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O Lindvall

Publications and source records attributed to O Lindvall.

At least 91 records · Page 5Linked to original sources
PubMed1995

Trophic and protective actions of brain-derived neurotrophic factor on striatal DARPP-32-containing neurons in vitro.

We have examined the effects of either brain-derived neurotrophic factor (BDNF), the BB-isoform of platelet-derived growth factor (PDGF-BB), or a combination of these growth factors on the survival and the morphological development of embryonic striatal neurons grown under serum-free culture conditions. Striatal neurons were identified using immunocytochemistry for "dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein with a molecular weight of 32 kilodalton" (DARPP-32). BDNF and PDGF-BB promoted the survival of DARPP-32-positive neurons, with the magnitude of their effects being comparable. A combination of these growth factors exerted no significant additive effects on cell survival. BDNF stimulated morphological differentiation of DARPP-32-containing neurons by increasing the length of neurites, the number of branching points on the neurites, and the soma area. By contrast, PDGF-BB increased the neurite length and the cell body area, but not the number of branching points. BDNF also protected striatal neurons from excitotoxicity induced by N-methyl-D-aspartate, whereas PDGF-BB had no effect under the same treatment conditions as those for BDNF. Thus, BDNF is trophic for striatal DARPP-32-containing neurons in vitro by enhancing the survival, morphological differentiation and resistance to excitotoxicity, and its mechanisms of action are probably different from those of PDGF-BB.

Animals↗
PubMed1995

Co-expression of TrkB and TrkC receptors in CNS neurones suggests regulation by multiple neurotrophins.

Using double-label in situ hybridization, we have explored the possibility that individual CNS neurones can co-express mRNAs for the high-affinity receptors of brain-derived neurotrophic factor and neurotrophin-3, TrkB and TrkC, respectively. The vast majority of TrkC mRNA-containing neurones in the hippocampal formation and cerebral cortex were also labelled for TrkB mRNA. Cells expressing only TrkB or TrkC mRNA were very scarce in these regions, representing < 15% of all labelled cells. These findings suggest that the same cortical or hippocampal neurone can be regulated by several members of the neurotrophin family, which may be important both during development and in response to physiological activity and pathological conditions.

Animals↗
PubMed1995

Suppressed epileptogenesis in BDNF mutant mice.

Kindling is an animal model of epilepsy in which repeated electrical stimulations lead to progressive and permanent amplification of seizure activity, culminating in generalized convulsions. Each brief period of seizure activity during kindling epileptogenesis causes a marked, transient increase of the synthesis of brain-derived neurotrophic factor (BDNF) in cortical and hippocampal neurons. We find that the development of kindling is markedly suppressed in mice heterozygous for a deletion of the BDNF gene. In contrast, the maintenance of kindling is unaffected. The mutant mice show lower levels of BDNF mRNA in cortical and hippocampal neurons after seizures than do wild-type mice. Hippocampal mossy fiber sprouting is augmented in BDNF mutants but there are no other morphological abnormalities. These results show that BDNF plays an important role in establishing hyperexcitability during epileptogenesis, probably by increasing efficacy in stimulated synapses.

Animals↗
PubMed1995

Regulation of brain-derived neurotrophic factor gene expression after transient middle cerebral artery occlusion with and without brain damage.

Levels of mRNA for c-fos, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), TrkB, and TrkC were studied using in situ hybridization in the rat brain at different reperfusion times after unilateral middle cerebral artery occlusion (MCAO). Short-term (15 min) MCAO, which does not cause neuronal death, induced elevated BDNF mRNA expression confined to ipsilateral frontal and cingulate cortices outside the ischemic area. With a longer duration of MCAO (2 h), which leads to cortical infarction, the increase was more marked and elevated BDNF mRNA levels were also detected bilaterally in dentate granule cells and CA1 and CA3 pyramidal neurons. Maximum expression was found after 2 h of reperfusion. At 24 h BDNF mRNA expression had returned to control values. In the ischemic core of the parietal cortex only scattered neurons were expressing high levels of BDNF mRNA after 15 min and 2 h of MCAO. Analysis of different BDNF transcripts showed that MCAO induced a marked increase of exon III mRNA but only small increases of exon I and II mRNAs in cortex and hippocampus. In contrast to BDNF mRNA, elevated expression of c-fos mRNA was observed in the entire ipsilateral cerebral cortex, including the ischemic core, after both 15 min and 2 h of MCAO. Two hours of MCAO also induced transient, bilateral increases of NGF and TrkB mRNA levels and a decrease of NT-3 mRNA expression, confined to dentate granule cells. The upregulation of BDNF mRNA expression in cortical neurons after MCAO is probably triggered by glutamate through a spreading depression-like mechanism. The lack of response of the BDNF gene in the ischemic core may be due to suppression of signal transduction or transcription factor synthesis caused by the ischemia. The observed pattern of gene expression after MCAO agrees well with a neuroprotective role of BDNF in cortical neurons. However, elevated levels of NGF and BDNF protein could also increase synaptic efficacy in the postischemic phase, which may promote epileptogenesis.

Animals↗
PubMed1995

Specific effects of platelet derived growth factor (PDGF) on fetal rat and human dopaminergic neurons in vitro.

The neurotrophic effects of the BB isoform of platelet-derived growth factor (PDGF) on rat and human fetal mesencephalic dopaminergic neurons have been characterized in vitro. A dose-response analysis demonstrated maximal responses at 30 ng/ml of PDGF-BB. This concentration resulted in a marked increase in the survival and neurite outgrowth from rat and human tyrosine hydroxylase-(TH) positive, presumed dopaminergic neurons after 7 days in vitro. The effects of PDGF-BB on survival of TH-positive neurons were comparable to those of brain-derived neurotrophic factor (BDNF), whereas neurite outgrowth was more pronounced after addition of BDNF. The combination of BDNF and PDGF-BB yielded no additive effects. Double immunohistochemical staining of rat cultures demonstrated PDGF beta-receptors on about 90% of the TH-positive neurons. PDGF-BB treatment of rat mesencephalic cultures induced an upregulation of c-fos and TH mRNA with maximal levels after 0.5-2 h as assessed by quantitative PCR analysis. An increased number of Fos protein-positive cells was detected immunohistochemically after 4 h of PDGF-BB treatment. The present results provide further evidence for specific and direct effects of PDGF-BB on gene expression, survival and neurite outgrowth of mesencephalic dopaminergic neurons of rat and human origin.

Animals↗
PubMed1995

Protective effects of BDNF and NT-3 but not PDGF against hypoglycemic injury to cultured striatal neurons.

Brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and platelet-derived growth factor (PDGF) exert trophic effects on striatal neurons in vitro, which raises the possibility that these growth factors might also counteract neuronal death provoked by various insults. We have found that BDNF and NT-3, but neither PDGF-AA nor -BB, added 24 h before the insult ameliorated hypoglycemic neuronal damage induced by 15 or 24 h of glucose deprivation in rat striatal cell cultures. BDNF and NT-3 afforded neuronal protection even when administered 8 or 4 h, respectively, after the onset of hypoglycemia. In normoglycemic striatal cultures exposed to these neurotrophins for several days, there was a slight, nonsignificant increase of the number of surviving microtubule-associated protein-2-positive cells (20-30%) compared to untreated control cultures, but no change of glial cells. Exposure of the cultures to BDNF or NT-3 produced a significant increase in the number of neurons expressing detectable levels of the calcium-binding protein, calbindin, suggesting that a stabilization of calcium homeostasis might be implicated in the neuroprotection. Immunocytochemical analysis revealed that the majority (70-80%) of neurons in the striatal cultures expressed TrkB and TrkC, the functional receptors for BDNF and NT-3, respectively, implying that the effects of the neurotrophins are most likely direct. These data indicate that BDNF and NT-3 can protect striatal neurons against hypoglycemia in vitro and raise the possibility that these neurotrophins could counteract striatal neuronal death induced by hypoglycemic and ischemic insults in vivo.

Animals↗
PubMed1995

Pen injected apomorphine against off phenomena in late Parkinson's disease: a double blind, placebo controlled study.

The effect, therapeutic dose range, and pharmacokinetics of apomorphine, given as subcutaneous injections by a single use pen, were evaluated in the treatment of off phenomena in 22 patients with idiopathic Parkinson's disease. At study entry a placebo controlled apomorphine test was performed, and apomorphine doses were then individually titrated (mean 3.4 (range 0.8-6.0) mg) and compared with placebo in a double blind cross over phase. With apomorphine compared with placebo the mean daily duration of off periods was reduced by 51% as assessed by the patients and by 58% as assessed by the staff. The severity of off periods was also significantly reduced. The effect was unchanged after a maintenance phase of eight weeks. At study termination 13 of 14 patients were able to inject themselves and 11 of 14 patients found that their feeling of freedom had increased. The most common adverse events were nausea, subcutaneous nodules, and increased frequency of involuntary movements. Pharmacokinetics were linear and did not change with repeat dosing. The tmax ranged from five to 45 minutes (16 patients). It is concluded that pen injected apomorphine is a valuable treatment for patients with advanced Parkinson's disease with on-off phenomena.

Adult↗
PubMed1994

BDNF makes cultured dentate granule cells more resistant to hypoglycaemic damage.

The aim of this study was to explore whether brain-derived neurotrophic factor (BDNF) can improve neuronal survival in cell cultures of rat dentate gyrus subjected to a hypoglycaemic insult. Glucose deprivation for 15 h caused severe neuronal loss (about 70%). BDNF added either 24 h before or 4 h after onset of hypoglycaemia completely protected granule cells against this insult-induced damage. Nerve growth factor (NGF) had similar effects. These findings support the hypothesis that the rapid upregulation of BDNF mRNA in dentate granule cells after brief periods of hypoglycaemic coma and other insults is a local protective mechanism.

Animals↗
PubMed1994

Brain insults in rats induce increased expression of the BDNF gene through differential use of multiple promoters.

The rat brain-derived neurotrophic factor (BDNF) gene consists of four short 5'-exons linked to separate promoters and one 3'-exon encoding the mature BDNF protein. Using in situ hybridization we demonstrate here that kindling-induced seizures, cerebral ischaemia and insulin-induced hypoglycaemic coma increase BDNF mRNA levels through insult- and region-specific usage of three promoters within the BDNF gene. Both brief (2 min) and longer (10 min) periods of forebrain ischaemia induced significant and major increases only of exon III mRNA in the dentate gyrus. Following hypoglycaemic coma (1 and 30 min), exon III mRNA was markedly elevated in the dentate gyrus and, in addition, exon I mRNA showed a moderate increase. Single and recurrent (n = 40) hippocampal seizures significantly increased expression of exon I, II and III mRNAs in the dentate gyrus granule cells. After recurrent seizures, including generalized convulsions, there were also major increases of both exon I and III mRNAs in the CA3 region, amygdala, piriform cortex and neocortex, whereas in the hippocampal CA1 sector marked elevations were detected only for exon III mRNA. The insults had no effect on the level of exon IV mRNA in the brain. The region- and insult-specific pattern of promoter activation might be of importance for the effectiveness of protective responses as well as for the regulation of plastic changes following brain insults.

Animals↗
PubMed1994

Evidence for long-term survival and function of dopaminergic grafts in progressive Parkinson's disease.

Two patients with idiopathic Parkinson's disease (Patients 3 and 4 in our series) were followed up to 3 years after grafting of human embryonic dopamine-rich mesencephalic tissue unilaterally into the putamen. During the first postoperative year both patients showed significant amelioration of parkinsonian symptoms and increased 6-L-[18F]-fluorodopa uptake in the grafted putamen, as assessed with positron emission tomography. Three years after grafting the patients still exhibited increased fluorodopa uptake in the grafted putamen and significant clinical improvements, evidenced by a reduction of the severity of symptoms and of the time spent in the "off" phase, and by a prolongation of the effect of a single dose of L-dopa. Between 1 and 3 years after surgery, Patient 3 showed only minor changes of parkinsonian symptoms on the side contralateral to the graft, whereas there was a worsening on the ipsilateral side. Fluorodopa uptake decreased in the nongrafted putamen but was unchanged in the grafted putamen. Patient 4 continued to improve after the first postoperative year and L-dopa was withdrawn after 32 months. The reduction of parkinsonian symptoms on the side contralateral to the graft became more pronounced between 1 and 3 years after surgery. Fluorodopa uptake further increased in the grafted putamen, whereas no change was detected on the non-grafted side. These results indicate that grafts of embryonic dopamine neurons can survive, grow, and exert functional effects up to at least 3 years after surgery in the parkinsonian brain, despite an ongoing disease process leading to degeneration of the intrinsic dopamine system.

Brain Tissue Transplantation↗
PubMed1994

Seizure development and noradrenaline release in kindling epilepsy after noradrenergic reinnervation of the subcortically deafferented hippocampus by superior cervical ganglion or fetal locus coeruleus grafts.

Solid pieces of fetal locus coeruleus (LC) or superior cervical ganglion (SCG) were placed into a fimbria-fornix lesion cavity in 6-hydroxydopamine-treated, noradrenaline (NA)-denervated rats. Six to 8 months later, all animals were subjected to electrical kindling stimulations in the hippocampus until they had reached the fully kindled state. Nongrafted lesioned animals showed markedly increased kindling rate which was partly attenuated by LC but not SCG grafts. In both LC- and SCG-grafted animals, dopamine beta-hydroxylase immunocytochemistry demonstrated a high density of graft-derived noradrenergic fibers in the dorsal hippocampus, whereas reinnervation of the ventral hippocampus was much more sparse. Subregional distribution of these fibers within the hippocampus was different in the two grafted groups. Both grafts partly restored basal extracellular NA levels in the hippocampus and reacted to generalized seizures by a significant (two- to threefold) increase of NA release, as measured by intracerebral microdialysis. Our data indicate (i) that seizure activity can regulate transmitter release from noradrenergic neurons in both LC and SCG grafts, (ii) that only fetal LC grafts retard seizure development in kindling, and (iii) that the inability of SCG implants to influence kindling epileptogenesis could be due to a lack of synaptic contacts between the graft-derived ganglionic fibers and host hippocampal neurons.

Animals↗
PubMed1994

Platelet-derived growth factor exerts trophic effects on rat striatal DARPP-32-containing neurons in culture.

The objective of the present study was to determine if either of the two isoforms of platelet-derived growth factor (PDGF), PDGF-AA and PDGF-BB, exerts trophic effects in vitro on developing rat strial neurons. Striatal neurons were identified using immunocytochemistry for dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein with a molecular weight of 32 kilodalton (DARPP-32). In control cultures without PDGF, the mean number of DARPP-32-positive neurons decreased by 47% at days 3 to 5 in vitro. PDGF-BB, but not PDGF-AA, significantly increased the number of DARPP-32-positive neurons both at day 3 (by 42%) and day 5 (by 149%). Total cell number was similar in control and PDGF-BB-treated cultures, suggesting that, in striatal cultures, the action of PDGF-BB is relatively specific for DARPP-32-positive neurons. The DARPP-32-positive neurons in PDGF-BB-treated cultures had longer neurites and larger soma areas than those in control and in PDGF-AA-treated cultures. Our data provide evidence that PDGF-BB exerts a trophic action on striatal DARPP-32-positive neurons in vitro by promoting cell survival and morphological differentiation, although a stimulatory effect on intraneuronal DARPP-32 levels also is possible. The findings raise the possibility that PDGF-BB might also be involved in the development and maintenance of striatal neurons in vivo, and could be used to counteract striatal degeneration in models of Huntington's disease.

Animals↗
PubMed1994

Clinical application of neuronal grafts in Parkinson's disease.

Fetal neural grafts, rich in dopamine neurons, taken from the ventral mesencephalon and implanted into the dopamine-denervated striatum, can reinnervate the striatum, form synaptic contacts with host neurons, release dopamine and improve motor function. In animal models of Parkinson's disease, the improvement resulting from transplantation is dependent on the number of surviving grafted dopamine neurons and the density and extent of graft-derived reinnervation. The major unresolved scientific question at present is not whether neural grafting is better than established drug treatments but if survival and function of such grafts are at all possible in patients with Parkinson's disease. A more general problem is that if cell transplantation is to become clinically useful for a large number of Parkinsonian patients and also be applied in other neurological disorders, alternative sources of donor tissue must be found; several have been proposed, including adrenal medulla cells and sympathetic ganglia but perhaps the most exciting strategy is to implant cells that have been genetically engineered to synthesize and release L-dopa or dopamine.

Animals↗
PubMed1994

Seizure suppression in kindling epilepsy by intracerebral implants of GABA- but not by noradrenaline-releasing polymer matrices.

Gamma-aminobutyric acid (GABA)-releasing polymer matrices were implanted bilaterally, immediately dorsal to the substantia nigra, in rats previously kindled in the amygdala. Two days after implantation, rats with GABA-releasing matrices exhibited only focal limbic seizures in response to electrical stimulation, whereas animals with control matrices devoid of GABA had generalized convulsions. GABA release from the polymer matrices was high during the first days after implantation, as demonstrated both in vitro and, using microdialysis, in vivo. The anticonvulsant effect was no longer observed at 7 and 14 days at which time GABA release was found to be low. In a parallel experiment, polymer matrices containing noradrenaline (NA) were implanted bilaterally into the hippocampus of rats with extensive forebrain NA depletion induced by an intraventricular 6-hydroxydopamine injection. No effect on the development of hippocampal kindling was observed, despite extracellular NA levels exceeding those of rats with intrahippocampal locus coeruleus grafts that have previously been shown to retard kindling rate. The results indicate that GABA-releasing implants located in the substantia nigra region can suppress seizure generalization in epilepsy, even in the absence of synapse formation and integration with the host brain. In contrast, the failure of NA-releasing polymer matrices to retard the development of seizures in NA-depleted rats suggests that such an effect can only be exerted by grafts acting through a well-regulated, synaptic release of NA.

Animals↗
PubMed1994

Neurotrophins and brain insults.

Epileptic, hypoglycaemic, ischaemic and traumatic insults to the brain induce marked changes of gene expression for the neurotrophins, nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3, and their high-affinity receptors, TrkB and TrkC, in cortical and hippocampal neurones. Release of glutamate and influx of Ca2+ are the most important triggering factors. The major hypotheses for the functional effects of the insult-induced neurotrophin changes are protection against neuronal damage and stimulation of sprouting and synaptic reorganization. More insight into the regulation and role of the neurotrophins after brain insults should increase our understanding of pathophysiological mechanisms in, for example, epileptogenesis and cell death, and could lead to new therapeutic strategies.

Animals↗