Tibor Kukorelli

Firing properties of cat basal forebrain neurones during sleep-wakefulness cycle.

Neuronal activity was studied in the basal forebrain area (BFA) of freely moving cats during wakefulness (W), slow wave sleep (SWS) and paradoxical sleep (PS). Two classically synchronizing and hypnogenic regions, the preoptic area (POA) and the olfactory tubercle (OT) were explored by microelectrodes. Compared to W, the discharge rate in most of the POA cells was not modified or was slightly reduced by SWS, but it was increased by PS. Half of the OT cells increased slightly their firing frequency during falling asleep. A great proportion of OT neurones showed facilitation of activity during PS also, which in half of the cells started already in the last seconds of SWS. The results are discussed from the point of view of the synchronizing and hypnogenic influence attributed to POA and OT.

Bimoclomol (BRLP-42) Ameliorates Peripheral Neuropathy in Streptozotocin-Induced Diabetic Rats

A reduction in nerve conduction velocity and an increase in resistance to ischemic conduction failure are early signs of neural dysfunction in both diabetic patients and animal models of diabetes. The effect of Bimoclomol (BRLP-42), a drug under clinical development for the treatment of diabetic complications, on experimental peripheral neuropathy was examined in rats made diabetic by injection of streptozotocin. Daily oral doses of Bimoclomol (10 or 20 mg/kg) or control dose of gamma-linolenic acid (260 mg/kg), an agent with known neuropathy-improving effects, were administered for 3 months. Treatments began 1 day after diabetes induction to assess the prophylactic efficacy of Bimoclomol. Neuropathy was evaluated electrophysiologically by measuring motor and sensory nerve conduction velocities and resistance to ischemic conduction failure of sciatic nerve in vivo. Bimoclomol significantly reduced nerve conduction slowing and retarded the typical elevated ischaemic resistance due to streptozotocin-induced neuropathy, suggesting that the drug might be a useful treatment for diabetic peripheral neuropathies.

Effect of BRX-220 against peripheral neuropathy and insulin resistance in diabetic rat models.

Abstract: Bimoclomol (BML), a symptomatic antidiabetic agent, has been developed by Biorex R & D Co. to treat diabetic neuropathy and retinopathy. BRX‐220, an orally active member of the BRX family, has been developed to treat diabetic complications and insulin resistance (IR) as a follow‐up compound. The effect of BRX‐220 on peripheral neuropathy was examined in rats with diabetes (type 1) induced by administration of a β‐cell toxin, streptozotocin (STZ, 45 mg/kg iv). Nerve functions were evaluated by electrophysiological measurements of muscle motor and sensory nerve conduction velocities (MNCV and SNCV, respectively). MNCV and SNCV decreased in diabetic rats by 25% (p < 0.001). A 1‐month preventive treatment with BRX‐220 (2.5, 5, 10, and 20 mg/kg po) dose‐dependently improved diabetes‐related deficits in MNCV (51.3%, 71.3%, 86.1%, and 91.3%) and SNCV (48.9%, 68.5%, 86.1%, and 93.2%). Insulin sensitivity was measured using the insulin tolerance test (ITT), both in STZ diabetic and in Zucker diabetic fatty (ZDF) rats (model of type 2 diabetes). Severe IR was detected in STZ diabetic and ZDF rats. This resistance was significantly (p < 0.05) reduced by BRX‐220 treatment.

Neuronal firing in the pallidal region: firing patterns during sleep-wakefulness cycle in cats.

Neuronal activity was investigated by extracellular microelectrodes in the pallidal region of freely moving cats during wakefulness (W), slow-wave sleep (SWS) and paradoxical sleep (PS). The firing of 150 units from 35 points was examined. On the basis of the modifications of firing rates and patterns during the sleep-wakefulness cycle, 5 groups of neurons were distinguished. Two of these groups were characterized by strong increase of firing rate in W and PS and in one of them this increase preceded the cortical activation at the SWS-PS transition by an average of 26 sec. The role played by the basal forebrain area in the regulation of the sleep-wakefulness cycle is discussed.

Bimoclomol improves early electrophysiological signs of retinopathy in diabetic rats

A silent process involving both neural and vascular structures in diabetic retina persists for several years before clinically detectable retinopathy. Recordings of the electroretinogram (ERG) and visual evoked potential (VEP) provide early warning of abnormalities in the visual pathway of diabetic patients and animal models. Treatment of streptozotocin-diabetic rats for 1 or 2 months with the heat-shock protein coinducer bimoclomol, a drug ameliorating experimental neuropathy, prevented and corrected the abnormal increase in latency and reduction of amplitude of ERG and VEP waves both in acute and chronic experiments. Improvements may be explained by cytoprotective effect of bimoclomol on retinal glia and/or neurons against diabetes-related ischemic cell damages. These findings suggest that bimoclomol may have future therapeutic use in diabetic retinopathy.

Differential EEG effects of the anxiolytic drugs, deramciclane (EGIS- 3886), ritanserin and chlordiazepoxide in rats

Abstract The influence of serotonergic and benzodiazepine type anxiolytic drugs on the cortical activation and sleep-wakefulness cycle were compared by evaluating the effects of ritanserin and deramciclane (EGIS-3886), two 5-HT2 receptor antagonists, and chlordiazepoxide on the electroencephalogram (EEG) in freely moving rats. Following drug administration (1, 3, and 10 mg/kg, PO for all drugs), EEG was continuously sampled for 6 h and power spectra were calculated for every 5 s to assess changes in slow wave activity and sleep phases. In a separate test, anticonvulsant effects of the drugs were examined in mice. Both deramciclane and ritanserin slightly increased total time spent in deep sleep (DS) and lengthened sleep episodes. In contrast, chlordiazepoxide had a strong inhibitory action on DS, sleep time being shifted to more superficial light sleep (LS). The incidence and length of the high voltage spindle (HVS) episodes characteristic for the motionless, awake rat were increased at the highest dose of both deramciclane and ritanserin, while it was decreased by chlordiazepoxide. In mice, chlordiazepoxide had a marked anticonvulsant effect, while deramciclane was moderately effective and ritanserin ineffective. In conclusion, the 5-HT2 receptor antagonist anxiolytic drugs seem to be superior compared to the benzodiazepine type anxiolytic drug, chlordiazepoxide, as ritanserin and deramciclane improved sleep quality by increasing sleep episode length and time spent in DS, while chlordiazepoxide enhanced sleep fragmentation and decreased DS.

Effects of hypnogenic vagal stimulation on thalamic neuronal activity in cats

Neuronal responses from the ventro-postero-medial (VPM) and reticular (NR) nuclei of cat thalamus to vagal stimulation was recorded during wakefulness (W), slow-wave-sleep (SWS), and paradoxical sleep (PS) using chronically implanted microelectrodes. Cellular firing was facilitated in NR and depressed in VPM when weak, hyponogenic stimuli were delivered to the vagal nerve during W and SWS. Higher intensity vagal stimulation increased firing frequency and duration of discharge in both nuclei. Vagally induced discharges of several VPM neurons were depressed by NR stimulation. We speculate that intrathalamic mechanisms play a role in the genesis of induced synchronization and sleep.

In vivo and in vitro electrophysiological monitoring of rat neocortical activity after dietary fumonisin exposure

Corn pellets, containing 30 mg/kg bw/day fumonisin B1 (FB1) or containing no FB1 were fed in two series of experiments to rats. Spontaneous and evoked potentials were measured in the neocortex both in vivo and in vitro in “corn fed control” rats and in rats after a five day dietary exposure to FB1. The FB1 content of corn was quantitated by HPLC. Auditory evoked potentials recorded in vivo on freely moving animals after feeding a corn diet containing FB1 for 5 days revealed a highly significant 20–60% decrease in the primary and mid-latency components; cortex slices in vitro showed a reduced excitability both in standard artificial cerebrospinal fluid (ACSF) solution and in a 4-aminopyridine induced epilepsy model. Spontaneous epileptic discharges after FB1 exposure had an increased latency, decreased frequency, longer duration and modified signal forms. Altered excitability and seizure susceptibility of the neocortex after fumonisin exposure are suspected to be associated with modified signal transmission. These changes may be due to concurrent effects of possible liver and renal toxicity or partly of nutritional deficiencies.

Long-term sleep deprivation by hypothalamic stimulation in cats

Several techniques were developed to prevent sleep in animals in order to examine the biological role fulfilled by sleep; however, most were either stressful or difficult to accomplish routinely, especially in such a large animal as the cat. Electrical stimulation of activating structures in the brain presents a very attractive alternative to peripheral stimulation used by the usual sleep deprivation methods although it has been rarely tried. The paper describes a microcomputer-based system used to achieve sleep deprivation in cats by stimulating the hypothalamic predatory area with short trains. During control days and deprivation the electrocorticogram (EEG), electromyogram (EMG) and electrooculogram (EOG) were continuously digitalized by the computer in 5 s epochs and the integrated power of the 4 usual frequency bands of the EEG (alpha, beta, delta, theta) as well as the variance of EMG and EOG signals were calculated. Criteria for stimulus delivery were based on the integrated power of the delta band and on the variance of EMG but the flexibility of the computer ensures that any other parameter can be used to achieve total or selective sleep deprivation.

MODIFICATION OF CORTICAL AND THALAMIC UNIT ACTIVITY BY VISCERAL STIMULATION DURING SLEEP IN CATS

Publisher Summary This chapter describes the modification of cortical and thalamic unit activity by visceral stimulation during sleep in cats. There are many studies that attest the relationships between homeostatic processes and the mechanisms controlling sleep. The activity of internal organs, which are the effectors of homeostatic regulation, varies with the sleep phases. By contrast, the changes of homeostasis are followed by modifications of sleep-wakefulness cycle. It has been found that sleep pattern is under the influence of the body temperature, the metabolic events, and the blood pressure. However, very little is known about the neuronal mechanisms brought into action by stimulation of visceroreceptors and vegetative nerves during wakefulness and sleep. Therefore, the chapter describes the characteristic patterns of thalamic and cortical responses elicited by stimulation of visceral afferents in three stages of the sleep-wakefulness cycle.