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Biomedical subjects

M Dragunow

Publications and source records attributed to M Dragunow.

At least 91 records · Page 5Linked to original sources
PubMed1994

Activation of pirenzepine-sensitive muscarinic receptors induces a specific pattern of immediate-early gene expression in rat brain neurons.

Accumulating evidence suggests that immediate-early gene transcription factors such as c-Fos, form part of an intracellular signalling pathway linking the activation of neuronal receptors by neurotransmitters to changes in neuronal gene expression. Recently it has been demonstrated that the centrally active muscarinic receptor agonist pilocarpine induces both c-fos mRNA and protein in rat brain. In this report using immunocytochemical and in situ hybridization techniques we demonstrate for the first time that in addition to c-fos, pilocarpine administration increases the neuronal expression of jun-B, krox-20 and krox-24 (zif-268) but not related c-jun and jun-D genes in rat cortex and hippocampus. Pretreatment of animals with atropine or pirenzepine significantly reduced induction of c-fos, jun-B, krox-20 and krox-24 genes in both hippocampus and cortex. These results show that activation of pirenzepine-sensitive muscarinic receptors results in a specific pattern of immediate-early gene expression in rat brain neurons. We suggest that the combinatorial complexity of immediate-early gene induction may allow receptor-specific control of gene expression in vivo.

Animals↗
PubMed1994

Clozapine and haloperidol produce a differential pattern of immediate early gene expression in rat caudate-putamen, nucleus accumbens, lateral septum and islands of Calleja.

Acute administration of the typical neuroleptic haloperidol (HAL, 2 mg/kg) induced the immediate-early gene proteins (IEGPs) c-Fos, Fos-related antigens (FRAs), FosB, JunB, JunD and Krox24 in the striatum and nucleus accumbens of the rat brain. In contrast, acute administration of the atypical antipsychotic drug clozapine (CLOZ, 30 mg/kg) induced only FRAs, JunB and Krox24 IEGPs in the striatum, and c-Fos, FRAs, and Krox24 IEGPs in the nucleus accumbens. c-Jun was not induced by acute administration of HAL or CLOZ in the rat brain. Differential induction of IEGs by HAL and CLOZ was also observed in the lateral septal nucleus and the islands of Calleja complex of the rat brain. These differences in IEG induction by HAL and CLOZ may be related to the different clinical profiles of the two drugs. Specifically, CLOZ induces FRAs in the islands of Calleja and lateral septum and this action may be involved in its therapeutic effects on the negative symptoms of schizophrenia, whereas HAL produces a coordinate induction of Fos and JunB in striatal neurons and this dimer combination may be involved in producing the extrapyramidal side-effects of typical neuroleptics.

Animals↗
PubMed1994

Immediate-early gene protein expression in neurons undergoing delayed death, but not necrosis, following hypoxic-ischaemic injury to the young rat brain.

A unilateral hypoxia-ischaemia (HI) 21-day-old rat preparation was used to assess the effects of HI on the expression of the immediate-early gene proteins (IEGPs) c-Fos/FRAs, Fos B, c-Jun, Jun B, Jun D, Krox 20, Krox 24, and on the mRNA for the neurotrophic factor, brain-derived neurotrophic factor (BDNF). Moderate HI (15 min hypoxia) produced delayed, selective neuronal death and was associated with a rapid induction of c-Fos, Fos B, Jun B, Jun D, and c-Jun proteins, but not Krox 20 protein or BDNF mRNA, in neurons on the side of HI and also a delayed expression of c-Jun (and to a lesser extent c-Fos/FRA's and Fos B) 24-48 h after HI in neurons that underwent delayed neuronal death. Krox 24 showed an initial induction followed by a long-lasting suppression of its expression in regions undergoing cell loss. Severe HI (60 min hypoxia) resulted in seizures and rapid neuronal loss and infarction (necrotic cell death) on the side of HI, and was associated with early induction of c-Fos, Fos B, c-Jun, Jun B, Jun D, Krox 20 and Krox 24 protein and BDNF mRNA in neurons on the non-ligated side of the brain. Fos, c-Jun, Jun B, Jun D and Krox 24, but not Krox 20, Fos B, or BDNF mRNA, were also induced in non-nerve cells on the damaged side of the brain after both moderate and severe HI, and many of these cells appeared to be dividing. Thus, moderate HI induces IEGP's in neurons and non-nerve cells in damaged regions, whereas severe HI induces IEGP's and BDNF in non-damaged regions. c-Jun (and to a lesser extent c-Fos/FRA's) showed a prolonged expression in neurons undergoing delayed, but not necrotic, cell death suggesting that they may be involved in the biochemical cascade that causes selective delayed neuronal death. BDNF was not induced by HI, and therefore, does not appear to play an endogenous neuroprotective role in the CNS.

Animals↗
PubMed1994

Status epilepticus may be caused by loss of adenosine anticonvulsant mechanisms.

The inhibitory neuromodulator adenosine is an endogenous anticonvulsant that terminates brief seizures in the brain and it has been proposed that loss of adenosine or adenosine-mediating systems may play a major role in the development of status epilepticus, a seizure condition characterized by prolonged and/or recurrent seizures that last by definition, at least 20 min. In this study, the effect of specific A1-adenosine agonists and antagonists were tested for their ability to prevent and cause status epilepticus in two electrical stimulation models in rats. In a recurrent electrical stimulation model, whereas no vehicle-treated animals developed status epilepticus after 20 recurrent electrical stimulations, rats injected with 10 mg/kg of the specific A1-adenosine antagonist 8-cyclopentyl-1,3-dimethylxanthine intraperitoneally developed status epilepticus after stimulation. 8-(p-Sulphophenyl)-theophylline, which has limited penetrability into the brain when administered peripherally, did not cause status epilepticus when injected intraperitoneally. However, when 200 micrograms of 8-(p-sulphophenyl)-theophylline were administered intracerebroventricularly, status epilepticus developed in all animals, suggesting status epilepticus developed as a result of central adenosine receptor antagonism. In the second study, whereas all vehicle-treated animals developed status epilepticus after constant electrical stimulation, administration of N6-cyclohexyladenosine and N6-cyclopentyladenosine prior to stimulation suppressed the development of status epilepticus. N6-Cyclohexyladenosine was also effective in terminating status epilepticus after it had progressed for 20 min. The effects of a selective A2-agonist was also tested on both stimulation models and had no anticonvulsant effects. An electrical stimulus given to rats pretreated three days prior to stimulation with pertussis toxin, a compound which inactivates Gi-proteins, also resulted in generalized status epilepticus, suggesting that impairment of G-protein-linked receptors is involved in the development of status epilepticus. The effects of a GABAB antagonist, phaclofen, and a GABAB agonist, baclofen, were also tested in the recurrent stimulation model, as GABAB receptors are also coupled to the same subset of K+ channels as the A1-receptor. Rats given phaclofen did not develop status epilepticus after recurrent electrical stimulation, although baclofen was effective at preventing the induction of status epilepticus in the constant stimulation model. These results, together with some preliminary data obtained showing that the GABAA antagonist picrotoxin did not cause status epilepticus after recurrent stimulation, suggest that loss of GABAergic inhibition only has a minor role in status epilepticus development in our models. Brains from all animals were also assessed for brain injury.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine↗
PubMed1993

c-fos antisense generates apomorphine and amphetamine-induced rotation.

Sodium pentobarbital anaesthetized rats were injected ipsilaterally with an antisense oligonucleotide to c-fos and contralaterally with a sense of oligonucleotide to c-fos in the striatum. Ten hours later they were injected with amphetamine or apomorphine and their behaviour was observed for a further 2 h at which time they were overdosed with anaesthetic and their brains were removed, frozen and processed for Fos and Jun B immunohistochemistry. Rats showed amphetamine- and apomorphine-induced rotation towards the antisense injected striatum. The antisense oligonucleotide also strongly inhibited the amphetamine-induced expression of c-Fos and Jun B in striatal neurones. These results suggest that antisense to c-fos produces a biochemical change in the injected striatum that then, 10 h later, blocks amphetamine- and apomorphine-induced behavioural and biochemical effects.

Amphetamine↗
PubMed1993

Non-NMDA glutamate receptors are involved in the maintenance of status epilepticus.

The role of N-methyl-D-aspartate (NMDA), non-NMDA glutamate, metabotropic and muscarinic receptors in the maintenance of status epilepticus (SE) was investigated. SE induced in rat brain by continuous electrical stimulation to the hippocampus was terminated by intracerebroventricular (i.c.v.) injection of the non-NMDA antagonists DNQX and NBQX, but not by the muscarinic antagonists scopolamine or atropine, or the metabotropic antagonist AP3. The NMDA antagonist, MK-801 suppressed motor seizure activity but did not terminate electrographic seizures when generalized SE was induced, suggesting that both non-NMDA and NMDA receptors maintain generalized convulsive SE. However, when limbic SE was induced, MK-801 also had an anticonvulsant effect suggesting differences in the mechanisms maintaining limbic SE and generalized SE.

Animals↗
PubMed1993

Brain-derived neurotrophic factor expression after long-term potentiation.

Long-term potentiation (LTP) of perforant-path dentate granule cell synapses, in awake rats, was followed by a time-dependent expression of brain-derived neurotrophic factor (BDNF) mRNA in dentate granule cells. This BDNF expression was blocked by the N-methyl-D-aspartate (NMDA) antagonist dizocilpine maleate (MK-801), which also blocked LTP induction, and by sodium pentobarbital, which shortens LTP persistence. These results suggest that BDNF may participate in the NMDA-receptor mediated cascade of events that result in LTP stabilization.

Animals↗
PubMed1993

Muscarinic receptor-mediated induction of Fos protein in rat brain.

Recent studies have shown that the centrally active muscarinic agonist pilocarpine induces c-fos mRNA in rat cortex. Here we describe the localization of muscarinic receptor-induced FOS protein, within the rat central nervous system (CNS), following administration of pilocarpine (25 mg/kg). High levels of FOS induction were apparent in many forebrain structures including the primary olfactory (piriform) cortex, nucleus accumbens, amygdala, hippocampus, neocortex and supra-optic nucleus of the hypothalamus. Within the neocortex FOS induction followed a laminar distribution being highest in layers 4 and 6 with lower induction seen in layers 2 and 5. Other areas showing FOS induction included the striatum, septum, inferior colliculus, thalamus, hypothalamus and several brainstem nuclei. Both atropine (10 mg/kg) and pirenzepine (100 mg/kg) reduced FOS induction suggesting that a pirenzepine-sensitive muscarinic receptor was involved. The possible significance of muscarinic-mediated FOS induction, to cholinergic kindling and the cholinergic hypothesis of learning and memory, is discussed.

Animals↗
PubMed1993

Differential expression of immediate early genes after hippocampal long-term potentiation in awake rats.

The pattern of expression of fos and jun family immediate early genes following the induction of long-term potentiation (LTP) was investigated in the dentate gyrus of awake rats. Rapid, transient increases in the levels of c-jun and jun-B mRNA and protein, and in the levels of Fos-related proteins (FRAs), occurred in the dentate gyrus after LTP-inducing tetanization of the perforant path. A delayed, and more prolonged induction occurred for jun-D mRNA and protein. The induction of c-Jun, Jun-B, Jun-D and Fos-related proteins was prevented by administration of an N-methyl-D-aspartate receptor antagonist, which also blocked LTP induction, and by pentobarbital, which reduced but did not block LTP. These findings show that differential expression of fos and jun gene family members occurs in a distinct pattern following LTP in awake rats. The responsive genes may participate in the biochemical cascade leading to the long-term stabilization of synaptic modifications.

Animals↗
PubMed1993

Is c-Jun involved in nerve cell death following status epilepticus and hypoxic-ischaemic brain injury?

Neurons undergoing delayed neuronal death produced by hypoxia-ischaemia (HI) or status epilepticus (SE) showed a massive expression of c-Jun in their nuclei 24 h after the insult. With SE there was also a weaker induction of c-Fos and Jun B in dying neurons. SE induced in the presence of the NMDA antagonist MK-801 produced no delayed c-Jun expression in the hippocampus and nerve cell death did not occur in this region, although there was a delayed c-jun expression in the amygdala/piriform region, and cell death occurred in this area. Activation of central muscarinic receptors with pilocarpine, or block of D2 dopamine receptors with haloperidol, treatments which do not cause neuronal damage, strongly induced Fos and Jun B in hippocampal and striatal neurons, but only induced c-Jun very weakly. Thus, c-Jun may participate in the genetic cascade of events that produce programmed cell death in neurons.

Animals↗
PubMed1993

Differential expression of insulin-like growth factor binding proteins (IGFBP) 4 and 5 mRNA in the rat brain after transient hypoxic-ischemic injury.

Recent studies suggest a role for the insulin-like growth factor (IGF) system in the repair of damaged tissue following hypoxic-ischemic injury in the infant rat brain. We have used a unilateral model of hypoxic-ischemic injury to assess the possible involvement of two IGF binding proteins (IGFBPs), IGFBP-4 and IGFBP-5, in the post-asphyxial response. Ligation of the right carotid artery of 21-day-old rats was followed by either 15 min or 60 min exposure to 8% oxygen to produce moderate and severe damage respectively. Using in situ hybridization, the distribution of IGFBP-4 and IGFBP-5 mRNA was determined in brains collected over 10 days following the insult. In the control brains (no damage), both IGFBPs were expressed in distinct regions. IGFBP-4 mRNA was detected in limited areas of the hippocampus and in several cortical layers, while IGFBP-5 mRNA was found primarily in the thalamus. In response to hypoxic-ischemic injury, IGFBP-4 mRNA expression was reduced in regions of neuronal loss, suggesting a neuronal origin for IGFBP-4. The expression of IGFBP-5 mRNA was not altered by the 15 min insult, but was heavily induced from 3 days following the 60 min insult, particularly in the subependymal layer and adjacent white matter on the ligated hemisphere. This suggests that IGFBP-5 may be involved in recovery from severe hypoxic-ischemic injury and may be important in the regeneration of oligodendrocytes.

Animals↗
PubMed1993

Brain-derived neurotrophic factor is induced as an immediate early gene following N-methyl-D-aspartate receptor activation.

Recent studies show that focal brain injury, cerebral ischaemia, hypoglycaemia and seizures increase the expression of c-fos and brain-derived neurotrophic factor in brain. Here we report that hippocampal focal brain injury transiently induces the immediate early genes c-fos, jun-B, c-jun and krox-24 (zif-268) messenger RNA and protein and brain-derived neurotrophic factor messenger RNA in rat dentate gyrus neurons, an effect that was blocked by the N-methyl-D-aspartate receptor antagonist MK-801. Prior administration of the protein synthesis inhibitor cycloheximide super-induced immediate early gene messenger RNA, abolished immediate early gene protein induction, but had no effect on injury-mediated induction of brain-derived neurotrophic factor messenger RNA. Thus, while N-methyl-D-aspartate receptor activation results in the induction of both immediate early genes and brain-derived neurotrophic factor messenger RNA, de novo synthesis of immediate early gene proteins is not critical for the increased expression of brain-derived neurotrophic factor messenger RNA seen in brain after focal injury. These results suggest that brain-derived neurotrophic factor is induced after injury as an immediate early gene.

Animals↗
PubMed1993

Expression of immediate early gene proteins following axotomy and inhibition of axonal transport in the rat central nervous system.

The expression of the immediate early gene-encoded proteins c-Jun, Jun B, Jun D, c-Fos, Fos B and Krox-24 in central neurons following transection of, or inhibition of, axonal transport in their axons was investigated in the rat using immunocytochemistry. Transection of the medial forebrain bundle, which produces an essentially complete axotomy of neurons in the ipsilateral mammillary nucleus, substantia nigra pars compacta, ventral tegmental area and parafascicularis, induced the expression of c-Jun, Jun D and, to a lesser extent, Krox-24, in these nuclei. Microinjection of colchicine into the medial forebrain bundle to chemically inhibit axonal transport similarly induced the expression of these proteins in these areas. The expression of the proteins was first evident 24 h after transection, reached a maximum at 48 h and was still present after 10 days. However, after 30 days the proteins were absent from the substantia nigra, ventral tegmentum and parafascicularis, and were still present only in the mammillary nuclei. The other immediate early genes, Jun B, c-Fos and Fos B, were never expressed above the basal levels seen in untreated rats. Transection of the corpus callosum and the hippocampal commissure, which produces only a partial axotomy of neurons in the cerebral cortex and hippocampus, respectively, did not induce the expression of any of the genes in these neurons. Microinjection of colchicine or vinblastine to produce a localized inhibition of axonal transport in the cerebral cortex, hippocampus, thalamus and cerebellum also induced the expression of c-Jun, Jun D and, again to a lesser extent, Krox-24, in neurons surrounding the injection site. In contrast to this selective expression, administration of the neuronal excitant metrazole induced the expression of all six immediate early gene proteins in central nervous system neurons. These results demonstrate that transection of, or inhibition of, transport in the axons of central neurons induces a particular pattern of expression of transcriptionally operating immediate early genes that may be related to the regenerative competency of the neurons.

Animals↗
PubMed1993

Loss of cannabinoid receptors in the substantia nigra in Huntington's disease.

Previous autoradiographic studies in rats using [3H]CP55,940 have demonstrated the cannabinoid receptor to be located on the axon terminals of striatal efferent neurons projecting to the globus pallidus and substantia nigra. Because these neurons are selectively lost in Huntington's disease, a loss of [3H]CP55,940 binding is predicted in the substantia nigra of the Huntington's disease brain. We have used autoradiography to compare the binding of [3H]CP55,940 in the substantia nigra of Huntington's disease and neurologically normal brains. The results have demonstrated that cannabinoid receptors in the normal human substantia nigra are discreetly localized within the substantia nigra pars reticulata. In contrast, the Huntington's disease brains show a massive loss (97.5%) of cannabinoid receptor binding in the substantia nigra pars reticulata. These results show that in the substantia nigra of the human brain cannabinoid receptors are located on striatonigral terminals which degenerate in Huntington's disease.

Aged↗
PubMed1993

Correlations between immediate early gene induction and the persistence of long-term potentiation.

The duration of long-term potentiation in the dentate gyrus of awake rats was examined following systematic manipulation of the number of stimulus trains delivered. This was correlated with the induction of immediate early genes in separate groups of animals given identical stimulus regimes. Following 10 trains of stimulation, long-term potentiation decayed with a time constant of up to several days (long-term potentiation 2), and this correlated with the appearance of an increase in the messenger RNA and protein levels of zif/268. Increasing the number of stimulus trains resulted in a greater probability of eliciting long-term potentiation with a time constant of several weeks (long-term potentiation 3), as well as increasing the induction of zif/268, c-Jun, Jun-B, Jun-D and Fos-related proteins. When 10 trains were delivered repeatedly on up to five consecutive days, only the zif/268 protein levels showed associated changes. These data provide support for the hypothesis that long-term potentiation 3 involves mechanisms additional to those for long-term potentiation 2. One possible mechanism is altered gene expression, initiated by immediate early gene transcription factors such as zif/268 and possibly homo- or heterodimers of Fos and Jun family members, that then contributes to the stabilization or maintenance of long-term potentiation 3.

Animals↗
PubMed1993

Differential expression of immediate-early proteins in non-nerve cells after focal brain injury.

We investigated the expression of the immediate-early proteins (IEPs, Fos, Fos B, Jun, Jun B, Jun D, Krox 20 and Krox 24) in non-nerve cells in rat brain after mechanical brain injury. Injury produced by infusion of 5 microliters of saline into the hippocampus produced a time-dependent expression of Fos, Jun and Krox 24, but not Fos B, Krox 20 or in non-nerve cells around the wound margin, in cells lining the lateral and third ventricles and in cells in the pial surfaces of the brain. Jun B and D were weakly induced in non-nerve cells 1-4 hr after brain injury. This differential expression of IEPs in non-nerve cells contrasted with neurons which expressed all IEPs measured. Thus, brain injury is associated with a differential expression of IEPs in non-nerve cells around the wound. The functional implications of this IEP expression after brain injury are presently unclear, but may be related to cellular proliferation after brain injury.

Animals↗
PubMed1993

MK801 induces immediate-early gene proteins and BDNF mRNA in rat cerebrocortical neurones.

Recent studies have shown that MK801, a potent phencyclidine receptor ligand, causes pathomorphological changes in rat cerebrocortical neurones. Here we report that doses of MK801 (1 and 5 mg kg-1) which have been shown to produce pathomorphological changes, induce the expression of immediate-early gene proteins (IEGPs) and brain-derived neurotrophic factor (BDNF) mRNA in rat cerebrocortical neurones. Blockade of central muscarinic receptors which has been shown to prevent MK801-induced pathomorphological changes in cerebrocortical neurones, also prevented MK801-induced expression of IEGPs and BDNF mRNA. The transiently increased expression of BDNF mRNA may be an acute compensatory response of these neurones to MK801-induced injury.

Animals↗