A. Pitkänen

Inhibitory and excitatory amino acids in CSF of patients suffering from complex partial seizures during chronic treatment with γ-vinyl GABA (vigabatrin)

The effect of chronic administration of gamma-vinyl GABA (GVG; vigabatrin) on levels of neurotransmission-related amino compounds was studied in lumbar cerebrospinal fluid of 65 patients with complex partial epilepsy. The first sample of cerebrospinal fluid was taken before a 3-month period of treatment with 3 g gamma-vinyl GABA/day, and the second was taken afterwards. From patients who showed a greater than 50% reduction in seizures (responders) or marked improvement in global performance, a third sample was taken at the end of the next 3-month phase, during which 3 g or 1.5 g gamma-vinyl GABA had been administered daily. During treatment with 3 g gamma-vinyl GABA/day, 55% of the patients showed more than 50% reduction in complex partial seizures; and at the same time free GABA, total GABA, homocarnosine, and glycine concentrations in the cerebrospinal fluid increased by 104%, 151%, 194% and 16%, respectively. After reduction of the daily dose to 1.5 g, the levels of free GABA, total GABA and homocarnosine were still increased by 65%, 115% and 102%, respectively. gamma-Vinyl GABA correlated with the levels of free GABA (P less than 0.002) and glycine (P less than 0.001). Concentrations of homocarnosine at baseline and homocarnosine and total GABA during gamma-vinyl GABA treatment were lower (P less than 0.005) in the group of non-responders than in the responder group. Glutamic acid, glutamine, aspartic acid, asparagine, and taurine levels did not change during gamma-vinyl GABA treatment. In conclusion, administration of gamma-vinyl GABA reduces epileptic seizures and produces dosage-dependent increases in levels of free GABA, GABA-containing peptides and of glycine in cerebrospinal fluid, without concomitant change in levels of excitatory amino acids.

Brain cholinergic enzymes and cortical EEG activity in young and old rats.

1. Cholinergic enzymes (ChAT, AChE) in different areas of the brain and cortical electroencephalography (EEG) activity were investigated in young and old rats. 2. In old rats, ChAT activity was low in the striatum, but high in the amygdala. Compared to young rats, ChAT activity in old rats was unchanged in the frontal, parietal/occipital and entorhinal cortex as well as in the hypothalamus, midbrain, hippocampus and brain stem. 3. AChE activity in old rats was lower than in young animals in the parietal/occipital cortex, hippocampus, striatum and brainstem. In other areas of the brain AChE activity was unchanged. 4. In old rats the peak frequency (Fp) of cortical EEG activity (mobility-related) was significantly lower than in young animals, both frontally and occipitally. The power of 5-10 Hz frequency band was markedly lower than in young rats. During immobility, the power of the 1.5-3 Hz and 3-5 Hz bands was lower in the frontal cortex of old rats. The power of 3-5 Hz, 5-10 Hz and 10-20 Hz bands was lower in the occipital cortex of old rats. In all of the old rats, but not in any of the young ones, symmetric high voltage activity was observed in the frontal pole of the cortex. 5. These results suggest that the age-related decrease of higher frequencies of cortical EEG activity may be related to the decrease of AChE activity in the parietal/occipital cortex. This decrease in AChE may reflect degeneration of the cholinergic synapses.

Seizure-induced damage to the hippocampus is prevented by modulation of the Gabaergic system

A variety of cerebral insults induce neuronal damage to the hippocampal formation. The somatostatin-immunoreactive (SOM-ir) neurones in the dentate hilus are particularly vulnerable. In the present study, we demonstrated that augmentation of hippocampal GABAergic inhibition by chronic infusion of gamma-vinyl GABA prevented the delayed seizure-induced damage to hilar SOM-ir neurones. Selective lesions of the cholinergic, serotonergic or noradrenergic pathways to the hippocampus did not attenuate the seizure-induced loss of SOM-ir neurones; rather, the damage was exacerbated by the cholinergic lesion. It is, therefore, the intrahippocampal GABAergic circuitries, rather than the selective subcortical pathways, that are critical for neuroprotection after seizures. Enhanced GABAergic inhibition in the hippocampus prevented damage to hilar SOM-ir neurones, even when started 2 days after status epilepticus. GABAergic agents may thus provide an alternative treatment for delayed neuronal damage caused by cerebral insults.

Specificity of Vigabatrin for the GABAergic System in Human Epilepsy

Summary: 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‐hydroxyin‐doleacetic acid), or peptidergic (somatostatin, prolactin, β‐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.

Somatostatin and β-endorphin levels in cerebrospinal fluid of nonmedicated and medicated patients with epileptic seizures

Neuropeptides have been proposed to play a role in regulation of the seizure threshold and interictal behavior in experimental models of epilepsy, but there are few studies concerning neuropeptides in human epilepsy. We compared the levels of two peptides, somatostatin (SLI) and beta-endorphin (BEP) in lumbar cerebrospinal fluid (CSF) of unmedicated (N = 18) and medicated (n = 24) epileptic patients with the levels of these peptides in control (n = 20). Peptide levels in the CSF of patients with panic disorder (8) were also evaluated. Patients with chronic medicated epilepsy had a SLl level 80% (p = 0.003, Mann-Whitney U-test) that of the controls, 76% (p = 0.011) that of unmedicated patients, and 84% (p = 0.028) that of the panic group. BEP in the CSF did not differ in unmedicated, medicated and control patients. On the other hand, patients with panic disorder had higher levels of BEP in CSF than did the controls (117%, p = 0.041). In panic patients SLl was at control level. The present study indicates that the peptidergic systems are affected differentially in epilepsy and in panic disorder. Furthermore, there seems to be selectivity in the affect on peptidergic systems during the period when the epilepsy becomes chronic.

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<0.01), glutamine 129% (p<0.001), and homocarnosine 127% (p< 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.

γ-Vinyl GABA (Vigabatrin) in Epilepsy: Clinical, Neurochemical, and Neurophysiologic Monitoring in Epileptic Patients

Summary: We report long‐term clinical, neurochemical, and electrophysiologic data of γ‐vinyl GABA (GVG, vigabatrin) in three groups of patients. GVG was started as add‐on therapy for 75 patients with refractory complex partial seizures (group A) and for 36 mentally handicapped patients with severe epilepsy (group B). The third group (C) consisted of 20 patients with carbamazepine (CBZ) monotherapy, in half of whom GVG monotherapy was substituted. After 3 months, 55% of patients in group A and 42% in group B were responders (reduction in seizure frequency >50%). After 6 (group A) and 3 years (group B) of follow‐up, 27 and 33% of the patients, respectively, still had good response to GVG. Neurochemical measurements showed a twofold increase in CSF GABA concentrations and minimal or no changes in other neurotransmitter‐related parameters. In group C, substitution of GVG as medication tended to normalize the lengthened latencies in somatosensory evoked potentials (SEPs) observed during CBZ treatment.

Brain amines and neocortical EEG in young and aged rats

1. Frontal and parieto-occipital electroencephalography (EEG) of young (4 months-old) and aged (17 and 22 months-old) Wistar rats were analyzed, both during movement and during waking immobility. 2. The levels of monoamines, serotonin and their metabolites were measured from the frontal cortex, parieto-occipital cortex, hippocampus, brainstem and midbrain. 3. In aged rats, as compared to young rats, the most apparent changes of the quantitative EEG spectrum were the decreased amplitude of alpha (5-10 Hz) and beta (10-20 Hz) frequency bands in the frontal and parieto-occipital cortices during both movement and waking immobility behavior (p less than 0.05). 4. The levels of dopamine (DA), homovanillinic acid (HVA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) or the ratios of 5-HT/5-HIAA and DA/HVA did not differ between young and aged rats in any brain region studied, with the exceptions of brainstem DA and parieto-occipital 5-HIAA, which were elevated in aged rats (p less than 0.05). 5. In the frontal cortex, hippocampus and midbrain, noradrenaline (NA) levels of aged rats were slightly increased as compared to young rats (p less than 0.05). 6. NA levels of the parieto-occipital cortex and brainstem did not change during aging. 7. Furthermore, there were no clear correlations between the decreased amplitude of the quantitative EEG spectrum and monoamine or serotonin concentrations, or the ratios of 5-HT/5-HIAA and DA/HVA in the cerebral cortex of aging Wistar rat.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Dopamine‐β‐hydroxylase and acetylcholinesterase activities of cerebrospinal fluid in Alzheimer's disease

Abstract– Recent neurochemical studies have indicated that in Alzheimers disease there is disturbance of the cholinergic metabolism of the brain. Defects in other transmitter systems have also been suggested. As a marker of noradrenergic metabolism of the central nervous system, we measured dopamine‐β‐hydroxylase (EC. 1.14.17.1) activity in cerebrospinal fluid (CSF) from 60 Alzheimer patients and 20 controls of the same age and sex. Dopamine‐β‐hydroxylase activities of the CSF from Alzheimer patients did not differ significantly from those for the controls. The dopamine‐β‐hydroxylase activities were not correlated with severity of dementia. As reported previously, the activity of a cholinergic marker, acetylcholinesterase (EC 3.1.1.7), was reduced in the CSF of Alzheimer patients. Interestingly, dopamine‐β‐hydroxylase activities were correlated with acetylcholinesterase activities both in Alzheimer patients and control group.