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Summary: Purpose: Valproate (VPA) is an extensively used drug in the therapy of epilepsies. One of the most frequently reported side effects of VPA is hemorrhagic diathesis. Some authors emphasized the decreased platelet count as the basis of VPA-induced hemorrhagic diathesis, but some reports suggested that a significant proportion of patients with normal platelet count may still have an altered platelet function. The mechanism of the VPA-induced platelet dysfunction has not yet been elucidated. A determining element of platelet functions is the arachidonate cascade. Present ex vivo experiments were designed to determine whether a relation exists between the incidence of hemostasis caused by VPA and the effect of this drug on the arachidonate cascade of platelets. Methods: Platelets were isolated from patients receiving long-term VPA treatment (serum level, 36.04 ± 16.12 μg/ml; n = 10) or carbamazepine (CBZ) treatment (serum level, 5.24 ± 2.67 μg/ml; n = 10) and were labeled with [14C]arachidonic acid. (CBZ-treated patients were chosen as a control group, because CBZ causes blood dyscrasias similar to those elicited by VPA, but there has been no report that CBZ induces a platelet dysfunction.) The 14C-eicosanoids were separated by means of overpressure thin-layer chromatography and determined quantitatively by liquid scintillation. Results: Even when the mean plasma concentration of the drug was low, VPA treatment reduced the activity of the arachidonate cascade in platelets. VPA effectively inhibited the cyclooxygenase pathway and the synthesis of the strong platelet aggregator thromboxane A2. Conclusions: Inhibition of the platelet arachidonate cascade may contribute to the platelet-function alterations caused by VPA.

Dystonia is a syndrome characterized by sustained muscle contraction. It is frequently causing twisting and repetitive movements, or leading to development abnormal postures. The management of the disease is usually consists of medication, surgical interventions, botulinum toxin injection, or other complementary methods. The authors have been using the botulinum toxin treatment since 1991.The goal of the study was to investigate the efficacy and safety of the botulinum toxin injection, in patients with focal dystonia and hemifacial spasm.A total of 94 patients diagnosed with cervical dystonia (n=33), blepharospasm (n=32), or hemifacial spasm (n=29) were treated. The mean age of the patients was 62.4 years, and the mean duration of the therapy was 6.8 years. The medication took place with local injection of botulinum toxin type A. The efficacy of the treatment was assessed with Patient Global Impression scale. The authors also evaluated the side effects and complications of the therapy, as well as the causes of the treatment discontinuation.The botulinum toxin treatment was effective in 92% of the patients. It is a great importance that the therapy resulted significantly improvement in 56% of the patients. There was no significant difference neither among the types of the dystonia (cervical dystonia 87%, blepharospasm 93%, and hemifacial spasm 96%), nor among the medications (Botox 92%, Dysport 92%) in point of efficacy. Temporary weakness occurred only at 6 patients. There was neither serious side effect, nor complication related to the treatment.The authors can conclude that the botulinum toxin injection is effective and safe therapy, in the patients with cervical dystonia, blepharospasm, and hemifacial spasm.

We investigated the influence of recurrent epileptic seizures on the arachidonic acid (AA) cascade in platelets and brain microvessels, using [(14)C]AA as a tracer substrate and chromatographic determination. The recurrent epileptic seizures of male Wistar rats were induced every second day with 3-aminopyridine (3-AP, 25 mg/kg ip) for two weeks. In the chronic 3-AP model, the earlier epileptic insults resulted in a decreased incidence of limbic seizures and higher survival rate at later administration of 3-AP. After 3-AP treatment, the formation of lipoxygenase products was unchanged, but the total amount of cyclooxygenase (COX) metabolites was decreased both in platelets and brain microvessels. The reduction in COX-mediated eicosanoid synthesis after recurrent seizures was due to the decreased synthesis of vasodilator and vasoconstrictor COX metabolites. In platelets, the 3-AP-treatment reduced the synthesis of vasodilator prostacyclin (PGI(2)), prostaglandin E(2) (PGE(2)) and 12-L-hydroxy-5,8,10-heptadecatrienoic acid (12-HHT), while the synthesis of prostaglandin D(2) (PGD(2)) remained unchanged. In isolated brain capillaries, the PGD(2), PGE(2) and 12-HHT synthesis was decreased after recurrent seizures. As for the vasoconstrictor COX metabolites, both platelets and brain microvessels synthesized significantly lesser amount of prostaglandin F(2alpha) (PGF(2alpha)) and thromboxane A(2) (TxA(2)) upon 3-AP administration. Our results indicate that platelets and isolated brain capillaries synthesize significantly lesser amount of COX metabolites after chronic 3-AP treatment. The decreased conversion of AA into different COX products may play a role in the neuroprotective/preconditional adaptation of the brain against subsequent seizures.

Summary: Purpose: The functional significance of gap-junction (GJ) channels in seizure susceptibility and induction and maintenance of seizures in the developing rat brain was investigated on the 4-aminopyridine (4-AP) in vivo epilepsy model. Methods: In electrophysiological experiments, GJs were manipulated with a blocker or opener before induction or at the active epileptic foci between postnatal days 9 and 28 (P9–28). Semiquantitative reverse transcriptase–polymerase chain reaction (RT-PCR) amplification was used to measure the levels of connexin (Cx) 26, 32, 36, and 43 mRNAs at the untreated cortex or epileptic foci. Results: The basic electrocorticogram (ECoG) and Cx messenger RNA (mRNA) expression patterns exhibited characteristic maturation; the 4-AP–induced epileptiform activity correlated well with these changes. Cx mRNA expressions were significantly upregulated around P16 (except for Cx26). The Cx26, 36, and 43 gene inducibility was highest around P16 and then declined significantly. In the youngest animals, the GJ opener induced rhythmic synchronous cortical activity. On maturation, the seizures became focalized and periodic; the discharges accelerated their amplitude and frequency increase. A transient decrease (P13–14) and then increase (P15–16) in seizure susceptibility were followed by a tendency to periodicity and focalization. Conclusions: The study suggests that GJ communication is involved in rhythm genesis and synchronization of cortical activity and may enhance the epileptogenicity of the developing brain.

Summary: Purpose: The selective contribution of neuronal gap junction (GJ) communication via connexin 36 (Cx36) channels to epileptogenesis and to the maintenance and propagation of seizures was investigated in both the primary focus and the mirror focus by using pharmacologic approaches with the 4aminopyridine in vivo epilepsy model. Methods: ECoG recording was performed on anesthetized adult rats, in which either quinine, a selective blocker of Cx36, or the broad-spectrum GJ blockers carbenoxolone and octanol were applied locally, before the induction or at already active epileptic foci. Results: The blockade of Cx36 channels by quinine before the induction of epileptiform activity slightly reduced the epileptogenesis. When quinine was applied after 25‐30 repetitions of seizures, a new discharge pattern appeared with frequencies >15 Hz at the initiation of seizures. In spite of the increased number of seizures, the summated ictal activity decreased, because of the significant reduction in the duration of the seizures. The amplitudes of the seizure discharges of all the patterns decreased, with the exception of those with frequencies of 11‐12 Hz. The blockade of Cx36 channels and the global blockade of the GJ channels resulted in qualitatively different modifications in ictogenesis. Conclusions: The blockade of Cx36 channels at the already active epileptic focus has an anticonvulsive effect and modifies the manifestation of the 1- to 18-Hz seizure discharges. Our findings indicate that the GJ communication via Cx36 channels is differently involved in the synchronization of the activities of the networks generating seizure discharges with different frequencies. Additionally, we conclude that both neuronal and glial GJ communication contribute to the manifestation and propagation of seizures in the adult rat neocortex. Ke yW ords: Gap junctions—Cx36—4-AP‐induced seizure—Epileptogenesis— Ictogenesis—In vivo—Quinine—Carbenoxolone. Epilepsy is one of the most prevalent neurologic disorders worldwide, but pharmacologic therapy remains the best remedy for its treatment. One reason for the incomplete effectiveness of the currently available anticonvulsants is that they were identified by using the same classic epilepsy models, which mainly involve the same actions, without a consideration of the variations in the pathophysiologic mechanisms that result in epilepsy. Growing evidence indicates that, besides the chemical synapses, direct coupling via gap junction (GJ) channels provides a second major pathway, contributing to normal and abnormal physiologic rhythms both during development and in the adult brain (1‐3). GJ channels mediating electrical signaling are involved in the physiologic synchronizing mechanism in the brain (3‐5) and contribute to pathologic hypersynchrony in various in vitro (6‐9) and in vivo (10‐13) epilepsy models.