hyperoxia and hypercarbia, only a nonsignificant (p greater than 0.20), 7% increase in GFAP staining was seen. Thus, SD may be a useful physiologic process with which to begin to explore the cellular mechanisms that induce the transformation of normal astrocytes into reactive species.
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PMID:Spreading depression increases immunohistochemical staining of glial fibrillary acidic protein. 190 91

Brain injury, including ischemia, changes normal astrocytes into reactive species that hypertrophy and begin to proliferate. Understanding the mechanisms that underlie these changes could lead to new abilities to promote regeneration and retard neural degeneration after ischemia. Because ionic changes occur after nonneural cells are exposed to mitogens, we have begun to examine the ionic changes that may trigger reactive gliosis. We showed that two changes thought to be important for mitogenesis, elevation of interstitial potassium or intracellular pH, are correlated with reactive gliosis as indicated by increased immunohistochemical staining for glial fibrillary acidic protein. This relation was seen after activation of cerebral cortex by recurrent spreading depression but not by physiologic stimulation. Deoxyribonucleic acid synthesis occurs in fibroblasts only when intracellular potassium exceeds 90 mM, a level seen in astrocytes only during spreading depression. Thus, our results support the contention that a threshold level of potassium (and pH) must be exceeded in eukaryotic cells before proliferation or anabolism will proceed.
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PMID:Ionic concomitants of astroglial transformation to reactive species. 223 80

While spreading depression has been shown to be a powerful stimulus in upregulating glial fibrillary acidic protein (GFAP) mRNA expression, the specific physiological signal underlying the upregulation is unknown. During spreading depression, extracellular ionic concentrations are altered markedly. The present study evaluates the role of these changes in extracellular ionic concentrations as potential signals influencing GFAP mRNA expression. Gel foam pledgets saturated with artificial cerebrospinal fluid (CSF) solutions in which [Na+], [Ca2+], [K+] and [H+] were altered one at a time to match concentrations seen in spreading depression were applied to exposed parietal cortex for one hour. Dot and in situ hybridization techniques were used to evaluate GFAP mRNA levels. We found that CSF containing 60 mM KCl produced a dramatic upregulation of GFAP mRNA levels throughout the cerebral cortex of the ipsilateral hemisphere without causing detectable tissue damage. The pattern and time course of the change were similar to those following application of 3 M KCl. Alteration of other ionic species did not affect GFAP mRNA levels. However, the upregulation of GFAP mRNA was not likely due directly to the increased [K+], but rather to the spreading depression that the elevated [K+] induced. This was demonstrated by the finding that the upregulation in GFAP mRNA induced by the potassium exposure was totally blocked by prior administration of MK-801, an NMDA antagonist that blocks spreading depression. These results demonstrate that an upregulation in GFAP mRNA can occur in the absence of degeneration debris and that the initiating events can be related to physiological changes, but that changes in extracellular ionic concentrations are not the likely molecular signals underlying the upregulation.
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PMID:The role of extracellular ionic changes in upregulating the mRNA for glial fibrillary acidic protein following spreading depression. 779 12

Beta-endorphin may induce respiratory depression and bradycardia. Elevated levels of hypoxanthine (HX) in vitreous humour (VH) may possibly indicate hypoxia before death. Furthermore, gliosis in the brain stem may reflect a previous hypoxic/ischaemic injury in the brain. In the present study we relate beta-endorphin immunoreactivity (BENDI) in the CSF to the presence or absence of reactive astrocytosis in the nucleus olivae inferior (NOI). The relationship between the HX concentration in VH and the number of reactive astrocytes in sudden infant death (SID) cases (n = 17) and controls (n = 23) was also studied. The number of reactive astrocytes was examined in the NOI by immunohistochemical demonstration of glial fibrillary acidic protein (GFAP). The BENDI in CSF and the number of reactive astrocytes in the NOI divided the SID victims into two subpopulations (P < 0.01). One had a median of < 4 fmol/ml BENDI in CSF (range < 4) and 2 reactive astrocytes (range 0-15), and was similar to the controls that died from infections. The other subpopulation had a median of 260 fmol/ml BENDI in CSF (range 160-400) and 13 reactive astrocytes (range 7-33), similar to the control infants with previous hypoxia. In this latter SID subpopulation the number of reactive astrocytes correlated positively with BENDI in CSF (r = 0.7, P < 0.05). All the SID victims had elevated levels of HX in VH. In the SID subpopulation with high level of BENDI in CSF and increased number of activated astrocytes, the correlation factor between HX in VH and activated astrocytes was r = 0.7 (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Beta-endorphin immunoreactivity in spinal fluid and hypoxanthine in vitreous humour related to brain stem gliosis in sudden infant death victims. 795 29

The present study evaluates the relative roles of seizure activity and spreading depression in upregulating glial fibrillary acidic protein (GFAP) mRNA expression. Stimulating electrodes were placed bilaterally in the angular bundle, and recording electrodes were placed bilaterally in the dentate gyrus of adult rats. Intense electrographic seizures were induced by delivering stimulus trains through one stimulating electrode. In some cases, spreading depression accompanied the seizures, while in other cases, the seizures occurred in the absence of spreading depression. Animals were killed 24 h following the last stimulus train, and the forebrains were prepared for quantitative in situ hybridization. Seizure activity and spreading depression led to significant increases in GFAP mRNA levels in the hippocampal formation. Seizure activity alone (without spreading depression) induced a 4-fold increase in GFAP mRNA levels in the hilus and molecular layer of the dentate gyrus and in stratum lacunosum-moleculare of the hippocampus. When seizure activity was accompanied by spreading depression, there was a 10-fold increase in GFAP mRNA levels in these same regions. Regional differences within the hippocampal formation in glial cell response were evident. While GFAP mRNA levels in stratum lacunosum-moleculare of the hippocampus were upregulated by seizure activity and spreading depression, levels in hippocampal stratum radiatum of the hippocampus remained unchanged. The results suggest that abnormal neuronal activity can influence glial cell gene expression and that spreading depression is a stronger signal than seizure activity in upregulating GFAP mRNA levels.
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PMID:Spreading depression and reverberatory seizures induce the upregulation of mRNA for glial fibrillary acidic protein. 806 84

Several reports have suggested that exposure to organophosphate pesticides damages the visual system. The prolonged effects of an acute dose of fenthion (dimethyl 3-methyl-4-methylthiophenyl phosphorothionate) were studied on the cholinergic system of the rat retina. Fenthion was administered in a single dose of 0 or 100 mg/kg (sc, in corn oil) to adult, male, Long-Evans rats. The animals were killed 4, 14, or 56 days after treatment and cholinesterase (ChE) activity as well as muscarinic receptor (mChR) function measured in the retina and frontal cortex. Fenthion produced 89% inhibition of ChE activity in both tissues at 4 days, and, although there was recovery, slight (15%) inhibition of the enzyme activity was still observed at 56 days in both tissues. A long-lasting decrease in carbachol-stimulated inositolphosphate (IP) release was observed following fenthion treatment in the retina: IP release was depressed at 4 days and this depression persisted up to 56 days after dosing. The density of mChR in the retina as well as in the cortex was decreased by 14-20% at 4 days and returned to control levels by 56 days. Fenthion had no effect on the metabolism of phospholipids in the retina following intraocular injections of labeled precursors [3H]myo-inositol, [methyl-14C]choline, or [2-3H]glycerol 4 days after fenthion treatment. These prolonged effects of fenthion on mChR function (signal transduction) appear to be specific to the retina as the cortex showed no change in receptor-stimulated IP release even in the presence of significant mChR down-regulation and ChE inhibition. This dose of fenthion did not produce overt morphological changes in the retina or in the cortex, as observed with light microscopy, although an increase in glial fibrillary acidic protein immunoreactivity (GFAP IR) extending from the internal limiting membrane to the external limiting membrane of the retina was noted. This increase in GFAP IR was observed at 14 days and persisted as long as 56 days post-treatment in the retina, but was not noted in the cortex at any of the time points studied. Thus, this long-lasting perturbation in the retinal cholinergic second messenger system induced by fenthion may occur independently of depressed ChE activity and down-regulation of mChR.
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PMID:Fenthion produces a persistent decrease in muscarinic receptor function in the adult rat retina. 817 35

Although tissue culture studies have shown a variety of neurotransmitter receptors on astroglial cells, verifying these observations in adult animals has been difficult and rarely accomplished. In the current study we have used double immunocytochemistry to localize 5-HT1a receptors to astroglial cells in fixed sections of adult rat brain. The astroglial cells were identified using an antibody raised against the astroglial-specific protein glial fibrillary acidic protein (GFAP). To label the 5-HT1a receptor, we used an antibody we recently raised against a unique peptide sequence occurring in the second extracellular loop of the receptor. Our results show that the 5-HT1a receptor occurs in relatively high abundance on astroglial cells. There is regional specificity, the receptor being much more commonly found in septum and hippocampus than striatum. There are also intraregional differences in that even within a single brain region one astrocyte may have very high levels of the receptor while an adjacent cell has none. We propose that the cellular localization of this receptor could have significance in understanding the mechanism of action of 5-HT1a receptor active drugs in alleviating anxiety and depression. The mechanism may be through the release of a neurotrophic agent, S-100 beta, from astrocytes. This factor may then cause regeneration or sprouting of neuronal terminals which have been lost due to a disease process.
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PMID:Localization of 5-HT1A receptors to astroglial cells in adult rats: implications for neuronal-glial interactions and psychoactive drug mechanism of action. 821 6

The expression of the nuclear c-JUN, JUN B, JUN D, c-FOS, FOS B, KROX-24, and CREB transcription factors was investigated in the cortex of adult rats by immunocytochemistry. The expression patterns were studied in untreated rats and up to 24 hours following topical application of 1 M KCl to the cortical surface (KCl) or i.v. injection of bicuculline (BIC). Topical KCl induced cortical spreading depression and systemic injection of bicuculline evoked generalized tonic-clonic seizures. In untreated rats, JUN B, c-FOS, and FOS B were expressed in a small number of neurons in the piriform, perirhinal, entorhinal, and insular cortex and in layers II, III, and VI of all neocortical areas. In contrast, c-JUN, JUN D, and KROX-24 were expressed in all cortical layers but with different intensities of immunoreactivity (IR): c-JUN-IR was generally weak and predominantly present in layers II, III, and VI. JUN D-IR was equally strong in all layers. KROX-24 showed a prominent expression in layers II, IV, and VI. The CREB protein exhibited a slight preponderance in layer II and piriform cortex. Following KCl or BIC, a strong induction was seen for c-FOS, JUN B, and KROX-24, whereas c-JUN, JUN D, and FOS B showed only a moderate increase compared to basal levels. Changes of CREB-IR could not be detected. The localization of induced JUN, FOS, and KROX proteins reflected the pattern of labelling in untreated animals but demonstrated a higher intensity of labelling and an increased number of immunoreactive nuclei. The intensity and persistence of IR as well as the number of labelled cells following BIC exceeded those following KCl. Following BIC, increased levels of FOS B and JUN D were still present after 24 hours. Counterstaining with cresyl-violet and GFAP, a marker for astrocytes, revealed that JUN, FOS, and KROX proteins were expressed in neurons but not in glial cell populations. The present data demonstrate that CREB, JUN, FOS, and KROX transcription factors exhibit a layer-specific expression in the cerebral cortex with only slight area-specific differences both in untreated rats and following stimulation with KCl and BIC. The expression of transcription factor proteins indicate complex molecular genetic changes in cortical neurons due to pathophysiological events such as seizure activity and spreading depression.
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PMID:JUN, FOS, KROX, and CREB transcription factor proteins in the rat cortex: basal expression and induction by spreading depression and epileptic seizures. 834 7


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