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Biomedical subjects

O Lindvall

Publications and source records attributed to O Lindvall.

At least 109 records · Page 6Linked to original sources
PubMed1994

Biphasic differential changes of GABAA receptor subunit mRNA levels in dentate gyrus granule cells following recurrent kindling-induced seizures.

GABAA receptor alpha 1, beta 3 and gamma 2 subunit mRNA levels have been measured in hippocampus using in situ hybridization, following 1, 10 and 40 seizures produced by rapid kindling stimulations. Major alterations of gene expression were largely confined to the dentate gyrus. One stimulus-induced seizure reduced gamma 2 mRNA levels in the dentate gyrus by 30%. In contrast, mRNA expression increased for alpha 1 in CA1 and CA3 and for beta 3 in CA1 to around 30% above control values. Ten stimulations reduced beta 3 (by 19%) and gamma 2 (by 37%) mRNA expression in the dentate gyrus. No changes were observed in other hippocampal subregions. Forty kindling-induced seizures led to biphasic alterations of subunit mRNA levels in dentate gyrus with only minor changes in CA1-CA3. Up to 4 h after the last seizure mRNA expression for alpha 1 was slightly decreased in dentate gyrus, whereas marked reductions were observed for beta 3 and gamma 2 (by 41% and 48%, respectively). Between 12 and 48 h there were major increases of alpha 1 (by 59%) and gamma 2 (by 35%) mRNA levels but no significant changes of beta 3 mRNA expression. Subunit mRNA levels had returned to control values after 5 days, which argues against a direct involvement of GABAA receptor in kindling-evoked hyperexcitability. The rapid and transient, biphasic changes of GABAA receptor subunits following recurrent seizures could play an important role in stabilizing granule cell excitability, thereby reducing seizure susceptibility. The differential regulation of subunit mRNA levels following seizures suggests a novel mechanism for changing the physiological properties of dentate granule cells through possible GABAA receptor complexes with different subunit composition.

Animals↗
PubMed1994

Clinical application of cell transplantation and neurotrophic factors in CNS disorders.

Cell transplantation and administration of neurotrophic factors are now being explored as new therapeutic strategies to restore and preserve function in the diseased human central nervous system. Neural grafts show long-term survival and restore function in patients with Parkinson's disease, but the symptomatic relief needs to be increased. Cell transplantation also seems justified in patients with Huntington's disease and, possibly, in demyelinating disorders. Clinical trials with neurotrophic factors have been initiated in amyotrophic lateral sclerosis, dementia and Huntington's disease, and may later be started in Parkinson's disease and after acute brain insults. However, it remains to be shown if neurotrophic factors can rescue damaged cells in the brain and spinal cord of patients with these disorders.

Animals↗
PubMed1993

Coexpression of neurotrophins and their receptors in neurons of the central nervous system.

Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are neuronal survival molecules which utilize the Trk family of tyrosine kinase receptors. Using double-label in situ hybridization, we demonstrate that mRNAs for BDNF and its high-affinity receptor TrkB are coexpressed in hippocampal and cortical neurons. Also, a large number of neurons in these areas coexpress NGF and BDNF mRNAs. Epileptic seizures lead to increased levels of both BDNF/TrkB and NGF/BDNF mRNAs in double-labeled cells. Our results show that individual neurons of the central nervous system can coexpress neurotrophins and their receptors and produce two neurotrophic factors. These factors could support neuronal survival after brain insults, not only via retrograde transport but also through autocrine mechanisms.

Animals↗
PubMed1993

Specific functions of grafted locus coeruleus neurons in the kindling model of epilepsy.

Grafts of fetal noradrenaline (NA)-rich locus coeruleus (LC) tissue implanted bilaterally into the hippocampus in 6-hydroxydopamine (6-OHDA) treated, hyperexcitable rats retard seizure development in hippocampal kindling. We report that bilateral intrahippocampal LC grafts failed to affect the severity of seizures when implanted in 6-OHDA-treated, already kindled rats. Furthermore, a noradrenergic hyperinnervation of the hippocampus, produced by grafting fetal LC tissue into the intact brain, did not influence hippocampal kindling development. Kindling leads to long-term reduction in basal hippocampal NA release from the intrinsic locus coeruleus system as monitored using intracerebral microdialysis. This deficit could be reversed by intrahippocampal LC grafts implanted into previously kindled rats. However, these unilateral grafts had no effect on the severity of the kindled convulsions despite a noradrenergic hyperinnervation of the hippocampus around the grafts. In conclusion, these data show a distinct functional specificity of intrahippocampal LC grafts in the kindling model of epilepsy. Similar to the intrinsic noradrenergic system, the grafted neurons have a major inhibitory influence on seizure development but are ineffective against established convulsions.

Animals↗
PubMed1993

Platelet-derived growth factor promotes survival of rat and human mesencephalic dopaminergic neurons in culture.

The effect of two isoforms of platelet-derived growth factor (PDGF), PDGF-AA and PDGF-BB, was tested on dissociated cell cultures of ventral mesencephalon from rat and human embryos. PDGF-BB but not PDGF-AA reduced the progressive loss of tyrosine hydroxylase- (TH)-positive neurons in rat and human cell cultures. The mean number of TH-positive cells in the PDGF-BB-treated rat culture was 64% and 106% higher than in the control cultures after 7 and 10 days in vitro, respectively. Corresponding figures for human TH-positive neurons were 90% and 145%. The influence of PDGF-BB was specific for TH-positive neurons and not a general trophic effect, since no change of either total cell number or metabolic activity was found. In PDGF-BB-treated cultures of human but not rat tissue the TH-positive neurons had longer neurites than observed in control or PDGF-AA-treated cultures. These data indicate that PDGF-BB may act as a trophic factor for mesencephalic dopaminergic neurons and suggest that administration of PDGF-BB could ameliorate degeneration and possibly promote axonal sprouting of these neurons in vivo.

Animals↗
PubMed1993

Rapid increase of BDNF mRNA levels in cortical neurons following spreading depression: regulation by glutamatergic mechanisms independent of seizure activity.

Levels of mRNA for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and the tyrosine kinase receptors trkB and trkC have been studied using in situ hybridization in the rat brain after topical application of KCl to the cortical surface (which induces spreading depression). Repeated episodes of spreading depression during 2 h caused a rapid and marked increase of BDNF mRNA levels in deep and, in particular, superficial cortical layers of the ipsilateral hemisphere (to 213 and 417% of control, respectively). Maximal levels were reached within 2 h after the cessation of spreading depression and at 24 h BDNF mRNA expression had returned to control values. Levels of BDNF mRNA were unaffected in the hippocampus, in areas outside the cerebral cortex and in the contralateral hemisphere. Furthermore, no change of the expression of mRNA for NGF, NT-3, trkC or the full length trkB receptor was detected at any time point. However, at 2 h after spreading depression there was an increased level (150% of control) in superficial cortical layers of mRNA hybridizing to an oligonucleotide probe detecting both truncated receptors lacking the tyrosine kinase domain and full length trkB receptors. Also one single episode of spreading depression gave rise to a significant increase of cortical BDNF mRNA levels (to 207% of control), which was attenuated (by 61%) after administration of the competitive NMDA receptor antagonist CGS 19755. The results provide evidence that mild brain insults associated with glutamate release and elevated intracellular calcium, such as spreading depression, also in the absence of seizure activity can lead to activation of the BDNF gene in cortical neurons.

Analysis of Variance↗
PubMed1993

Differential regulation of N-methyl-D-aspartate receptor subunit messenger RNAs in kindling-induced epileptogenesis.

N-methyl-D-aspartate-receptors are implicated in several neuropathological conditions including epilepsy. As a model of complex partial seizures, rapid hippocampal kindling was chosen to investigate changes in the expression of messenger RNAs encoding the N-methyl-D-aspartate-receptor subunits NR1, NR2A and NR2B both during and in the period immediately following the induction of the kindled state. The study demonstrates a cell-specific, time-dependent modulation of the N-methyl-D-aspartate-receptor subunit messenger RNAs almost entirely restricted to the granule cells of the dentate gyrus. In partially kindled animals (10 stimulations), while the NR1 subunit messenger RNA remained unaltered after a period of 2 h, the NR2A and NR2B subunit messenger RNAs were bilaterally reduced in dentate gyrus granule cells by around 50% below control values. In fully kindled animals (40 stimulations), a progressive reduction in NR1 subunit messenger RNA levels in the dentate gyrus was observed, being maximal after 4 h (-67%). At the same time point, NR2A and NR2B transcript levels were transiently increased by 102% and 46% above control values, respectively. These data point to a differential regulation of N-methyl-D-aspartate-receptor subunit messenger RNAs. No alterations were detected in pyramidal cells. Long-term maintenance of the kindled state was not associated with alterations in N-methyl-D-aspartate-receptor subunit messenger RNAs since control levels of messenger RNA were attained by 12 h and persisted for at least five days. The early changes in messenger RNAs described in this study indicate that the expression of N-methyl-D-aspartate-receptor subunits is under independent regulatory control. This phenomenon may contribute to epileptogenesis and to kindling-associated plasticity by mediating a structural reorganization of N-methyl-D-aspartate-receptors, leading to an altered excitability of dentate gyrus granule cells.

Animals↗
PubMed1993

Regulation of neurotrophin and trkA, trkB and trkC tyrosine kinase receptor messenger RNA expression in kindling.

Levels of messenger RNA for nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and the tyrosine kinase receptors trkA, trkB and trkC have been studied using in situ hybridization in the rat brain 2 h and four weeks after kindling-induced seizures. Epileptiform activity evoked by hippocampal stimulation and exceeding 70 s lead to a concomitant and transient increase of brain- derived neurotrophic factor, nerve growth factor, trkB and trkC messenger RNA expression in dentate granule cells after both focal and generalized seizures. Brain-derived neurotrophic factor messenger RNA levels were also increased bilaterally in the CA1-CA3 regions, amygdala and the piriform, entorhinal, perirhinal, retrosplenial and temporal cortices after generalized seizures. The magnitude of the increases was similar throughout the development of kindling and in the fully kindled brain. No changes of trkA messenger RNA were observed. In amygdalar kindling, elevated brain-derived neurotrophic factor messenger RNA levels developed more rapidly in the amygdala-piriform cortex than after stimulation in the hippocampus but changes in the hippocampal formation were only seen in few animals. Intraventricular 6-hydroxydopamine or a bilateral fimbria-fornix lesion did not alter basal expression or seizure-evoked changes in messenger RNA levels for neurotrophins or trk receptors but increased the number of animals exhibiting elevated levels after the first stimulation, probably due to a prolongation of seizure activity. Both in sham-operated and fimbria-fornix-lesioned rats seizure activity caused a marked reduction of neurotrophin-3 messenger RNA levels in dentate granule cells. The results indicate that activation of the brain-derived neurotrophic factor gene, at least in dentate granule cells, is an "all-or-none" type of response and dependent on the duration but not the severity of seizures or the stage of kindling epileptogenesis. Changes in brain-derived neurotrophic factor, nerve growth factor, neurotrophin-3 and trkB and trkC were observed concomitantly in the dentate gyrus, which suggests that seizure activity sets in motion a cascade of genomic events possibly mediated via a common mechanism. Since altered messenger RNA levels outside hippocampus were detected only for brain-derived neurotrophic factor, neurotrophin and trk gene expression in these regions seems to be regulated differently.

Amygdala↗
PubMed1993

Increased production of the TrkB protein tyrosine kinase receptor after brain insults.

The protein-tyrosine kinases Trk, TrkB, and TrkC are signal-transducing receptors for a family of neurotrophic factors known as the neurotrophins. Here we show that seizures induced by hippocampal kindling lead to a rapid, transient increase of trkB mRNA and protein in the hippocampus. TrkB is a component of a high affinity receptor for brain-derived neurotrophic factor (BDNF). No change was detected in mRNAs for Trk or TrkC, components of the high affinity nerve growth factor or neurotrophin-3 receptors, respectively. trkB mRNA was also transiently increased in the dentate gyrus following cerebral ischemia and hypoglycemic coma; these treatments had no effect on trk and trkC mRNAs. The increase in trkB mRNA and protein showed the same time course and distribution as the increase in BDNF mRNA. These data suggest that BDNF and its receptor may play a local role within the hippocampus in kindling-associated neural plasticity and in neuronal protection following epileptic, ischemic, and hypoglycemic insults.

Animals↗
PubMed1992

Bilateral fetal mesencephalic grafting in two patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

BACKGROUND: Intracerebral transplantation of fetal dopaminergic neurons is a promising new approach for the treatment of Parkinson's disease. Patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have a relatively stable lesion limited to the nigrostriatal system, rendering them ideal candidates for transplantation. Improvement of motor function after neural grafting has previously been observed in nonhuman primates with MPTP-induced parkinsonism. METHODS: We grafted human fetal tissue from the ventral mesencephalon (obtained six to eight weeks after conception) bilaterally to the caudate and putamen in two immunosuppressed patients with severe MPTP-induced parkinsonism, using a stereotaxic technique. The patients were assessed regularly with clinical rating scales, timed tests of motor performance, and [18F]fluorodopa positron-emission tomography during the 18 months before the operation and the 22 to 24 months after the operation. RESULTS: Both patients had substantial, sustained improvement in motor function and became much more independent. Postoperatively, the second patient's maintenance dose of levodopa was decreased to 150 mg daily, which was 30 percent of the original dose. Striatal uptake of fluorodopa was unchanged 5 to 6 months postoperatively but was markedly and bilaterally increased at 12 to 13 and 22 to 24 months in both patients, closely paralleling the patients' clinical improvement. There were no serious complications. CONCLUSIONS: Bilateral implantation of fetal mesencephalic tissue can induce substantial long-term functional improvement in patients with parkinsonism and severe dopamine depletion and is accompanied by increased uptake of fluorodopa by the striatum. The results in these patients resemble those obtained in MPTP-treated primates and suggest that this will be a useful model for the assessment of transplantation therapies in Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

Long distance directed axonal growth from human dopaminergic mesencephalic neuroblasts implanted along the nigrostriatal pathway in 6-hydroxydopamine lesioned adult rats.

Dissociated ventral mesencephalon of 6 to 8-week-old human embryos were implanted by stereotaxic injection at different sites along the nigrostriatal pathway in adult rats, previously subjected to a 6-hydroxydopamine lesion of the intrinsic mesotelencephalic dopamine pathways. The recipients were immunosuppressed by daily injections of cyclosporin A to prevent rejection. At 13-20 weeks after transplantation, the implanted human neurons and their associated fiber outgrowths were visualized with a species-specific antibody recognizing human, but not rat, intermediary neurofilaments (HNF). From implants placed in the host rostral mesencephalic region, HNF-positive axonal projections were seen to extend in large numbers rostrally along the medial forebrain bundle and the internal capsule, and ramify within the caudate putamen, the ventral striatum and the amygdaloid nuclei (a distance of about 5-6 mm), and more sparsely in the frontal cortex and the olfactory bulb (a distance of about 10 mm). From implants placed in the internal capsule, abundant HNF-positive axons extended in the rostral, but not caudal, direction along the myelinated fiber bundles into the caudate putamen and the ventral striatum. Tyrosine hydroxylase (TH) immunohistochemistry revealed that the vast majority of the rostrally projecting HNF-positive axons were also TH-positive, and that the graft-derived axons gave rise to dense TH-positive terminal networks, above all in large areas of the previously denervated caudate putamen. From control implants of cortical neuroblasts, axonal projections were seen along the medial forebrain bundle and the internal capsule, but the axons were TH-negative and showed only sparse projections to the striatal areas. Instead, dense projections were seen, e.g., in the frontal cortex. The results demonstrate a remarkable ability of human mesencephalic neuroblasts to extend axons along the trajectories of the nigrostriatal and mesolimbocortical pathways to reach and innervate the principal striatal and limbic target areas in the forebrain. This shows that the basic requirements for the formation of long axonal pathways may be present in the adult mammalian central nervous system (CNS) at least for certain types of projection neurons. Furthermore, it implies that the developing human neuroblasts can escape the inhibitory features known to be present along myelinated growth trajectories in the adult mammalian brain. In addition, the present approach may offer new possibilities for functional neural grafting in the rat Parkinson model, since transplanted nigral neurons placed in their natural position within the rostral mesencephalon could provide an anatomically and functionally more integrated system than the standard model with ectopically placed intrastriatal nigral grafts.

Animals↗
PubMed1992

Widespread increase of nerve growth factor protein in the rat forebrain after kindling-induced seizures.

Nerve growth factor (NGF) protein levels were determined in various forebrain regions using a two-site immunoassay following kindling-induced seizures. In the dentate gyrus the NGF content was significantly elevated 7 days after the last seizure (to 152% of control). In the piriform and parietal cortices, maximal increases were seen at 12 h (to 261% of control) and at 24 h (to 169% of control), respectively, and the NGF content was then normalized at 7 days. The increased production of NGF might be a protective response or could be involved in plastic changes underlying kindling epileptogenesis.

Animals↗
PubMed1992

Differential regulation of mRNAs for nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 in the adult rat brain following cerebral ischemia and hypoglycemic coma.

In situ hybridization was used to study expression of mRNAs for members of the nerve growth factor (NGF) family in the rat brain after 2 and 10 min of forebrain ischemia and 1 and 30 min of insulin-induced hypoglycemic coma. Two hours after the ischemic insults, the level of brain-derived neurotrophic factor (BDNF) mRNA was markedly increased in the granule cells of the dentate gyrus, and at 24 h it was still significantly elevated. NGF mRNA showed a pronounced increase 4 h after 2 min of ischemia but had returned to a control level at 24 h. Both 2 and 10 min of ischemia caused a clear reduction of the level of mRNA for neurotrophin 3 (NT-3) in the dentate granule cells and in regions CA2 and medial CA1 of the hippocampus 2 and 4 h after the insults. The increase of BDNF mRNA could be partially blocked by the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist NBQX but was not influenced by the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801. Both NBQX and MK-801 attenuated the decrease of NT-3 mRNA after ischemia. One and 30 min of hypoglycemic coma also induced marked increases in BDNF and NGF mRNA in dentate granule cells with maximal levels at 2 h. If the changes of mRNA expression lead to alterations in the relative availability of neurotrophic factors, this could influence functional outcome and neuronal necrosis following ischemic and hypoglycemic insults.

Animals↗
PubMed1992

Transplantation of fetal dopamine neurons in Parkinson's disease: one-year clinical and neurophysiological observations in two patients with putaminal implants.

Ventral mesencephalic tissue from aborted human fetuses (age, 6-7 weeks' postconception) was implanted unilaterally into the putamen using stereotaxic surgery in 2 immunosuppressed patients (Patients 3 and 4 in our series) with advanced idiopathic Parkinson's disease. Tissue from 4 fetuses was grafted to each patient. Compared with our previous 2 patients, the following changes in the grafting procedure were introduced: the implantation instrument was thinner, more tissue was placed in the operated structure, and the time between abortion and grafting was shorter. There were no postoperative complications. Both patients showed a gradual and significant amelioration of parkinsonian symptoms (most marked in Patient 3) starting at 6 and 12 weeks after grafting, respectively, reaching maximum stability at approximately 4 to 5 months; patients remained relatively stable thereafter during the 1-year follow-up period. Clinical improvement was observed as a reduction of the time spent in the "off" phase and the number of daily "off" periods; a lessening of bradykinesia and rigidity during the "off" phase, mainly but not solely on the side contralateral to the graft; and a prolongation and change in the pattern of the effect of a single dose of L-dopa. Neurophysiological measurements revealed a more rapid performance of simple and complex arm and hand movements bilaterally, but primarily contralateral to the graft. The results indicate that patients with Parkinson's disease can show significant and sustained improvement of motor function after intrastriatal implantation of fetal dopamine-rich mesencephalic tissue. The accompanying paper by Sawle and colleagues describes the results of repeated positron emission tomography scans in these patients.

Combined Modality Therapy↗
PubMed1992

Transplantation of fetal dopamine neurons in Parkinson's disease: PET [18F]6-L-fluorodopa studies in two patients with putaminal implants.

Two patients with Parkinson's disease who underwent implantation of fetal mesencephalic tissue into the putamen were serially studied using positron emission tomography and [18F]6-L-fluorodopa ([18F]dopa). The uptake of [18F]dopa is related to the functional integrity of the presynaptic dopaminergic system. Preoperative studies revealed a marked decrease in putamen [18F]dopa uptake, with lesser involvement of the caudate. Two and 4 months, respectively, after operation, both patients demonstrated functional improvement, as described elsewhere. One patient was scanned 5, 8, and 13 months after the operation and the other was scanned 7 and 12 months after the operation. In both patients, [18F]dopa uptake increased within the operated putamen despite a progressive decrease in tracer uptake in the unoperated striatal structures. We believe that this increased uptake of [18F]dopa at the implantation site represents functional integrity within a surviving neural graft. While there has been little further clinical improvement beyond the fifth postoperative month, the uptake of [18F]dopa at the operation site in both patients has progressively increased. The kinetic data provide evidence of disease progression in the unoperated striatum, which, balanced against increasing graft function, may explain why clinical improvement reached a plateau within months after surgery.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗