The influence of stereotaxic lesions of claustrum on motor movements and behaviour in rats.

BACKGROUND: This study aimed to expand our existing information on changes in the regulation of motor movement and behaviour by investigating the effects of unilateral and bilateral lesions on the claustrum (CL). MATERIAL AND METHODS: 36 Wistar Albino adult male rats were randomly divided into six groups. An electrical lesion was created with a constant current source in the unilateral and bilateral anterior clastrum using a stereotaxic frame in rats. The lesioned groups and the control group underwent an automatic behaviour recording device such as mobilisation, freezing, eating, drinking behaviour, grooming, turning, etc. behaviour was recorded and analysed. Simultaneously, ultrasonic sounds in rats were examined with ultrasonic sound recording program. Anxiety was then reassessed with the elevated plus maze test. Data were compared with the control group. Rats were eventually sacrificed and the brain tissue was post-fixed. Histochemical examination was done and lesions' existence was confirmed. RESULTS: In this study, lesions of ventral of CL can cause increase in spontaneous behaviours such as freezing and rearing. And, it has been shown to cause a statistically significant change. In addition to the behavioural changes, right CL lesions have caused a significant increase in drinking behaviour associated with increased anxiety. All operated groups showed a significant decrease in clockwise and counterclockwise rotation movements. CONCLUSION: Experimental results show that CL lesions influence spontaneous behaviour which indicate the need for new studies to understand the role of CL in anxiety-depression.

Interrupted processing of paired somatosensory stimuli in short interstimulus intervals: role of thalamo-cortical oscillations.

BACKGROUND: Discrimination of consecutive sensory stimuli is imperative for proper sensory perception and behavioral response. We aimed to investigate the emergence of paired somatosensory responses in relation to the interstimulus interval (ISI) change. METHODS: Paired stimulus with 35 ms, 50 ms, 80 ms, 140 ms, and 500 ms ISI was applied to the median nerve and evoked responses were recorded from the primary somatosensory cortex in rats. Early and late components of both responses were analyzed in different frequency bands. RESULTS: The amplitudes were comparable for the 1st responses (S1), while the amplitude of the 2nd responses (S2), and S2/S1 sensory gating ratio were significantly lower at 35 and 50 ms ISI values. S2/S1 ratio was close to 1 at 500 ms ISI. The duration and latency of the 2nd response was also different at 35 ms ISI. In the 2nd responses, area of early high-frequency oscillations (150-400 Hz) was significantly lower at 35 ms ISI values. DISCUSSION: The shaping of 2nd somatosensory response is dependent on ISIs. Early high-frequency oscillations changes without accompanying late high-frequency oscillations alterations, may indicate that reduced thalamo-cortical drive to the cortex take a part in determining the 2nd response at short ISI. Further research is required by using neuropsychiatric disorder models where somatosensory perception is impaired.

Endothelial and Autonomic Functions in Patients with Migraine.

OBJECTIVE: It has been shown that patients with migraine have endothelial dysfunction. Migraine patients with aura, especially, have more clinical manifestations of autonomic nervous system dysfunction. We aimed to evaluate the endothelial and autonomic functions in migraine patients during both migraine headache attack and headache-free periods. DESIGN: This was a cross-sectional, randomized study. SUBJECTS AND METHODS: A total of 130 participants (67 male and 63 female patients, minimum age = 19 years, maximum age = 71 years, mean age = 38.8 ± 12.2 years) were enrolled into the study. For the statistical evaluation of data, we classified the participants of the study as follows: group 1: headache (+) aura (+); group 2: headache (+) aura (-); group 3: headache (-) aura (+); group 4: headache (-) aura (-). Noninvasive evaluation of endothelial function was performed by flow-mediated dilation (FMD) and pulse wave analysis methods. Heart rate variability measurements were used for noninvasive evaluation of autonomic functions. RESULTS: Group 1 had a higher FMD ratio than the control group, group 3, or group 4 (P < 0.001, P < 0.001, and P = 0.003, respectively). Group 4 had lower FMD ratio levels than the other migraine groups and or the control group (P < 0.001). Group 3 had the highest high-frequency (HF) power levels among all migraine groups (P < 0.001). Group 2 had higher low-frequency/HF ratio values than other migraineurs (P < 0.001). CONCLUSIONS: We concluded that endothelial dysfunction and headache are closely related. Additionally, higher parasympathetic tonus might be associated with the presence of aura.

CGRP receptor antagonist MK-8825 attenuates cortical spreading depression induced pain behavior.

BACKGROUND AND OBJECTIVE: The present study aimed to investigate the effects of selective calcitonin gene related peptide (CGRP) receptor antagonist (MK-8825) on cortical spreading depression (CSD) induced pain behavior and anxiety in freely-moving rats, and neuronal activation in the correlated anatomical regions. METHODS: CSD was induced while keeping all meningeal layers and BBB intact and MK-8825 was administered in two different doses. Regional cerebral blood flow (rCBF), arterial pressure and DC shift were recorded. Behavioral studies were conducted in freely-moving rats. Spontaneous behavior, mechanical allodynia, ultrasonic vocalization, and anxiety were evaluated. Immunohistochemistry of c-fos, CGRP, calcitonin receptor like-receptor (CLR) and receptor activity modifying protein 1 (RAMP1) were studied. RESULTS: MK-8825 did not block DC shifts in the cerebral cortex and accompanied hemodynamic response. CSD significantly induced freezing and grooming behavior in freely-moving rats. MK-8825 reversed increased episodes of freezing, grooming, wet dog shake and head shake behavior. MK-8825 increased CSD-induced reductions in von Frey thresholds, but did not change elevated plus maze results. MK-8825 blocked c-fos induction by CSD in the brainstem trigeminal nucleus caudalis (TNC) and reticular nucleus of thalamus (TRN) but not in the amygdala. Immunofluorescence analysis showed no co-localization of CGRP, CLR or RAMP1 with c-fos positive cells. CONCLUSION: CGRP receptor antagonist MK-8825 dose dependently attenuated CSD-induced trigeminal nerve mediated pain response without altering CSD waves and accompanied rCBF response. While blocking TNC activation, MK-8825 did not exert any effect on amygdala and anxiety behavior. CGRP receptor antagonists may also modulate thalamo-cortical gating.

The effect of endothelin receptor antagonists in the endotoxin-induced uveitis rabbit model.

PURPOSE: To investigate the effect of Bosentan (non-selective endothelin receptor antagonist) and BQ123 (ETA receptor antagonist) on intraocular inflammation in an endotoxin-induced uveitis (EIU) rabbit model. METHODS: Uveitis was induced by intravitreal injection of lipopolysaccharide (LPS). The animals were divided into 7 groups and there were six rabbits in each group (saline, saline and ethanol, bosentan, BQ123, lipopolysaccharide (LPS), bosentan and LPS, BQ123 and LPS-injected groups). Bosentan and BQ123 were applied before LPS injection. Aqueous humour was collected at 24th hour post-injections and enucleation was performed for the evaluation of histopathological changes. RESULTS: BQ123 decreased clinical score, cell counts and protein amount more than bosentan and it was significant for cell counts (p = 0.018). Bosentan significantly diminished inflammatory reactions more than BQ123 as shown in histopathological specimens (p = 0.002). CONCLUSIONS: ETA receptor blockage is effective on uveitis treatment by its protective effect on blood aqueous barrier.

Migraine mutations impair hippocampal learning despite enhanced long-term potentiation.

To explain cognitive and memory difficulties observed in some familial hemiplegic migraine (FHM) patients, we examined hippocampal neurotransmission and plasticity in knock-in mice expressing the FHM type 1 (FHM1) R192Q gain-of function mutation in the CACNA1A gene that encodes the α1A subunit of neuronal CaV2.1 channels. We determined stimulus intensity-response curves for anterior commissure-evoked hippocampal CA1 field potentials in strata pyramidale and radiatum and assessed neuroplasticity by inducing long-term potentiation (LTP) and long-term depression (LTD) in anesthetized mice in vivo. We also studied learning and memory using contextual fear-conditioning, Morris water maze, and novel object recognition tests. Hippocampal field potentials were significantly enhanced in R192Q mice compared with wild-type controls. Stimulus intensity-response curves were shifted to the left and displayed larger maxima in the mutants. LTP was augmented by twofold in R192Q mice, whereas LTD was unchanged compared with wild-type mice. R192Q mice showed significant spatial memory deficits in contextual fear-conditioning and Morris water maze tests compared with wild-type controls. Novel object recognition was not impaired in R192Q mice; however, mice carrying the more severe S218L CACNA1A mutation showed marked deficits in this test, suggesting a genotype-phenotype relationship. Thus, whereas FHM1 gain-of-function mutations enhance hippocampal excitatory transmission and LTP, learning and memory are paradoxically impaired, providing a possible explanation for cognitive changes detected in FHM. Data suggest that abnormally enhanced plasticity can be as detrimental to efficient learning as reduced plasticity and highlight how genetically enhanced neuronal excitability may impact cognitive function.

The thalamic reticular nucleus is activated by cortical spreading depression in freely moving rats: prevention by acute valproate administration.

This study investigated the effect of repetitive cortical spreading depression (CSD) on behaviour and the anatomical and physiological patterns of cellular activation of cortical and subcortical areas in awake, moving rats. Rat behaviours in response to repetitive CSD events evoked by the application of KCl were quantified with electrophysiological recording. Immunohistochemistry was used to quantify anatomical regions of cellular activation. The effects of acute valproic acid administration on the behavioural parameters and cellular activation were evaluated. CSD significantly decreased locomotor activity and induced freezing in awake, moving rats, and stimulated c-Fos expression in the cortex, trigeminal nucleus caudalis (TNC), and amygdala. CSD also resulted in a prominent increase in c-Fos expression in the ipsilateral thalamic reticular nucleus (TRN) visual sector. Electrophysiological recordings revealed propagation of CSD into the TRN. Valproic acid pretreatment decreased the duration of CSD-induced freezing episodes and reversed the CSD-induced reduction in locomotor activity. Acute valproic acid administration also significantly blocked CSD-induced c-Fos expression in the TNC and TRN. These findings show that CSD events cause consistent behavioural responses and activate specific brain regions in awake, freely moving rats. Selective activation of TRN by CSD and the suppression of this activation by valproic acid suggest that this brain region may play an important role in migraine pathogenesis and may represent a novel target for migraine therapy.

Enhanced subcortical spreading depression in familial hemiplegic migraine type 1 mutant mice.

Familial hemiplegic migraine type 1, a monogenic migraine variant with aura, is linked to gain-of-function mutations in the CACNA1A gene encoding Ca(V)2.1 channels. The S218L mutation causes severe channel dysfunction, and paroxysmal migraine attacks can be accompanied by seizures, coma, and hemiplegia; patients expressing the R192Q mutation exhibit hemiplegia only. Familial hemiplegic migraine knock-in mice expressing the S218L or R192Q mutation are highly susceptible to cortical spreading depression, the electrophysiological surrogate for migraine aura, and develop severe and prolonged motor deficits after spreading depression. The S218L mutants also develop coma and seizures and sometimes die. To investigate underlying mechanisms for these symptoms, we used multielectrode electrophysiological recordings, diffusion-weighted magnetic resonance imaging, and c-fos immunohistochemistry to trace spreading depression propagation into subcortical structures. We showed that unlike the wild type, cortical spreading depression readily propagated into subcortical structures in both familial hemiplegic migraine type 1 mutants. Whereas the facilitated subcortical spread appeared limited to the striatum in R192Q, hippocampal and thalamic spread was detected in the S218L mutants with an allele-dosage effect. Both strains exhibited increased susceptibility to subcortical spreading depression and reverberating spreading depression waves. Altogether, these data show that spreading depression propagates between cortex, basal ganglia, diencephalon, and hippocampus in genetically susceptible brains, which could explain the prolonged hemiplegia, coma, and seizure phenotype in this variant of migraine with aura.

Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1.

Familial hemiplegic migraine type 1 (FHM1) is an autosomal dominant subtype of migraine with aura that is associated with hemiparesis. As with other types of migraine, it affects women more frequently than men. FHM1 is caused by mutations in the CACNA1A gene, which encodes the alpha1A subunit of Cav2.1 channels; the R192Q mutation in CACNA1A causes a mild form of FHM1, whereas the S218L mutation causes a severe, often lethal phenotype. Spreading depression (SD), a slowly propagating neuronal and glial cell depolarization that leads to depression of neuronal activity, is the most likely cause of migraine aura. Here, we have shown that transgenic mice expressing R192Q or S218L FHM1 mutations have increased SD frequency and propagation speed; enhanced corticostriatal propagation; and, similar to the human FHM1 phenotype, more severe and prolonged post-SD neurological deficits. The susceptibility to SD and neurological deficits is affected by allele dosage and is higher in S218L than R192Q mutants. Further, female S218L and R192Q mutant mice were more susceptible to SD and neurological deficits than males. This sex difference was abrogated by ovariectomy and senescence and was partially restored by estrogen replacement, implicating ovarian hormones in the observed sex differences in humans with FHM1. These findings demonstrate that genetic and hormonal factors modulate susceptibility to SD and neurological deficits in FHM1 mutant mice, providing a potential mechanism for the phenotypic diversity of human migraine and aura.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome mutations increase susceptibility to spreading depression.

Migraine with aura is often the first manifestation of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome (CADASIL), a disorder caused by NOTCH3 gene mutations expressed predominantly in vascular smooth muscle. Here, we report that cortical spreading depression (CSD), the electrophysiological substrate of migraine aura, is enhanced in mice expressing a vascular Notch 3 CADASIL mutation (R90C) or a Notch 3 knockout mutation. The phenotype was stronger in Notch 3 knockout mice, implicating both loss of function and neomorphic mutations in its pathogenesis. Our results link vascular smooth muscle Notch 3 mutations to enhanced spreading depression susceptibility, implicating the neurovascular unit in the development of migraine aura.

Microemboli may link spreading depression, migraine aura, and patent foramen ovale.

OBJECTIVE: Patent foramen ovale and pulmonary arteriovenous shunts are associated with serious complications such as cerebral emboli, stroke, and migraine with aura. The pathophysiological mechanisms that link these conditions are unknown. We aimed to establish a mechanism linking microembolization to migraine aura in an experimental animal model. METHODS: We introduced particulate or air microemboli into the carotid circulation in mice to determine whether transient microvascular occlusion, insufficient to cause infarcts, triggered cortical spreading depression (CSD), a propagating slow depolarization that underlies migraine aura. RESULTS: Air microemboli reliably triggered CSD without causing infarction. Polystyrene microspheres (10 microm) or cholesterol crystals (<70 microm) triggered CSD in 16 of 28 mice, with 60% of the mice (40% of those with CSD) showing no infarcts or inflammation on detailed histological analysis of serial brain sections. No evidence of injury was detected on magnetic resonance imaging examination (9.4T; T2 weighted) in 14 of 15 selected animals. The occurrence of CSD appeared to be related to the magnitude and duration of flow reduction, with a triggering mechanism that depended on decreased brain perfusion but not sustained tissue damage. INTERPRETATION: In a mouse model, microemboli triggered CSD, often without causing microinfarction. Paradoxical embolization then may link cardiac and extracardiac right-to-left shunts to migraine aura. If translatable to humans, a subset of migraine auras may belong to a spectrum of hypoperfusion disorders along with transient ischemic attacks and silent infarcts.

Oxcarbazepine does not suppress cortical spreading depression.

BACKGROUND: Cortical spreading depression is the electrophysiological substrate of migraine aura, and may trigger headache. Recently, chronic treatment with five migraine prophylactic drugs was shown to suppress cortical spreading depression, implicating spreading depression as a common therapeutic target in migraine prophylaxis. MATERIALS AND METHODS: In order to assess the negative predictive value of spreading depression susceptibility as a preclinical drug screening tool, we tested oxcarbazepine, an anti-epileptic ineffective in migraine prophylaxis. Valproate served as the positive control. Cortical spreading depression susceptibility was measured in rats using topical KCl or electrical stimulation. RESULTS: Oxcarbazepine did not suppress spreading depression either after a single dose or after daily treatment for 5 weeks. As previously shown, valproate suppressed spreading depression susceptibility after chronic dosing, while a single dose was ineffective. CONCLUSIONS: These data provide further support for spreading depression as a relevant target in migraine prophylaxis, and demonstrate the predictive utility of employed spreading depression models.

Chronic daily cortical spreading depressions suppress spreading depression susceptibility.

BACKGROUND: Migraine is a disabling chronic episodic disorder. Attack frequency progressively increases in some patients. Incremental cortical excitability has been implicated as a mechanism underlying progression. Cortical spreading depression (CSD) is the electrophysiological event underlying migraine aura, and a headache trigger. We hypothesized that CSD events during frequent migraine attacks condition the cortex to increase the susceptibility to further attacks. METHODS: A single daily CSD was induced for 1 or 2 weeks in mouse frontal cortex; contralateral hemisphere served as sham control. At the end of CSD conditioning, occipital CSD susceptibility was determined by measuring the frequency of CSDs evoked by topical KCl application. RESULTS: Sham hemispheres developed 8.4 ± 0.3 CSDs/hour, and did not significantly differ from naïve controls without prior cranial surgery (9.3 ± 0.4 CSDs/hour). After 2 but not 1 week of daily CSD conditioning, CSD frequency (4.9 ± 0.3 CSDs/hour) as well as the duration and propagation speed were reduced significantly in the conditioned hemispheres. Histopathological examination revealed marked reactive astrocytosis without neuronal injury throughout the conditioned cortex after 2 weeks, temporally associated with CSD susceptibility. CONCLUSIONS: These data do not support the hypothesis that frequent migraine attacks predispose the brain to further attacks by enhancing tissue susceptibility to CSD.

Simultaneous imaging of cerebral partial pressure of oxygen and blood flow during functional activation and cortical spreading depression.

We developed a novel imaging technique that provides real-time two-dimensional maps of the absolute partial pressure of oxygen and relative cerebral blood flow in rats by combining phosphorescence lifetime imaging with laser speckle contrast imaging. Direct measurement of blood oxygenation based on phosphorescence lifetime is not significantly affected by changes in the optical parameters of the tissue during the experiment. The potential of the system as a novel tool for quantitative analysis of the dynamic delivery of oxygen to support brain metabolism was demonstrated in rats by imaging cortical responses to forepaw stimulation and the propagation of cortical spreading depression waves. This new instrument will enable further study of neurovascular coupling in normal and diseased brain.

Hydrogen peroxide and antioxidizing enzymes involved in modulation of transient facilitatory effects of nicotine on neurogenic contractile responses in rat gastric fundus.

Nicotine acts as an agonist of nicotinic acetylcholine receptors. Nicotinic acetylcholine receptors play a role in the modulation of neurotransmitter release in both the central and the peripheral nervous system. Moderate reactive oxygen species levels modulate the regulation of physiological functions e.g. neurotransmitter release. Previously in rabbit gastric fundus we demonstrated that nicotine transiently increased neurogenic contraction induced by electrical field stimulation (EFS). In this study we aimed to investigate the effects of hydrogen peroxide (H2O2), antioxidizing enzymes catalase and superoxide dismutase (SOD) on nicotine induced increases at cholinergic neurotransmission in rabbit gastric fundus. Although H2O2 did not alter nicotine induced transient neurogenic contractions at concentrations of 10(-6) and 10(-5) M, at high concentration (10(-4) M) H2O2 inhibited nicotine induced increases. Catalase (500 units/ml), enhanced the effect of nicotine but did not alter nicotine induced transient neurogenic contractions at the concentrations of 100 and 250 units/ml. SOD (75,150 and 225 units/ml) did not alter nicotine induced transient neurogenic contractions. In conclusion, at high concentration H2O2 (10(-4) M) inhibited nicotine's transient ability to augment neurogenic contractions and catalase (500 units/ml) enhanced the effect of nicotine.

Enhancement effects of nicotine on neurogenic contractile responses in rabbit gastric fundus.

Nicotine, a nicotinic acetylcholine receptor agonist, plays a role in the modulation of neurotransmitter release following nerve stimulation in both the central and the peripheral nervous system. Nitric oxide and prostaglandins modulate the release of various neurotransmitters in different tissues. We aimed to investigate the effects of nicotine on neurogenic contractile responses via nicotinic acetylcholine receptors and, if a change occurred, to investigate the effects of N(W)-nitro-L-arginine methyl ester (L-NAME) and indomethacin on this change in rabbit gastric fundus. Electrical field stimulation (EFS)-evoked contractile responses were recorded from gastric fundus strips obtained from rabbits with an isometric force displacement transducer. Nicotine was applied to preparations at varying concentrations. Then, the effects of hexamethonium, cadmium (Cd(2+)), indomethacin, and L-NAME were tested on the EFS-evoked contractions in the presence of nicotine. Nicotine-induced transient neurogenic contractions in a dose-dependent manner. Cd(2+) and hexamethonium inhibited nicotine-induced transient neurogenic contractions, but indomethacin and L-NAME produced no effect. In conclusion, nicotine increased EFS-evoked contractile responses, possibly by facilitating neurotransmitter release from nerve terminals by a mechanism dependent on the influx of Ca(2+) from voltage-gated Ca(2+) channels via activation of nicotinic acetylcholine receptors in isolated rabbit gastric fundus. Endogenous nitric oxide and prostaglandins do not play a physiological role in the regulation of this neurotransmitter release.

Effects of thymoquinone in a rat model of reserpine-induced depression

The objective of this study is to examine the antidepressant and antioxidant effects of thymoquinone (TQ) on reserpine-induced depression, and to investigate the antidepressant and antioxidant activity of combined treatment of TQ+citalopram. In total, 36 male Wistar rats were randomly divided into 6 groups: 1)control1, 2)control2, 3)reserpine, 4)reserpine+TQ 5)reserpine+citalopram and 6)reserpine+TQ+citalopram. Depression was induced by administering intraperitoneal reserpine of 0.2mg/kg/14days. For antidepressant effects, 10 mg/kg TQ and/or 10 mg/kg citalopram was administered intragastrically 30 minutes prior to the administration of reserpine. Rat behavior was examined using the Behavioral Test following the completion of treatment protocol. Total nitric oxide (NOx) levels, malondialdehyde (MDA) levels, total oxidants status (TOS), total antioxidant status (TAS) in brain cortex, plasma as well as brain cortex glutathione (GSH) and levels of plasma total sulfhydryl groups (RSH) were examined. Treatment with TQ ameliorated the reserpine-induced changes in the Behavioral Test (p<0.05). TQ treatment significantly increased dopamine (DA) and noradrenaline (NA) expressions when compared to the R group (p<0.01). Serotonin (5-HT) expression also increased significantly (p<0.05). Brain cortex and plasma TOS, MDA and NOx levels decreased, whereas TAS, GSH and RSH levels increased (p< 0.05). TQ has the ability to prevent depression induced by reserpine. The combination of TQ+citalopram can be used in the treatment of depression with a stronger antioxidant effect

Examination of the rescue effects of folic acid on derangement of the tubo-ovarian ultrastructural architecture caused by methotrexate.

The purpose of this examination was to observe the effects of folic acid (FA) on methotrexate (MTX)-induced derangements in the fallopian tubes. Investigators in this study sought to explore whether MTX-induced dysfunction in the fallopian tubes would be lessened by the addition of FA to MTX treatment. For this study, 18 albino Wistar rats were randomly divided into 6 groups, each of which comprised 3 rats; 0.1 mg/kg FA, 1 mg/kg MTX + 0.1 mg/kg FA, 5 mg/kg MTX + 0.1 mg/kg FA, 1 mg/kg MTX, and 5 mg/kg MTX were given to groups 2, 3, 4, 5,and 6, respectively; group 1 was the control group. After MTX injection, fallop-ian tube samples from all groups were prepared for examination under electron microscopy. The findings observed in groups 1 and 2 were similar. The level of cellular destruction was greater with the higher doses of MTX without FA; in particular, loss of cilia in the epithelium was prominent in groups 5 and 6. However, there was less cellular destruction observed in groups 3 and 4 than in groups 5 and 6. As a result, the addition of FA should not be overlooked, even when a single-dose MTX regimen is chosen for the treatment of patients with unruptured ectopic pregnancy.

Increased inhibitory synaptic activity in the hippocampus (CA1) of genetic absence epilepsy rats: Relevance of kindling resistance.

PURPOSE: Genetic absence epilepsy rats from Strasbourg (GAERS), a well-validated genetic rat model for typical absence epilepsy, are known to manifest a resistance to secondary generalization of abnormal focal electrical activity evoked by kindling. The mechanism of this resistance is still unclear. In order to understand the possible mechanism of kindling resistance, we investigated for the first time, the differences of short-term synaptic plasticity by using a paired-pulse paradigm as an indicator of GABAergic activity in CA1 region of hippocampus in GAERS and non-epileptic Wistar rats in-vivo. METHODS: Rats were subjected to kindling process, basolateral amygdala was stimulated twice a day, with a supra-threshold current, until they displayed limbic or convulsive seizures. One hour after the last kindling stimulation, evoked field potentials from CA1 pyramidal layer of hippocampus were recorded in-vivo under urethane anesthesia. RESULTS: In response to supra-threshold kindling stimulations GAERS showed a significantly delayed kindling progression and displayed a significant increase in hippocampal excitability at early stages of kindling that is the critical for the development of convulsive seizures. In control rats that were not received kindling stimulation, paired-pulse depression (PPD) was significantly pronounced in GAERS with respect to the Wistar group. During the kindling course, PPD was gradually reduced in the Wistar rats as kindling progression was advanced. However in GAERS, PPD ratios were not significantly changed at early stages of kindling. When GAERS reached convulsive stage, their PPD ratios became similar to that of Wistar rats. DISCUSSION: The increased inhibition in paired-pulse responses at early stages of kindling in GAERS suggests the role of augmented GABAergic activity as one of the underlying mechanisms of kindling resistance observed in genetic rat models of absence epilepsy.

Effects of amifostine on glycerol-pretreated rabbit kidneys.

Glycerol-induced acute renal failure is an experimental model for myoglobinuric nephropathy. Amifostine is a cytoprotective agent which scavenges the free radicals. Since there is enhanced production of reactive oxygen metabolites in glycerol-induced acute renal failure, we wanted to examine whether amifostine has a protective role against vascular reactivity and histological changes in kidneys isolated from glycerol-pretreated rabbits. Perfusion pressure was recorded from kidneys obtained from rabbits injected with glycerol 3 hr before the experiments and from glycerol-pretreated and non-pretreated rabbits injected with amifostine 30 min. before the experiments. Acetylcholine-induced (10(-8)-10(-5) M) vasodilatation was tested following the construction of submaximal vasoconstriction by phenylephrine. Histological investigation was performed using light microscope. Acetylcholine-induced vasodilatation was found to be significantly decreased in glycerol, glycerol+amifostine and amifostine groups compared to controls at all concentrations. Reduction in acetylcholine-induced vasodilation was more prominent in amifostine group compared to amifostine+glycerol group. There was histological renal damage in all experimental groups and this damage was more pronounced in glycerol+amifostine group. In conclusion, contrary to expectation, amifostine per se led to histological damage and potentiated the histological damage caused by glycerol and produced a decrease in acetylcholine-induced vasodilatation. The mechanisms by which amifostine exerts its effects are not known.