Suicidal behaviors and the tryptophan hydroxylase gene.

BACKGROUND: To determine whether the tryptophan hydroxylase gene (ie, the gene that codes for the rate-limiting enzyme in the metabolic pathway of serotonin) may be a susceptibility factor for suicidal behavior. METHODS: Genotypic and allelic frequencies at a polymorphic Ava II restriction site were revealed with the use of the complementary DNA tryptophan hydroxylase probe C2-38 in 62 suicide attempters. The psychiatric characteristics of these suicide attempters were determined using the Schedule for Affective Disorders and Schizophrenia-Lifetime version with modification for the study of anxiety disorders, and these characteristics were compared with those in 52 healthy controls. RESULTS: No association between tryptophan hydroxylase and suicidal behavior was detected. CONCLUSION: The tryptophan hydroxylase gene was not a susceptibility factor for suicidal behaviors in the group of suicide attempters in this study.

Early postnatal muscle contractile activity regulates the carbonic anhydrase phenotype of proprioceptive neurons in young and mature mice: evidence for a critical period in development.

Carbonic anhydrase activity, a marker of mouse proprioceptive neurons in adult dorsal root ganglia, is first detectable in the perinatal period, increases until postnatal day 60 and remains stable in adulthood. The onset of carbonic anhydrase staining begins after the neurons have made connections with their targets suggesting that neuron-target interactions regulate carbonic anhydrase phenotype development. To examine this possibility, we first analysed carbonic anhydrase expression in mdx mice which are characterized by a massive but reversible degeneration of skeletal muscle concomitant with the carbonic anhydrase ontogenesis. Neuronal carbonic anhydrase expression in mdx mice stopped developing when the period of muscular degeneration-regeneration began. Furthermore this alteration persisted during adulthood. We then analysed carbonic anhydrase expression in fifth lumbar dorsal root ganglion of developing control mice before and after surgical procedures that might interfere with central and peripheral target influences on dorsal root ganglion neurons. Central disconnection (dorsal rhizotomy) did not affect the development of carbonic anhydrase activity. Disrupting neuron-peripheral target interactions by sciatic nerve transection or blocking muscle contraction by tenotomy stopped the development of neuronal carbonic anhydrase content. Finally, recovery was monitored following sciatic nerve crush. In adults, recovery of carbonic anhydrase activity was obtained after functional recuperation; similar manipulations during the first month of life induced irreversible alteration of the carbonic anhydrase phenotype. These results show that the development of carbonic anhydrase activity in proprioceptive neurons is regulated by neuron-muscle interactions (i.e. muscle contraction). They also provide evidence for a critical period in the development of the carbonic anhydrase phenotype. We suggest that these two mechanisms are responsible for the altered carbonic anhydrase phenotype of the dorsal root ganglion neurons in mdx mice, a model of human muscular dystrophy.

Opposite developmental regulation of P- and Q-type calcium currents during ontogenesis of large diameter mouse sensory neurons.

Analysis of neuronal development has emphasized the importance of voltage-activated Ca2+ currents during the initial period of differentiation. We investigated non-N, non-L Ba2+ currents through Ca2+ channels in freshly dissociated large diameter embryonic mouse dorsal root ganglion neurons using the whole-cell patch-clamp technique. Two types of omega-agatoxin IVA-sensitive currents were clearly distinguished at embryonic day 13: a sustained P-type current blocked selectively at 30 nM (IC50 = 3nM) and an inactivating Q-type current blocked in the range 50-500 nM (IC50 = 120nM). The P-type Ca2+ current disappeared at day 15 whereas the Q-type Ca2+ current increased two- to three-fold during the same embryonic period. In contrast, the contribution of the non-L, non-N, omega-agatoxin IVA-resistant current (R-type) was constant during this developmental span. In conclusion, our results clearly show that P- and Q-type Ca2+ currents are differentially expressed during ontogenesis in large diameter dorsal root ganglion neurons. The developmental change, which occurs during the period of target innervation, could be related to specific key events such as natural neuron death and onset of synapse formation.

Lack of association between juvenile myoclonic epilepsy and GABRA5 and GABRB3 genes.

Alpha 5 and beta 3 GABAA receptor genes are major candidates for epilepsy, as they code for subunits of the most important human inhibitory neurotransmitter. Moreover, they are located within a region of the human genome previously implicated in disorders including epilepsy. We carried out an association study between dinucleotide repeat polymorphisms in these two genes and juvenile myoclonic epilepsy (JME). JME is the most common idiopathic epilepsy and is characterized by a complex mode of inheritance. We did not find significant differences between controls and patients for allele or genotype frequencies.

Alterations of metallothionein II and apolipoprotein J mRNA levels in kainate-treated rats.

Although different mechanisms have been proposed, it has been suggested that apolipoprotein J (ApoJ) and metallothionein II (MTII), expressed by astrocytes, are protective proteins. Alterations in their expression may contribute to the involvement of astrocytes in epileptogenesis. We studied the expression of MTII and ApoJ genes 7 days following status epilepticus induced in rats by intra-amygdala injection of kainate (KA). ApoJ mRNA levels were increased in both cortex (77%, p < 0.01) and hippocampus (64%, p < 0.02), whereas, in contrast to previous findings 3 days after KA injection, DNA fragmentation was not detected on agarose gel electrophoresis. These results show that ApoJ is induced along with early genes during massive apoptosis, and remains induced after the acute phase. MTII mRNA levels were altered only in hippocampus (62%, p < 0.05), whereas KA-treated rats had no seizure for 7 days. The sustained induction of MTII mRNA shows that zinc homeostasis is not returned to normal or alternatively that astrocytes maintain an altered phenotype in spite of normal zinc release. Polyadenylated RNA and beta-actin mRNA levels were in contrast unaltered in cortex or hippocampus at this time point. These specific variations in ApoJ and MTII mRNA expression during the latent period suggest that they are part of long term biochemical and/or phenotypic alterations in astrocytes, following a single episode of severe seizures.

The influence of hippocampal kindling on sleep organization in cats. Effects of alpha-methylparatyrosine.

The effects of daily electrical stimulation of ventral hippocampus (hippocampal kingling) on the sleep-waking cycle were studied in the cat. Hippocampal kindling developed in 61 days and 4 stages according to progressive development of EEG and behavioral seizures and culminated in generalized convulsions. The 'all or none' response of Goddard was found once generalized seizures appeared. The influence of the hippocampal kindling effect on the sleep-waking cycle was investigated kindling and kindled cats. Paradoxical sleep (PS) decreased from stage 2 to stage 4. This diminution persisted even if stimulation was stopped. No significant modifications of waking (W) and slow wave sleep (SWS) occurred. A peculiar facilitation of interictal discharges by SWS was noticed. In contrast, waking and PS inhibited them. The influence of the modification of the sleep-waking cycle induced by alpha-methylparatyrosine (AMPT) known as an inhibitor of catecholamine (CA) synthesis was investigated in hippocampal kidling. Two principal results were found: (1) a PS increase during the 6 h following AMPT injection; (2) a lack or a delay of kindling in two animals which showed an increase of PS after AMPT injections. The results are discussed according to the modifications of both the sleep-waking cycle and the brain catecholamine levels secondary to AMPT treatment.

Developmental regulation of carbonic anhydrase expression in mouse dorsal root ganglia.

The development of proprioceptive neurons in mammalian dorsal root ganglia (DRG) remains poorly documented since few specific markers for these neurons are known. Recent studies suggest that carbonic anhydrase (CA) is a specific marker of this functionally defined neuronal population. The present study was designed to investigate the development of CA staining in sensory neurons. We investigated CA reactivity in mouse lumbar DRGs from embryonic day 13 (E13) to postnatal day 100 (P100) using a modified cytoenzymatic Hansson method. Neuronal CA reactivity was first detected during the perinatal stage (1-3% of DRG neurons) and increased progressively from P0 to P60 when it reached a plateau (about 30-33% of DRG neurons). Statistical morphometric analysis was used to define whether CA staining identifies the same population(s) during development. The results demonstrated that, whatever the stage of development, reactive neuronal cells are included in the well-defined large type A population. The possibility that neuronal CA expression is a reliable marker of the 'functional activity' of the proprioceptive neurons in mammals is discussed. The late development expression of the enzyme (after target innervation) raises the possibility of a regulation of the CA phenotype by neuron-target interactions.

Sleep influence on seizures and epilepsy effects on sleep in partial frontal and temporal lobe epilepsies.

OBJECTIVES: A reciprocal effect is observed between sleep and epilepsy. Sleep effect on epilepsy is protective and facilitating. Reciprocally epilepsy alters sleep organization and microarchitecture. This interelationship is well established for some epilepsies but remains undefined for cryptogenic and symptomatic frontal and temporal lobe epilepsies. In order to research sleep influence on seizures and epilepsy effects on sleep we carried out two studies in patients with cryptogenic/symptomatic frontal or temporal lobe epilepsies. METHODS: The occurrence of seizures in relation to the state of alertness was analyzed in patients with (1) mesial temporal and frontal lobe epilepsy, and (2) in patients with mesio-lateral temporal and mesial temporal lobe epilepsy in several conditions. Sleep analysis (organization and microarchitecture) was realized. RESULTS: We found: (1) a precise relationship between sleep and seizures in frontal lobe epilepsy (FLE); (2) a precise relationship between wakefulness and seizures in temporal lobe epilepsy (TLE); (3) sleep organization was normal in FLE and altered in TLE; (4) alterations of sleep microarchitecture in FLE and TLE. CONCLUSIONS: Seizure occurrence was mainly in relation to sleep for FLE and to wakefulness for TLE. Sleep organization appeared more altered for TLE than FLE. These results allow practical applications to localize and study FLE and TLE.

Skeletal muscle extracts promote the survival of neurofilament-positive mammalian sensory neurons.

Cultured neurons of the mammalian dorsal root ganglia (DRG) can be divided, as in intact ganglia, into two classes: 'large light' (neurofilament-positive) and 'small dark' (neurofilament-negative) neurons. While 'small dark' neuron survival depends on NGF during ontogenesis, little is known about the neurotrophic factor requirement of the 'large light' sub-population. This study demonstrates that the in vitro survival of neonatal mammalian neurofilament-positive DRG neurons requires the presence of a neurotrophic factor present in skeletal muscle extract.

Inhibition of T-type calcium currents by dihydropyridines in mouse embryonic dorsal root ganglion neurons.

The effects of dihydropyridines (DHPs) normally considered to be specific for L-type calcium channels were studied on the T-type Ca channel current of acutely isolated dorsal root ganglion (DRG) neurons taken from 13-day-old (E13) mouse embryos. Potent but reversible inhibitory effects of the DHP nicardipine were found in the micromolar range. For example, 5 microM nicardipine suppressed 93 +/- 5% of T-type currents. In comparison, other classical DHPs such as nifedipine, PN 200-110 and nitrendipine had only weak effects (less than 20% inhibition) at the same concentration. The inhibition by nicardipine was found slightly to be voltage dependent and the drug induced a leftward shift in the steady-state inactivation. The DHP agonist (-)-Bay K 8644, which dramatically increased the L-type current, weakly decreased T-type Ca currents (17 +/- 8% at 5 microM). In conclusion, neuronal T-type Ca channels may be potential targets for some dihydropyridines. This property is not only a feature of the central nervous system (J. Physiol., 412 (1989) 181-195) and can be extended to peripheral neurons.

Facilitation of olfactory bulb kindling after specific destruction of serotoninergic terminals in the olfactory bulb of the rat.

The role of serotonin (5-HT) in the kindling model of epilepsy was investigated by performing specific lesions of the 5-HT innervation at the level of the primary epileptogenic focus. We injected bilaterally 5,6-dihydroxytryptamine in the olfactory bulb (OB) of adult rats which were submitted to electrical stimulations of the OB until the occurrence of stage-5 seizures. Immunohistochemical controls of lesions were realized with a specific anti-5-HT antibody. Results revealed that the lesions facilitated the initial development of kindling (increase of afterdischarge duration and of kindling rate), suggesting that 5-HT terminals exert a modulatory effect on the propagation of the epileptic activity.

N-[1-(2-thienyl)cyclohexyl]-piperidine (TCP) does not block kainic acid-induced status epilepticus but reduces secondary hippocampal damage.

Distant damage, localized in the CA3 and CA1 areas, was observed in the hippocampus of rats as a consequence of status epilepticus (SE) induced by the injection of 2.5 nmol of kainic acid (KA) into the amygdala. In animals pretreated with an intraperitoneal injection of the non-competitive antagonist of the N-methyl-D-aspartate receptor, N-[1-(2-thienyl)cyclohexyl]-piperidine (TCP) (20 mg/kg), distant neuronal damage was reduced (CA1 neurons were always spared) whereas the rats still developed SE with an earlier onset. These results demonstrate the protective effect of TCP and confirm that epileptic activity and brain damage may be dissociated by NMDA receptor antagonists.

Initiation of carbamazepine therapy in partial epilepsy: a regional cerebral blood flow study.

The effect of the initiation of carbamazepine (CBZ) treatment on regional cerebral blood flow (rCBF) was studied using the intravenous Xenon technique in a group of epileptic patients suffering from complex partial seizures. A slight increase in mean rCBF (10.8 +/- 8.8%, P less than 0.01) was observed in 12 patients after the first month of CBZ treatment, while no rCBF change was found after 6 months of CBZ treatment. Regional analysis showed that the rCBF increase following 1 month of CBZ treatment involved all cortical regions with the exception of the right occipital region, irrespective of the initial value. Repeated rCBF measurements performed in normal volunteers (N = 6) and in epileptic patients (N = 10), chronically treated and not subjected to therapeutic modification, showed no significant change. The initial effect of CBZ on CBF found at the onset of the treatment but not after 4-6 months may be related to the improvement in epilepsy and in cerebral function (as suggested by cognitive findings).

Catecholaminergic systems and amygdala kindling development. Effects of bilateral lesions of substantia nigra dopaminergic or locus coeruleus noradrenergic neurones.

The effects of the bilateral and selective destruction of substantia nigra (SN) dopaminergic or locus coeruleus (LC) noradrenergic neurones, consecutive to a local injection of 6-hydroxydopamine, were studied on the development of amygdala kindling. Immunohistochemical controls of lesions were performed using selective dopamine (DA) or norepinephrine (NE) antibodies. The results demonstrated that a massive destruction of SN pars compacta neurones did not modify the rate of kindling development. Conversely, the lesions of LC neurones (sparing lateral tegmental nuclei) markedly facilitated the development of amygdala kindling. This effect was related to the extent of NE denervation. Together, these results suggest that DA is not strongly involved in the development of kindling, and that the nigrostriatal output does not play a major role in the generalization of kindled seizures. In contrast, they confirm an inhibitory influence exerted by LC noradrenergic ascending pathways on the development of kindling.

Treatment of infantile spasms with intravenous gamma-globulins.

In a prospective study, 23 children with infantile spasms received intravenous gammaglobulins in high doses. 19 patients present a West syndrome. 4 older patients were included in the study because infantile spasms had preceded their Lennox-Gastaut syndrome. None of the patients had recently undergone corticosteroid therapy. No effect was observed in 15 patients, while transitory clinical and/or electroencephalographic improvement was noted in 3. Complete normalization was obtained in the remaining 5 patients, of whom 4 had severe brain lesions. No correlation existed between the therapeutic results and immunological abnormalities, a deficiency in IgG subclasses in particular. On the whole, the therapeutic results were disappointing. But the existence of some cases in which spectacular electroencephalographic and/or clinical improvement was obtained leads us to suggest that IV gamma-globulins be used as auxiliary treatment in infantile spasms.

Therapeutic strategies against epilepsy in Mediterranean countries: a report from an international collaborative survey.

A collaborative survey was performed to compare prescribing strategies for the treatment of epilepsy in Mediterranean countries, based on analysis of 500 questionnaires compiled by physicians in 14 different countries. For partial seizures, carbamazepine was the drug of choice in most countries, whereas the second choice of drug differed widely. For primarily generalized tonic-clonic seizures, valproic acid was usually preferred, but other drugs used widely in some countries included phenobarbital, phenytoin and carbamazepine. Lamotrigine was the most popular second-line drug for primarily generalized tonic-clonic seizures in the European countries. In patients where the initial drug failed, switching to an alternative monotherapy was usually the preferred strategy, but advocates of early use of combination therapy exceeded 30% in the respondents of seven countries. Most respondents, in all countries except Turkey, did not prescribe drugs to prevent recurrence of febrile seizures; however, intermittent prophylaxis with a benzodiazepine was advocated by a considerable number of physicians, and continuous prophylaxis was prescribed by a significant minority of respondents in France, Syria and Tunisia. New drugs were rarely used as first-line treatment due to high cost and inadequate experience. Overall, this survey indicates that there is a wide variability in therapeutic practices between and within countries. This information may be useful for the implementation of national educational activities and for the design of pragmatic trials aimed at comparing different therapeutic strategies.

Some neuropharmacological effects of an ethanolic extract of Maprounea africana in rodents.

The ethanolic extract of the leaves of Maprounea africana (Euphorbiaceae), a medicinal plant in the Congolese traditional medicine, induced hypothermia and reduced the latency to the loss of the righting reflex and prolonged the sleeping time induced by pentobarbital in mice. It also significantly delayed the onset of clonic convulsions induced by pentylenetetrazole in mice. However, the extract did not affect either generalized convulsions induced by maximal electroshock and picrotoxin or limbic status epilepticus produced by pilocarpine and kainic acid.

Effects of an ethanolic extract of Desmodium adscendens on central nervous system in rodents.

This study investigates some pharmacological effects of the ethanolic extract of the leaves of Desmodium adscendens (Papillionaceae), a medicinal plant in the African traditional medicine, on the central nervous system. The plant extract induced hypothermia and had analgesic effect in mice. D. adscendens suppressed the tonic phase of convulsion and mortality induced by pentylenetetrazole (PTZ) in mice. In addition, the plant extract delayed the onset of PTZ forelimb clonus, and generalized limbic seizures induced by kainic acid. In contrast, the plant extract did not affect either tonic convulsion induced by maximal electroshock in mice or the progression of limbic seizures towards the status epilepticus in rats.

[What organisation to improve health care management of patients with partial refractory epilepsy?]. / Quelle organisation de soins pour améliorer la qualité de la prise en charge des patients avec une épilepsie partielle pharmaco-résistante?

Management of refractory epilepsy requires a comprehensive approach with cooperation between primary care physicians, neurologists or neuropaediatricians and specialist epilepsy centres. A regional or interregional network organisation may provide improved access to care provision including inpatient facilities for emergencies, early referral to an epilepsy specialist centre. Such organisation should be appropriate to quality standards for neurophysiology and neuroimaging assessment, epilepsy surgery programme and psychological and social counselling services.

[Neurogenesis in the adult brain: the demise of a dogma and the advent of new treatments]. / La neurogénèse dans le cerveau adulte: de l'effondrement des dogmes vers de nouvelles thérapies?

Since the early sixties, many concepts concerning neurogenesis have been progressively ruled out. Proof of the persistence of a physiological neurogenesis in adult mammals, including humans, raised the concept of a unique precursor cell giving birth to neurons and glial cells. According to this concept, a real continuum between neuroepithelial cells, radial glia and astrocytes exists from the embryonic period to adult age and generates both neurons and glial cells. Different factors, either secreted in situ or transported by blood, can influence this physiological neurogenesis process. The targets and role of newborn neurons are not clearly understood. In pathological conditions (ischemia, epilepsy, lesions), the physiological neurogenesis process is enhanced; however the significance of this neurogenesis excess (beneficial or deleterious) is not completely known. Advances in understanding the regulation of neurogenesis in these different conditions represent hopes of new therapeutic procedures, not only by improving the control of differentiation and survival of transplanted stem cells, but also by the possibility of modifying the processes of "endogenous neurogenesis".