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Biomedical subjects

T Halonen

Publications and source records attributed to T Halonen.

At least 37 records · Page 2Linked to original sources
PubMed1995

Alpha 2-adrenoceptor agonist, dexmedetomidine, protects against kainic acid-induced convulsions and neuronal damage.

Kainic acid (KA)-induced convulsions are accompanied by histopathological changes that are most prominent in the temporal lobe structures. In the present study, we investigated whether a selective alpha2-adrenoceptor agonist, dexmedetomidine could attenuate KA-induced epileptic convulsions and subsequent neuronal damage in the rat hippocampus. Rats were pretreated 30 min before KA injection (9 mg/kg, i.p.) with dexmedetomidine (3 micrograms/kg, s.c.). The behavior of animals was observed for at least 3 h. Dexmedetomidine suppressed the development (p < 0.001), generalization (p < 0.05) and severity (p < 0.01) of convulsions. In addition, histological analysis revealed that dexmedetomidine-treated animals without convulsions or with only partial convulsions had no neuronal damage in the principal cell layers of the hippocampus. A selective alpha2-antagonist, atipamezole (1 mg/kg, s.c.) potentiated KA-induced convulsions and increased the mortality in status epilepticus. In conclusion, the present study demonstrated that dexmedetomidine, in addition to possessing anticonvulsant properties, has a neuroprotective effect in the KA model of status epilepticus.

Adrenergic alpha-Agonists↗
PubMed1995

NADPH diaphorase-containing nonpyramidal cells in the rat hippocampus exhibit differential sensitivity to kainic acid.

Neurons containing nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase exhibit high resistance to several excitotoxins. In the neocortex and striatum, however, these neurons are sensitive to kainic acid. Here we report that, 2 weeks after i.p. injection of kainic acid, the number of NADPH diaphorase neurons in the hilus and CA1 subfield was decreased, whereas the cell counts in the other hippocampal areas were to a great extent similar to those for the controls. We propose that the loss of NADPH diaphorase neurons in the hippocampus after systemic injection of kainic acid is associated with the pathophysiological processes involved in the spreading of epileptic seizure activity rather than to the direct neurotoxic effect of the kainic acid per se.

Animals↗
PubMed1995

Vigabatrin protects against kainic acid-induced neuronal damage in the rat hippocampus.

We studied the neuroprotective effect of vigabatrin (gamma-vinyl GABA, VGB) in the rat hippocampus after status epilepticus (SE) induced by kainic acid (KA). Rats were treated with VGB (500 or 1000 mg/kg, i.p.) 24 h before KA injection (9 mg/kg, i.p.). The lower dose of VGB had no effect on the generation or severity of convulsions. However, VGB decreased neuronal damage in the CA3a (P < 0.05) and CA1 (P < 0.01) subfields of the hippocampus. The higher dose of VGB attenuated the severity of convulsions (P < 0.05) but had no effect on the development or generalization of convulsions. This finding may have clinical implications in the prevention of neuronal damage induced by drug refractory seizures or SE.

Animals↗
PubMed1995

Prevention of neuronal cell death by anticonvulsants in experimental epilepsy (extended abstract).

In human temporal lobe epilepsy, neuronal cell damage is found in the hippocampus (1) as well as in the amygdaloid complex (2) and entorhinal cortex (3). Data from animal studies show that recurrent seizures selectively injure certain populations of neurons in the temporal lobe structures (4). Whether or not recurrent seizures cause neuronal damage in human epilepsy is still under investigation. A new challenge for anti-epilepsy medication is not only to suppress clinical seizures but also to prevent any neuronal damage caused by the seizures.

Amygdala↗
PubMed1994

Posterior piriform and perirhinal cortex relay seizures evoked from the area tempestas: role of excitatory and inhibitory amino acid receptors.

The functional relationship between the area tempestas (AT), an epileptogenic site within the deep prepiriform cortex, and the regions in the posterior piriform cortex which are innervated by AT, were studied in the rat. The GABAA receptor agonist, muscimol (390 pmol) was microinjected unilaterally into the posterior piriform cortex and adjacent regions in the same hemisphere from which seizures were evoked by focal application of bicuculline into AT. Pretreatment with muscimol into either the ventral posterior piriform cortex or perirhinal cortex, protected against the bilateral clonic seizures evoked from the ipsilateral AT. No seizure protection was obtained when muscimol was placed into adjacent areas of amygdala, entorhinal cortex, neocortex and ventral hippocampus. Seizure protection was also obtained when kynurenic acid, but not 2-amino-7-phosphonoheptanoic acid, was microinjected into the ventral posterior piriform cortex, suggesting that glutamate transmission mediated via non-N-methyl-D-aspartate (non-NMDA) receptors is required for the relay of seizure discharge through this region. Our data indicate that a specific region of the temporal cortex, the posterior piriform and perirhinal area, functions as a critical link in the propagation of limbic seizures evoked from AT.

2-Amino-5-phosphonovalerate↗
PubMed1993

Elevated seizure threshold and impaired spatial learning in transgenic mice with putrescine overproduction in the brain.

We have studied the role of putrescine by using transgenic mouse lines overexpressing the human ornithine decarboxylase gene in most of their tissues. The aberrant expression of the transgene is most strikingly manifested in the brain, leading to an increase of up to 20-fold in putrescine content. We report that the transgenic mice with grossly elevated putrescine in all brain regions analysed (cortex, striatum, hippocampus and cerebellum) showed a significantly elevated seizure threshold to chemical and electrical stimuli, and impaired performance in spatial learning and memory tests. The view that putrescine may be primarily responsible for these changes was supported by the fact that the concentrations of the major neurotransmitter amino acids, glutamate and GABA in the brain, were not changed in the transgenic animals, and by the finding that a further increase in brain putrescine, achieved by inhibition of the catabolism of L-ornithine, appeared to provide additional protection against electroshock-induced seizures. These results suggest that the commonly observed increase in ornithine decarboxylase activity and the massive increase in brain putrescine in connection with neuron damage is a neuroprotective measure rather than a cause of the damage.

Animals↗
PubMed1993

Biochemical and morphological changes in the rat hippocampus following transection of the fimbria-fornix.

According to electrophysiological studies, the subcortically denervated hippocampus has been suggested as a model for limbic epilepsy. We investigated a) whether fimbrial lesioning leads to any biochemical or morphological changes in the rat hippocampus, b) if these changes give any explanation to the previously indicated hyperexcitability, and c) if the changes are in line with the findings in other experimental models and human epilepsy. The fimbria-fornix transection was done by aspiration. Four months later, spontaneous EEG activities were recorded, and the hippocampal formation was processed for histology. In addition, a separate group of lesioned rats was used for hippocampal amino acid analysis. Hyperexcitable functioning of the hippocampus was seen as frequent and rhythmic spiking activity in 25% of the fimbria-fornix-lesioned rats, although the rest of them had spikes occasionally. The amino acids analysis revealed a notable decrease in the concentration of GABA but no significant changes in the amount of excitatory amino acids. This suggests impaired GABAergic functioning but does not exclude possible abnormalities in the release of both excitatory and inhibitory amino acids. The number of somatostatin-immunoreactive (SOM-IR) neurons, a subpopulation of GABAergic neurons, was decreased in all the areas of the hippocampus (CA3 > CA1 > hilus), but this was statistically significant only in the CA3 area. Interestingly, it is the region from which interictal spiking activity in the subcortically denervated rat presumable originates. Immunostaining for synaptophysin showed a dense band of granules in the inner molecular layer of the dentate gyrus, indicating probable synaptic reorganization of associational afferents.

Acetylcholinesterase↗
PubMed1993

Amino acid levels in the cerebrospinal fluid of newly diagnosed epileptic patients: effect of vigabatrin and carbamazepine monotherapies.

We studied the CSF amino acid levels of 42 patients with newly diagnosed epilepsy before treatment with antiepileptic medication and during monotherapy with either vigabatrin or carbamazepine. The present study shows that patients with newly diagnosed epilepsy have elevated levels of the excitatory amino acid glutamate in CSF. Vigabatrin monotherapy effectively prevents the appearance of seizures in patients with high baseline CSF glutamate levels. In these patients, vigabatrin not only elevates the levels of gamma-aminobutyric acid, but also decreases the elevated levels of glutamate in CSF, which may also be important to the antiepileptic efficacy of vigabatrin. Patients with low CSF glutamate levels did not benefit from vigabatrin-induced changes in amino acid levels and successful monotherapy with carbamazepine did not affect CSF amino acid levels. The elevation of gamma-aminobutyric acid is thus not the only way to achieve seizure control and there are several factors underlying the generation and control of seizures. Follow-up of the patients with high baseline glutamate CSF levels will show if the observed abnormalities are related to the severity of epilepsy in individual patients and if early treatment with vigabatrin of these patients could prevent the development of intractable epilepsy.

Adolescent↗
PubMed1993

Gamma-vinyl GABA decreases voluntary alcohol consumption in alcohol-preferring AA rats.

The effect of a GABA transaminase inhibitor, gamma-vinyl GABA, on the voluntary alcohol consumption of alcohol-preferring AA rats produced by selective breeding for high alcohol preference, was studied. The rats were first trained to voluntarily drink 10% (v/v) ethanol solution until their ethanol consumption stabilized. Gamma-vinyl GABA (100, 200 or 500 mg/kg) was then injected intraperitoneally in three groups of rats, with saline-injected animals serving as a control group. The rats continued to have a free choice between 10% ethanol and plain tap water for five days after the injection, and their ethanol, water and food consumptions were measured daily. Gamma-vinyl GABA decreased ethanol consumption by the rats in a dose-dependent way. The consumption remained significantly decreased for three days in the two groups receiving the highest doses, with only a small concomitant tendency to decreased food intake. The results suggest that an increase in brain GABA concentration decreases alcohol drinking, possibly through potentiation of the pharmacological action of ethanol.

4-Aminobutyrate Transaminase↗
PubMed1992

Amino acid levels in cerebrospinal fluid of rats after administration of pentylenetetrazol.

1. We studied the effect of pentylenetetrazol (PTZ)-induced myoclonic jerks and generalized clonic-tonic convulsions (GC) on the levels of neurotransmitter amino acids in the cisternal CSF of rats. 2. The levels of aspartate, glutamate, glycine, and taurine were elevated in the CSF during myoclonic jerks and more distinctly immediately after GC. 3. During the recovery period of postictal depression seen in EEG (5 min after GC), the CSF levels of transmitter amino acids were lower than in the control group. 4. PTZ-induced irritative activity in the EEG disappeared in 24 hr but the levels of amino acids remained abnormal. 5. Amino acid changes in the CSF following PTZ-induced convulsions might indicate that the release of amino acids into the extracellular space is increased before and during the propagation of PTZ-induced seizure and decreased during postictal depression.

Amino Acids↗
PubMed1992

Cognitive effects of oxcarbazepine and phenytoin monotherapy in newly diagnosed epilepsy: one year follow-up.

We evaluated the effect of initial oxcarbazepine (OXC) monotherapy on memory, attention and simple psychomotor speed in 14 patients; 15 patients with initial phenytoin (PHT) monotherapy served as reference patients. Neuropsychological assessments were performed before starting the treatment and after 6 and 12 months follow-up with steady-state drug treatment. Differential cognitive effects of OXC and PHT were not apparent in our study. As the efficacy of present antiepileptic drugs in adult epilepsy is analogous, the choice of drug is determined by the comparative side effects of the drugs. In the present study the number of successfully treated patients was similar in both OXC and PHT groups. As far as cognitive side effects are concerned our results revealed no evidence favoring either antiepileptic over the other.

Adult↗
PubMed1991

The effect of subchronic administration of vigabatrin on learning and memory in nonepileptic rats.

The present experiments investigated whether subchronic administration of vigabatrin, a GABA-mimetic drug, affects the performance of normal rats in the behavioural tasks assessing learning and memory. The effects of vigabatrin [50-200 mg/kg (IP)/day] administration on the acquisition and retention of water maze and passive avoidance task were studied. According to the results of three experiments, vigabatrin treatment did not markedly impair the acquisition or retention of water maze task. Furthermore, vigabatrin-treated rats were not inferior to saline-treated rats in reversal learning of water maze task. On the other hand, vigabatrin treatment slightly increased the speed of swimming in rats. The administration of vigabatrin did not affect the performance (training latency, number of training trials, testing latency) of rats in the passive avoidance task. According to these results, the effects of vigabatrin, a new antiepileptic drug, on the performance of nonepileptic rats were modest in behavioural tasks used to assess learning and memory.

Amino Acids↗
PubMed1990

Administration of vigabatrin (gamma-vinyl-gamma-aminobutyric acid) affects the levels of both inhibitory and excitatory amino acids in rat cerebrospinal fluid.

The effect of vigabatrin (gamma-vinyl-gamma-aminobutyric acid), a new anticonvulsant drug, on the transmitter amino acids in rat cisternal CSF was studied. CSF was collected through a permanently implanted polyethylene cannula from freely moving rats at 5, 24, 48, and 96 h after administration of 1,000 mg/kg of vigabatrin. The free gamma-aminobutyric acid (GABA) level was elevated maximally (13.5-fold; p less than 0.01) at 24 h after injection. The homocarnosine (GABA-histidine) level also was increased (123%; p less than 0.01) at 24 h after injection, and its concentration remained at the same level for the next 3 days. Glycine and taurine concentrations had increased [31% (p less than 0.05) and 63% (p less than 0.01), respectively] at 5 h after injection. It is interesting that the levels of glutamate and aspartate increased [330% (p less than 0.05) and 421% (p less than 0.01), respectively] at 96 h after injection, the time when the free GABA level had returned to the baseline concentration and the vigabatrin level was 3% of the maximal concentration. The present study indicates that a single dose of vigabatrin in rats elevates levels of both the inhibitory and excitatory amino acids in CSF. However, the temporal profile of observed changes in relation to vigabatrin injection shows that neither the long-lasting elevation of GABA content nor the increase in glutamate and aspartate levels correlates with the level of vigabatrin in CSF. These findings suggest that the excitatory mechanisms are also augmented following acute administration of vigabatrin, especially when the content of GABA had decreased to the baseline level and the level of vigabatrin was low.

Amino Acids↗
PubMed1989

Inhibitory and excitatory amino acids in cerebrospinal fluid of chronic epileptic patients.

We studied the levels of excitatory and inhibitory amino acids in the cerebrospinal fluid (CSF) of 28 epileptic patients (24 with partial type seizures, 4 with primary generalized seizures) and 12 controls. The levels of aspartate were 63% (p less than 0.01), glutamine 129% (p less than 0.001), and homocarnosine 127% (p less than 0.005) that of controls. The concentrations of glutamate, asparagine, total GABA, free GABA, taurine, and glycine did not differ between epileptic patients and controls. Patients with partial epilepsy had a pattern of amino acids in CSF similar to that in patients with primary generalized seizures. In the present study we did not observe increased excitation or decreased inhibition in the seizure-active brains of epileptics, as far as the CSF levels of amino acids reflect their levels in the brain.

Adolescent↗
PubMed1989

Cerebrospinal fluid GABA and seizure control with vigabatrin.

1. To evaluate the relationship between the clinical response and enhancement of GABAergic neurotransmission, for 6 months we administered vigabatrin (gamma-vinyl-GABA, GVG) to 75 patients with complex partial epilepsy. Total GABA (TGABA), free GABA (FGABA), homocarnosine (HC), and GVG concentrations were measured in CSF of these patients before and during GVG treatment. 2. Over 50% reduction in seizures was found in 55% of the patients. Dose-reduction resulted in a relapse, i.e. the return of seizures. 3. At baseline TGABA, FGABA, and HC did not differ in responders and nonresponders. After GVG treatment, the TGABA and HC levels were lower in nonresponders (P less than 0.001), but the GVG and FGABA levels did not differ. The GVG dose reduction resulted in a concomitant decrease in TGABA, FGABA, HC and GVG (P less than 0.001). 4. According to our results GVG is an effective anticonvulsant drug in complex partial seizures. In nonresponders the poor anticonvulsant response may be related to the lower elevation of the CSF markers of GABAergic neuronal activity in this group compared with the responders.

Adolescent↗
PubMed1989

Specificity of vigabatrin for the GABAergic system in human epilepsy.

The therapeutic action of vigabatrin (gamma vinyl GABA, GVG) has been reported to be mediated by GABAergic neurotransmission. In the present study, we evaluated different neurotransmitter systems in the cerebrospinal fluid (CSF) of patients with complex partial epilepsy, before and during GVG treatment. The markers of the GABAergic system (free GABA, total GABA, homocarnosine) showed a two- to threefold elevation. There was also an increase in glycine during the 6 months of GVG treatment. In contrast, we did not find any constant CSF changes in either excitatory amino acids or in markers of the cholinergic (acetylcholinesterase), dopaminergic (homovanillic acid), serotonergic (5-hydroxyindoleacetic acid), or peptidergic (somatostatin, prolactin, beta-endorphin) systems. This finding (except an elevation in glycine) was in agreement with previous studies which suggest a specific action of GVG on the GABAergic system. The role of glycine in antiepileptic efficacy of GVG needs further evaluation.

Adult↗
PubMed1988

Free amino acids in the brain of patients with Parkinson's disease.

To study free brain amino acids and their relation to dementia, the levels of glutamate, glutamate, asparagine, aspartate, glycine, taurine, homocarnosine and gamma-aminobutyric acid were determined in the temporal cortex and caudate nucleus in demented and non-demented patients with Parkinson's disease. In the temporal cortex, the levels of aspartate and asparagine were significantly increased in non-demented parkinsonian patients as compared both to demented patients and to controls. In the caudate nucleus no significant changes in amino acid levels were seen. Thus, the cortical and striatal glutamate/aspartate systems seem to be preserved in dementia in Parkinson's disease.

Aged↗