Synthesis and biological effects of some kynurenic acid analogs.

The overactivation of excitatory amino acid receptors plays a key role in the pathomechanism of several neurodegenerative disorders and in ischemic and post-ischemic events. Kynurenic acid (KYNA) is an endogenous product of the tryptophan metabolism and, as a broad-spectrum antagonist of excitatory amino acid receptors, may serve as a protective agent in neurological disorders. The use of KYNA is excluded, however, because it hardly crosses the blood-brain barrier. Accordingly, new KYNA analogs which can readily cross this barrier and exert their complex anti-excitatory activity are generally needed. During the past 6 years, we have developed several KYNA derivatives, among others KYNA amides. These new analogs included one, N-(2-N,N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride (KYNA-1), that has proved to be neuroprotective in several models. This paper reports on the synthesis of 10 new KYNA amides (KYNA-1-KYNA-10) and on the effectiveness of these molecules as inhibitors of excitatory synaptic transmission in the CA1 region of the hippocampus. The molecular structure and functional effects of KYNA-1 are compared with those of other KYNA amides. Behavioral studies with these KYNA amides demonstrated that they do not exert significant nonspecific general side-effects. KYNA-1 may therefore be considered a promising candidate for clinical studies.

CREB controls cortical circuit plasticity and functional recovery after stroke.

Treatments that stimulate neuronal excitability enhance motor performance after stroke. cAMP-response-element binding protein (CREB) is a transcription factor that plays a key role in neuronal excitability. Increasing the levels of CREB with a viral vector in a small pool of motor neurons enhances motor recovery after stroke, while blocking CREB signaling prevents stroke recovery. Silencing CREB-transfected neurons in the peri-infarct region with the hM4Di-DREADD blocks motor recovery. Reversing this inhibition allows recovery to continue, demonstrating that by manipulating the activity of CREB-transfected neurons it is possible to turn off and on stroke recovery. CREB transfection enhances remapping of injured somatosensory and motor circuits, and induces the formation of new connections within these circuits. CREB is a central molecular node in the circuit responses after stroke that lead to recovery from motor deficits.

Kynurenine administered together with probenecid markedly inhibits pentylenetetrazol-induced seizures. An electrophysiological and behavioural study.

The kynurenine pathway converts tryptophan into various compounds, including l-kynurenine, which in turn can be converted to the excitatory amino acid receptor antagonist kynurenic acid, which may therefore serve as a protective agent in such neurological disorders as epileptic seizures. Kynurenic acid, however, has a very limited ability to cross the blood-brain barrier, whereas kynurenine passes the barrier easily. In this study, we tested the hypothesis that kynurenine administered systemically together with probenecid, which inhibits kynurenic acid excretion from the cerebrospinal fluid, results in an increased level of kynurenic acid in the brain that is sufficiently high to provide protection against the development of pentylentetrazol-induced epileptic seizures. CA3 stimulation-evoked population spike activity was recorded from the pyramidal layer of area CA1 of the rat hippocampus, and in another series of behavioural experiments, water maze and open-field studies were carried out to test the presumed protective effect of kynurenine + probenecid pre-treatment against pentylenetetrazol-induced seizures. This study has furnished the first electrophysiological proof that systemic kynurenine (300 mg/kg, i.p.) and probenecid (200 mg/kg, i.p.) administration protects against pentylenetetrazol-induced (60 mg/kg, i.p.) epileptic seizures.

The effects of brain lesions on the course of chronic epilepsies.

The effect of intercurrent brain lesions on the characteristics of chronic epilepsies has not yet been the subject of detailed investigation. We therefore retrospectively examined this issue for idiopathic, cryptogenic as well as symptomatic chronic epilepsies in patients documented in routine investigations at our outpatient seizure unit between the occurrence of epilepsy and commencement of the study. The clinical criteria for inclusion in this study were brain injury by trauma, stroke or intracerebral hemorrhage, documented by CT scan, and the occurrence of this so-called index event in patients with established chronic epilepsy. These requirements were met by 63 patients (40 male, mean age 44.8 years, SD 14.7 a; 23 female, mean age 43.1 years, SD 16.4 a). Seizure characteristics, EEG recordings as well as seizure frequencies before and after the index event were compared. Patients and controls were observed for a mean time of 22.12 years (SD 7.33 a) and 22.01 years (SD 11.31 a), respectively. Two patients presenting with generalized seizures prior to brain injury underwent a change in seizure characteristics. One control (without intercurrent brain lesion; matched for age, sex, age at onset of seizure disorder and classification of seizure disorder) primarily presenting with partial seizures evolving to generalized seizures showed changed seizure characteristics. These changes are statistically insignificant (McNemar test for the significance of changes). Seizure frequencies decreased significantly after brain injury. EEG recordings mirrored clinical findings with additional focal aspects according to brain lesion. These findings are discussed mainly with respect to the cofactorial etiology of epilepsies.(ABSTRACT TRUNCATED AT 250 WORDS)

Agenesis of the corpus callosum and epilepsy in two brothers. Neurophysiological and MRI features.

We report on two brothers with partial agenesis of the corpus callosum and seizure disorder presumably related to ectopic grey matter. Development of both patients was characterized by psychomotor retardation and focal epileptic seizures. Genetic examination revealed normal karyotypes. One brother showed a remarkable focal miniature spike and wave periodicity constantly observed on sequential EEG records. Magnetic resonance imaging revealed partial agenesis of the corpus callosum and ectopic grey matter. Prior computerized tomography failed to visualize ectopic grey matter and overestimated corpus callosum agenesis. The heterotopic grey matter, isolated from the surrounding inhibiting influences, is the most probable source of focal seizures and the partial connection of both hemispheres may explain secondary generalization of seizures.

[Clinical aspects of brain death]. / Die Klinik des Hirntodes.

The cause of brain death must be known irreversible primary or secondary structural damage of brain and brain stem. The clinical signs and symptoms of the irreversible cessation of brain functions enable to diagnose brain death. An EEG at maximal gain reflects absence of cerebral electrical activity. The presence of an isoelectric EEG is a mandatory requirement for the diagnosis of brain death. Angiographic, sonographic or other methods to assure cessation of cerebral blood flow but also other methods as the apnea test etc. are helpful but seem to be not necessary. Nearly in every case typical signs and symptoms of an acute midbrain- and bulbar brain syndrome can be diagnosed in the pre-stage of brain death. In about 60% medullary-initiated movements and spinal reflexes can appear and persist for prolonged periods in brain dead patients.

[Control of serum concentration of anticonvulsants in pregnancy]. / Serumkonzentrationskontrollen der Antiepileptika in der Schwangerschaft.

In a prospective study we investigated the serum concentrations and frequency of seizures in 38 women with epilepsy in a total of 44 pregnancies. Monthly follow-up examinations were carried out in cooperation with the risk outpatient unit of the Department of Gynecology. Antiepileptic serum concentrations were determined using the technique of fluorescence polarisation. At constant dosage, a decrease in serum concentration occurred in most cases with a maximum at the 5th and 6th month of gestation, regardless of the kind of antiepileptic medication. No changes in seizure frequency have been observed. The treatment of epilepsy during pregnancy should in any case depend on the course of the illness, rather than on laboratory parameters.

[Cerebellar atrophy and phenytoin poisoning. An MR study]. / Kleinhirnatrophie und Phenytoinintoxikation. Eine MR-Studie.

Phenytoin has been considered a possible cause of cerebellar degeneration, especially after clinical intoxication. Magnetic resonance provides the diagnosis of anatomical structures in the posterior fossa without the limitation of beam hardening artefacts. The aim of this study was to evaluate the relationship of phenytoin medication and cerebellar atrophy in 11 patients with increased serum levels (21.4 micrograms/ml-95.6 micrograms/ml). Five patients had normal cerebellar structures, although three of them had a history of clinical intoxication and all had at least one episode of increased serum level of DPH. The remaining six patients had moderate severe cerebellar atrophy (n = 4) and atrophy of the vermis cerebelli (n = 5). Two of them had never experienced clinical intoxication. There was no correlation between the degree of atrophy and severity of clinical symptoms and evaluation of serum DPH levels (up to four times normal values). There was also no correlation between cerebellar atrophy, duration of epilepsy and frequency of seizures. We conclude that phenytoin overdosage does not necessarily result in cerebellar atrophy and it is unlikely that phenytoin medication was the only cause of cerebellar atrophy in the remaining patients.

Statistical modelling in analysis of outcome after trauma Glasgow-Coma-Scale and Innsbruck-Coma-Scale.

AIM OF THE STUDY: The current study investigated the Glasgow-Coma-Scale (GCS) and the Innsbruck-Coma-Scale (ICS) for accuracy and reliability of prehospital prediction of non-survival. METHODS: 254 patients were scored immediately after trauma. RESULTS: Both scales equally predicted non-survival with low scores (p < 0.001). The ICS was slightly better in overall prediction of patient outcome (ICS: 84.98%; GCS: 82.68%), but more importantly, statistical analysis (logistic regression model) showed a greater distance between the median scores of survivors and non-survivors, when scored with the ICS (survival: 12; non-survival: 3) than when scored with the GCS (survival: 7; non-survival: 4). CONCLUSION: The results of the present study not only suggest that it is possible to predict mortality prior to therapy for any individual GCS and ICS coma score, but also indicated the ICS to be safer to use than the GCS because of the greater distance of the median scores for survivors and non survivors.

Association of serum antibodies to heat-shock protein 65 with carotid atherosclerosis.

Arteriosclerotic lesions can be induced in normocholesterolaemic rabbits by immunisation with heat-shock protein (hsp) 65, a stress protein expressed in high concentrations in human atherosclerotic lesions. If an immune reaction to hsp65 also plays a part in human atherogenesis, it should be possible to detect anti-hsp65 antibodies in patients with atherosclerotic lesions. To study the possible relation between immune reaction to hsp65 and atherosclerosis, 867 normal inhabitants of South Tyrol, aged 40-79 years, were selected randomly for determination of serum antibodies against hsp65, simultaneous sonographic assessment of carotid atherosclerotic lesions, and evaluation of established risk factors--ie, blood cholesterol, hypertension, smoking, diabetes mellitus, and obesity. Autoantibodies to nuclear antigens, thyroid antigens, and rheumatoid factors were also measured. Serum anti-hsp65 antibodies were significantly (p < 0.05) increased in subjects aged 60-79 years with carotid atherosclerosis compared with those without lesions, and increased antibody concentration was independent of age, sex, and other established risk factors. On the other hand, the incidence and titres of autoantibodies did not correlate with carotid atherosclerotic lesions. Our data provide the first evidence of a strong correlation between anti-hsp65 antibodies and carotid atherosclerosis, suggesting that hsp65 might be involved in the pathogenesis of atherosclerosis.

Indication, efficiency and complications of intrathecal pump supported baclofen treatment in spinal spasticity.

In 19 patients, who suffered from severe spinal spasticity of different etiologies and did not respond sufficiently to oral antispastic therapy, intrathecal Baclofen test boli were administered. In 11 patients a DAD (Drug Administration Device) [SynchroMedR Model 8611 H, Medtronic Inc. Minneapolis, USA] was implanted. Catheter dislocation or torsion was the most common complication to be observed in these 11 patients. Long term intrathecal Baclofen application was effective in all patients, as reducing spasticity, flexor spasms and spasm induced pain. In some cases the motor performance ameliorated.

Long-term intrathecal baclofen treatment in supraspinal spasticity.

Baclofen, a derivate of gamma-amino butyric acid (GABA), is known to be a useful drug in spasticity treatment. To achieve a good therapeutic response higher oral dosages have to be administered related with central side effects. Intrathecal application of Baclofen in microgram range dosages is proved to be effective in spinal spasticity. The efficiency of intrathecal Baclofen in patients suffering from supraspinal spasticity is discussed controversially. We report on 9 patients with long-term intrathecal Baclofen treatment, all of them responding well presenting a marked reduced muscle tone. In most cases an improvement of motor performance and in two cases improved bladder function was observed. The therapeutical dosages administered to patients with supraspinal spasticity exceed those administered to patients with spinal spasticity by approximately 100% without provoking central side effects. Despite the risks connected with this method it has to be considered as treatment of choice in cases of severe supraspinal spasticity.

Prediction of non-survival after trauma: Innsbruck Coma Scale.

421 severely injured patients admitted to a major trauma centre in Innsbruck during the ten years, 1981 to 1990, were investigated retrospectively for early prediction of survival by means of the Innsbruck Coma Scale (ICS). All 79 patients scoring 0 or 1 died within 21 days. The findings of this study indicate that the ICS allows a highly accurate prediction of non-survival in patients with scores of 0 or 1 even at the time of first examination after trauma.