Progesterone-responsive vaginal leiomyoma and hyperprogesteronemia due to ovarian luteoma in an older bitch.

BACKGROUND: This is the first report about a vaginal leiomyoma concomitant with an ovarian luteoma in a bitch. CASE PRESENTATION: A 11-year-old intact female Labrador retriever was referred because of anuria, constipation and protrusion of a vaginal mass through the vulvar commissure. The bitch had high serum progesterone concentration (4.94 ng/ml). Because of the possibility of progesterone responsiveness causing further increase of the vaginal mass and since the bitch was a poor surgical candidate a 10 mg/kg aglepristone treatment was started SC on referral day 1. A computerized tomography showed a 12.7 × 6.5 × 8.3 cm mass causing urethral and rectal compression, ureteral dilation and hydronephrosis. A vaginal leiomyoma was diagnosed on histology. As serum progesterone concentration kept increasing despite aglepristone treatment, a 0.02 ng/mL twice daily IM alfaprostol treatment was started on day 18. As neither treatment showed remission of clinical signs or luteolysis, ovariohysterectomy was performed on referral day 35. Multiple corpora lutea were found on both ovaries. On histology a luteoma was diagnosed on the left ovary. P4 levels were undetectable 7 days after surgery. Recovery was uneventful and 12 weeks after surgery tomography showed a reduction of 86.7% of the vaginal mass. The bitch has been in good health and able to urinate without any complication ever since. CONCLUSIONS: This case demonstrates the importance of identifying progesterone related conditions as well as the importance of judiciously using a combined medical and surgical approach.

The cell biology of the thyroid-disrupting mechanism of dichlorodiphenyltrichloroethane (DDT).

OBJECTIVE: Dichlorodiphenyltrichloroethane (DDT) is an organochlorine known for its pesticide properties and for its negative effects on human health. It was banned in most countries for its toxicity to the endocrine system, but due to its persistence at clinically relevant concentrations in both soil and animal tissues, DDT is still linked to several health and social problems. METHODS: We have previously shown that DDT exposure is causally related to the extracellular release of vesicular organelles such as microvesicles and/or exosomes by using immunocytochemistry with gold-tagged antibodies and various fluorescent membrane markers. RESULTS: It is now well recognized that microvesicles and/or exosomes organelles are implicated in cell-to-cell communication, and that they are fundamental elements for transferring proteins, RNA, DNA, lipids and transcriptional factors among cells. In this short review, we discussed the role of extracellular vesicle formation in the thyroid-disrupting mechanism of DDT. In particular, we described how DDT, by dislodging the thyrotropin hormone (TSH) receptor from the raft containing compartments of the cells, prevents its activation and internalization. CONCLUSION: Based on our earlier finding and on the large body of evidence here reviewed, we propose that DDT-induced formation of extracellular vesicles containing the TSH receptor could be directly involved in the development of autoimmune responses against the TSH receptor and that, therefore, their release could lead to the development of the Graves' disease.

Spatial Integration of Somatosensory Inputs during Sensory-Motor Plasticity Phenomena Is Normal in Focal Hand Dystonia.

Background: Surround inhibition is a system that sharpens sensation by creating an inhibitory zone around the central core of activation. In the motor system, this mechanism probably contributes to the selection of voluntary movements, and it seems to be lost in dystonia. Objectives. To explore if sensory information is abnormally processed and integrated in focal hand dystonia (FHD) and if surround inhibition phenomena are operating during sensory-motor plasticity and somatosensory integration in normal humans and in patients with FHD. Methods. We looked at the MEP facilitation obtained after 5 Hz repetitive paired associative stimulation of median (PAS M), ulnar (PAS U), and median + ulnar nerve (PAS MU) stimulation in 8 normal subjects and 8 FHD. We evaluated the ratio MU/(M + U) ∗ 100 and the spatial and temporal somatosensory integration recording the somatosensory evoked potentials (SEPs) evoked by a dual nerve input. Results: FHD had two main abnormalities: first, the amount of facilitation was larger than normal subjects; second, the spatial specificity was lost. The MU/(M + U) ∗ 100 ratio was similar in healthy subjects and in FHD patients, and the somatosensory integration was normal in this subset of patients. Conclusions. The inhibitory integration of somatosensory inputs and the somatosensory inhibition are normal in patients with focal dystonia as well as lateral surrounding inhibition phenomena during sensory-motor plasticity in FHD.

Low-intensity repetitive paired associative stimulation targeting the motor hand area at theta frequency causes a lasting reduction in corticospinal excitability.

OBJECTIVE: Sub-motor threshold 5 Hz repetitive paired associative stimulation (5 Hz-rPAS25ms) produces a long-lasting increase in corticospinal excitability. Assuming a spike-timing dependent plasticity-like (STDP-like) mechanism, we hypothesized that 5 Hz-rPAS at a shorter inter-stimulus interval (ISI) of 15 ms (5 Hz-rPAS15ms) would exert a lasting inhibitory effect on corticospinal excitability. METHODS: 20 healthy volunteers received two minutes of 5 Hz-rPAS15ms. Transcranial magnetic stimulation (TMS) was applied over the motor hotspot of the right abductor pollicis brevis muscle at 90% active motor threshold. Sub-motor threshold peripheral electrical stimulation was given to the left median nerve 15 ms before each TMS pulse. We assessed changes in mean amplitude of the unconditioned motor evoked potential (MEP), short-latency intracortical inhibition (SICI), intracortical facilitation (ICF), short-latency afferent inhibition (SAI), long-latency afferent inhibition (LAI), and cortical silent period (CSP) before and for 60 minutes after 5-Hz rPAS15ms. RESULTS: Subthreshold 5-Hz rPAS15ms produced a 20-40% decrease in mean MEP amplitude along with an attenuation in SAI, lasting at least 60 minutes. A follow-up experiment revealed that MEP facilitation was spatially restricted to the target muscle. CONCLUSIONS: Subthreshold 5-Hz rPAS15ms effectively suppresses corticospinal excitability. Together with the facilitatory effects of subthreshold 5-Hz rPAS25ms (Quartarone et al., J Physiol 2006;575:657-670), the results show that sub-motor threshold 5-Hz rPAS induces STDP-like bidirectional plasticity in the motor cortex. SIGNIFICANCE: The results of the present study provide a new short-time paradigm of long term depression (LTD) induction in human sensory-motor cortex.

Thyroid disruptor 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) prevents internalization of TSH receptor.

The thyroid-stimulating hormone (TSH) receptor (TSHr) was made specifically fluorescent by insertion of a tetracysteine motif (TSHr-FlAsH) into the C-terminal end and transiently transfected into COS-7 and HeLa cells. The observation that TSH administration caused the intracellular level of cAMP to increase in both TSHr-FlAsH-transfected cell types indicated that the FlAsH binding motif did not alter normal TSHr functioning. When transfected into HeLa cells and stimulated with TSH, the TSHr-FlAsH receptor exhibited a pronounced perinuclear labelling pattern, whereas labelling remained on the cell surface following pre-incubation with 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT). Chinese hamster ovary (CHO)-TSHr cells probed with anti-TSHr antibodies were fluorescent mainly in the proximity of the plasma membrane, with fluorescence being primarily restricted to a juxta-nuclear position when exposed to 10 mU/ml TSH for 1 or 5 min. However, in the presence of DDT, the anti-TSHr fluorescence maintained a peripheral location along the cell plasma membrane, even if CHO-TSHr cells were stimulated with TSH for 1 and 5 min. To verify that DDT acted specifically on the TSHr, CHO cells transfected with the A(2)a receptor were used as controls. Following a 1-min stimulation with 5'-(N-ethyl-carboxamido)-adenosine, A(2)a receptors were gradually internalized regardless of the presence of DDT in the culture medium. Finally, immunoelectron microscopy of CHO-TSHr cells showed that a 1-min exposure to TSH sufficed to displace anti-TSHr antibodies tagged with 10-nm gold particles into coated pits and vesicles but that their superficial location was retained along the plasma membrane in the presence of DDT.

Sulodexide counteracts endothelial dysfunction induced by metabolic or non-metabolic stresses through activation of the autophagic program.

OBJECTIVE: Endothelial dysfunction (ED) predisposes to venous thrombosis (VT) and post-thrombotic syndrome (PTS), a long-term VT-related complication. Sulodexide (SDX) is a highly purified glycosaminoglycan with antithrombotic, pro-fibrinolytic and anti-inflammatory activity used in the treatment of chronic venous disease (CVD), including patients with PTS. SDX has recently obtained clinical evidence in the "extension therapy" after initial-standard anticoagulant treatment for the secondary prevention of recurrent deep vein thrombosis (DVT). Herein, we investigated how SDX counteracts ED. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVEC) were used. Metabolic and non metabolic-induced ED was induced by treating with methylglyoxal (MGO) or irradiation (IR), respectively. Bafilomycin A1 was used to inhibit autophagy. The production of reactive oxygen species (ROS), tetrazolium bromide (MTT) assay for cell viability, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay for cell apoptosis, Real-time PCR and Western blot analysis for gene and protein expression were used. RESULTS: SDX protected HUVEC from MGO- or IR-induced apoptosis by counteracting the activation of the intrinsic and extrinsic caspase cascades. The cytoprotective effects of SDX resulted from a reduction in a) ROS production, b) neo-synthesis and release of pro-inflammatory cytokines (TNFα, IL1, IL6, IL8), c) DNA damage induced by MGO or IR. These effects were reduced when autophagy was inhibited. CONCLUSIONS: Data herein collected indicate the ability of SDX to counteract ED induced by metabolic or non-metabolic stresses by involving the intracellular autophagy pathway. Our experience significantly increases the knowledge of the mechanisms of action of SDX against ED and supports the use of SDX in the treatment of CVD, PTS and in the secondary prevention of recurrent DVT.

Reduction of autophagy and increase in apoptosis correlates with a favorable clinical outcome in patients with rheumatoid arthritis treated with anti-TNF drugs.

BACKGROUND: Autophagy has emerged as a key mechanism in the survival and function of T and B lymphocytes, and its activation was involved in apoptosis resistance in rheumatoid arthritis (RA). To investigate whether the relationship between autophagy and apoptosis may impact the response to the therapy, we analyzed ex vivo spontaneous autophagy and apoptosis in patients with RA subjected to treatment with anti-tumor necrosis factor (TNF) drugs and in vitro the effects of TNFα and anti-TNF drugs on cell fate. METHODS: Peripheral blood mononuclear cells (PBMCs) from 25 RA patients treated with anti-TNF drugs were analyzed for levels of autophagy marker LC3-II by western blot and for the percentage of annexin V-positive apoptotic cells by flow cytometry. The same techniques were used to assess autophagy and apoptosis after in vitro treatment with TNFα and etanercept in both PBMCs and fibroblast-like synoviocytes (FLS) from patients with RA. RESULTS: PBMCs from patients with RA responsive to treatment showed a significant reduction in LC3-II levels, associated with an increased apoptotic activation after 4 months of therapy with anti-TNF drugs. Additionally, the expression of LC3-II correlated with DAS28. TNFα was able to induce autophagy in a dose-dependent manner after 24 h of culture in RA PBMCs and FLS. Moreover, etanercept caused a significant reduction of autophagy and of levels of citrullinated proteins. CONCLUSIONS: Our results show how the crosstalk between autophagy and apoptosis can sustain the survival of immune cells, thus influencing RA progression. This suggests that inhibition of autophagy represents a possible therapeutic target in RA.

Inhibitory effect of synthetic cannabinoids on cytokine production in rheumatoid fibroblast-like synoviocytes.

OBJECTIVE: To verify whether synthetic cannabinoids (CP55,940 and WIN55,212-2) are able to exert an anti-inflammatory effect on rheumatoid fibroblast-like synoviocytes (FLS) by down-regulating cytokine production, and determine whether this effect could be mediated by CB1/CB2 cannabinoid receptors. METHODS: Interleukin-6 (IL-6) and interleukin-8 (IL-8) were assayed in the supernatant from cultured FLS by ELISA method before and after 3 hours of incubation with CP55,940 (10 microM) and WIN55,212-2 (10 microM). Co-stimulation of cells with the cannabinoid receptor antagonists was performed to evaluate receptor involvement in cytokine modulation. All the experiments were conducted in basal conditions and after 1 hour pre-incubation with 0.1 ng/ml IL-1beta. FLS expression of CB1 and CB2 receptor was studied by Western Blot analyses. RESULTS: Both CP55,940 and WIN55,212-2 induced a potent and significant reduction in IL-6 and IL-8 secretion from IL-1beta. stimulated FLS. Although FLS express CB1 and CB2 receptor, cannabinoid receptor antagonists did not significantly modify the inhibition of cytokines secretion induced by CP55,940 and WIN55,212-2. CONCLUSIONS: In vitro, CP55,940 and WIN55,212-2 exert a potent anti-inflammatory effect on rheumatoid FLS via a non-CB1/CB2 receptor mediated mechanism.

An integrated analysis of micro- and macro-habitat features as a tool to detect weather-driven constraints: A case study with cavity nesters.

The effects of climate change on animal populations may be shaped by habitat characteristics at both micro- and macro-habitat level, however, empirical studies integrating these two scales of observation are lacking. As analyses of the effects of climate change commonly rely on data from a much larger scale than the microhabitat level organisms are affected at, this mismatch risks hampering progress in developing understanding of the details of the ecological and evolutionary responses of organisms and, ultimately, effective actions to preserve their populations. Cavity nesters, often with a conservation status of concern, are an ideal model because the cavity is a microenvironment potentially different from the macroenvironment but nonetheless inevitably interacting with it. The lesser kestrel (Falco naumanni) is a cavity nester which was until recently classified by as Vulnerable species. Since 2004, for nine years, we collected detailed biotic and abiotic data at both micro- and macro-scales of observation in a kestrel population breeding in the Gela Plain (Italy), a Mediterranean area where high temperatures may reach lethal values for the nest content. We show that macroclimatic features needed to be integrated with both abiotic and biotic factors recorded at a microscale before reliably predicting nest temperatures. Among the nest types used by lesser kestrels, we detected a preferential occupation of the cooler nest types, roof tiles, by early breeders whereas, paradoxically, late breeders nesting with hotter temperatures occupied the overheated nest holes. Not consistent with such a suggested nest selection, the coolest nest type did not host a higher reproductive success than the overheated nests. We discussed our findings in the light of cavity temperatures and nest types deployed within conservation actions assessed by integrating selected factors at different observation scales.

Response to Alpha-Interferon Treatment of the Congenital Dyserythropoietic Anemia type I in Two Sicilian Beta Thalassemia Carriers.

Congenital dyserythropoietic anemia type I (CDAI) is an autosomal recessive inherited haematological disorder associated with moderate-to-severe anemia characterized by ineffective erythropoiesis with distinct morphological abnormalities in erythroid precursors. We present two case of congenital dyserythropoietic anemia type I in two Sicilian patients heterozygous for ß0 39 globin gene cod 39 C > T with marked bone marrow abnormalities, responding to treatment with alpha interferon. The diagnosis was established using routine haematological and biochemical test, light and electron microscopy; molecular analysis of the CDAN1 gene associated to the CDAI disease was performed. The response to the treatment was monitored using the hemoglobin levels, the red cell count, the reticulocyte count and the transfusional requirement. This report points out the usefulness of the treatment with interferon alpha in two Sicilian beta thalassemia carriers, in which the therapy was well tolerated without producing any side effects; in these patients the transfusion requirements after the initiation of interferon therapy decreased.

Co-heredity of silent CAP + 1570 T>C (HBB:c*96T>C) defect and severe ß-thal mutation: a cause of mild ß-thalassemia intermedia.

INTRODUCTION: During an intensive screening program aimed at identifying the healthy carriers of thalassemia and the couples at risk of bearing an affected fetus, a rare single nucleotide variation (SNV), CAP + 1570 T > C (HBB:c*96T > C), located 12 nucleotides upstream of the polyadenylation signal in 3'UTR of the beta globin gene was identified. It was previously reported as a ß+ thalassemia mutation and later as a plain polymorphism. METHODS: Genotype identification of globin gene mutations was carried out using sequencing analysis, GAP-PCR, and MLPA methods. RESULTS: CAP + 1570 T > C (HBB:c*96T > C) was found in 39 heterozygotes, in one case in homozygous state and in thirteen cases of co-inheritance of this nucleotide substitution with other mutations in globin genes. Carriers of this mutation showed a 'silent' phenotype without appreciable microcytosis and hypochromia, so they cannot be differentiated from noncarrier individuals. Compound heterozygotes for this mutation and severe ß-thal mutations showed a variable phenotype ranging from ß-thal carrier to mild form of ß-thalassemia intermedia, revealing new aspects and allowing to better understand the clinical implications of this nucleotide substitution that can be classified as a silent ß-thalassemic defect. CONCLUSION: Data reported in this study indicate the need of investigating partner of ß-thalassemia carrier by complete sequencing analysis of ß-globin gene and of providing an appropriate genetic counseling for couples at risk undergoing prenatal diagnosis.

Species differences in the role of excitatory amino acids in experimental parkinsonism.

The present review discusses species differences in relation to the effects produced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); in particular, it focuses on recent evidence regarding the role of excitatory amino acids in experimental parkinsonism. The main aim of the review is to provide a phylogenetic perspective which may serve as a useful tool to study Parkinson's disease in rodents. Excitotoxicity might represent the final common pathway on which the actions of different neurotoxins, selectively directed towards nigrostriatal dompaminergic neurons, converge. This is clearly demonstrated in methamphetamine- and 6-dihydroxy-dopamine-induced parkinsonism. The role of excitotoxicity in the mechanism of action of MPTP is less clear. Although there are several species differences for MPTP it is possible to obtain in mice the same effects induced in MPTP-treated primates by combining acetaldehyde or diethyldithiocarbamate with MPTP administration. When mice are administered these combined treatments, the onset of experimental parkinsonism can be prevented using the same pharmacological agents (i.e. glutamate N-methyl-D-aspartate antagonists) that are effective in primates.

Reconstitution of functional muscarinic receptors by co-expression of amino- and carboxyl-terminal receptor fragments.

Truncated m2 and m3 muscarinic receptors (referred to as m2- and m3-trunc), containing transmembrane domains I-V and the N-terminal portion of the third cytoplasmic loop, were co-expressed in COS-7 cells with the corresponding C-terminal receptor fragments (referred to as m2- and m3-tail; containing transmembrane domains VI and VII). Expression of any of these four polypeptides alone did not result in any detectable [3H]N-methylscopolamine ([3H]NMS) binding activity. However, specific [3H]NMS binding sites were observed after co-expression of m2-trunc with m2-tail and m3-trunc with m3-tail. These sites displayed ligand binding properties similar to those of the two wild-type receptors. The 'reconstituted' m3-trunc/m3-tail receptor was also able to stimulate agonist-dependent phosphatidyl inositol hydrolysis in a fashion similar to the wild-type m3 receptor, whereas all other polypeptide combinations were inactive. These data suggest that muscarinic receptors are assembled in a fashion analogous to two-subunit receptors.

Selective stimulation of kainate but not quisqualate or NMDA receptors in substantia nigra evokes limbic motor seizures.

Bilateral microinjection of kainic acid (30-117 pmol) into the substantia nigra induced convulsive seizures resembling those elicited from limbic system structures. The convulsive seizures, which consisted of facial and forelimb clonus with rearing and falling, developed after a latency of more than 30 min and were preceded by wet dog shakes and non-convulsive seizure activity registered electroencephalographically. The convulsant effect of intranigral kainic acid was strictly dose-dependent (ED50 = 60 pmol) and anatomically site-specific. Stimulation of nigral neurons by focal application of agonists for NMDA or quisqualate receptors, or by focal application of the GABA antagonist, bicuculline, was without convulsant effects. The convulsant action of intranigral kainic acid was prevented by the focal application of kynurenic acid (100 nmol) but not by 2-amino-7-phosphonoheptanoic acid (AP-7) (25 nmol) or 7-chlorokynurenic acid (20 nmol), suggesting that the convulsant effect of kainic acid in the substantia nigra does not depend upon activation of NMDA receptors in this region.

Lack of proconvulsant action of GABA depletion in substantia nigra in several seizure models.

The effect of intranigral application of a gamma-aminobutyric acid (GABA) synthesis inhibitor, was examined in 3 different rat seizure models. Bilateral intranigral infusion of isoniazid (150 micrograms) did not potentiate the effect of subcutaneous administration of a threshold dose (1.5 mg/kg) of the GABA antagonist bicuculline. Similarly, following pretreatment with intranigral isoniazid, neither severity nor latency to onset of seizures elicited by systemic injection of kainic acid (9 mg/kg) were modified. In addition, convulsive seizures evoked by the focal injection of bicuculline methiodide (40 ng) in an epileptogenic site within the deep prepiriform cortex (area tempestas) were not potentiated by intranigral isoniazid. These results were in sharp contrast to the marked potentiating effect of intranigral isoniazid (150 or 85 micrograms) on seizures induced by systemic administration of a subconvulsant dose of pilocarpine (150 mg/kg). In addition, we attempted to evoke a proconvulsant action from striatum. The striatum, origin of GABAergic projections to substantia nigra, is a region in which application of GABA antagonists have been found to be anticonvulsant in several seizure models. We therefore examined the effect of bilateral intrastriatal infusion of the GABA agonist, muscimol (5 ng) on the convulsant effect of threshold doses of systemically administered bicuculline (1.5 mg/kg). As was true with intranigral isoniazid, no proconvulsant effect was found using intrastriatal muscimol. Our data demonstrate that whereas striatonigral GABA circuitry can be activated by exogenous treatments so as to produce anticonvulsant actions in most seizure models, suppression of this circuitry does not potentiate convulsant activity in many of the same models.

L-deprenyl fails to protect mesencephalic dopamine neurons and PC12 cells from the neurotoxic effect of 1-methyl-4-phenylpyridinium ion.

L-Deprenyl, a monoamine oxidase (MAO)-B inhibitor, appears to slow down the progression of Parkinson's disease. While inhibition of MAO-B activity can account for some of the effects of this substance, the basis by which L-deprenyl slows the progression of the disease remains controversial. In recent years, a new mechanism of action has emerged that may explain the ability of L-deprenyl to increase neuronal survival. L-deprenyl has been reported to modify gene expression and protein synthesis in astrocytes and PC12 cells. In this study, we tested the ability of L-deprenyl to protect mouse mesencephalic cells from the toxicity of the 1-methyl-4-phenyl pyridinium ion (MPP+). We exposed mouse mesencephalic cell cultures to L-deprenyl (10 microM) and, 24 h later, to MPP+ (2.5 microM). On the fifth day after L-deprenyl and MPP+ exposition, cells were washed free of drugs, and the following day they were tested for dopamine uptake, intracellular dopamine content and tyrosine hydroxylase immunoreactivity. The experiments were performed either in the presence or in the absence of glia. It was found that L-deprenyl pretreatment failed to achieve any protection against MPP+ toxicity. The fall in dopamine uptake and intracellular dopamine content, and the diminution of tyrosine hydroxylase immunoreactivity observed in cells pretreated with L-deprenyl and then given MPP+ were not significantly different from the values observed in cells treated with MPP+ alone. Additional experiments performed in PC12 cells, confirmed the failure of L-deprenyl to abolish the toxicity of MPP+. Our data seem to be at variance with previous reports demonstrating that the MAO-B inhibitor L-deprenyl protects dopaminergic neurons against MPP+ toxicity [12,20]; furthermore they do not support alternative mechanisms of action of L-deprenyl against MPP+ toxicity.

Motor expression of kainic acid seizures is attenuated by dopamine depletion in mice.

We studied the effect of striatal dopamine depletion induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice on kainic acid (KA) evoked seizures. MPTP, 36 mg/kgp i.p. for 3 days, caused an 80% drop of striatal dopamine. Animals pretreated with MPTP, plus controls treated with saline, were challenged with five different convulsant doses of KA (3, 6, 12, 18 and 36 mg/kg i.p.). The seizures were monitored by electrographic recording and behavioral observation. MPTP pretreatment greatly attenuated the severity of the convulsions and the mortality induced by KA. The effect was mostly evident at the intermediate and at the high doses of KA. Surprisingly, no differences between the MPTP and control groups were found on the intensity and time course of the electrical seizures. Increment doses of KA resulted in a more severe electrographic seizure pattern in both the saline and the MPTP pretreated groups. Our data suggest that the dopamine depletion induced by MPTP does not alter the genesis of KA induced seizures, but may alter the function of cerebral structures involved in the control of seizure motor expression.

Blockade of GABA receptors in superior colliculus protects against focally evoked limbic motor seizures.

Blockade of GABA receptors in the rat superior colliculus (SC) has been shown to protect against maximal electroshock-induced tonic convulsions and spontaneous generalized non-convulsive seizures. In the present study, we determined that blockade of GABA receptors in SC could also protect against focally evoked limbic motor seizures. Limbic motor seizures were induced by the unilateral focal application of bicuculline methiodide into area tempestas (AT), an epileptogenic site in the deep prepiriform cortex. Control rats (receiving bilateral infusions of saline into SC) all exhibited convulsive seizures following bicuculline in AT. Rats pretreated (5 min before) with bicuculline (50 pmol) bilaterally in the deep layers of the SC, were protected against the AT-evoked convulsive seizures. Unilateral application of bicuculline in the deep SC or bilateral application in the superficial layers of the SC did not alter the convulsive response to bicuculline in AT. These results indicate that the anticonvulsant action of GABA blockade in SC is not limited to tonic convulsive seizures but extends to the clonic manifestations evoked by seizures originating in forebrain limbic circuits. Given that the deep layers of SC receive inputs from GABA neurons in substantia nigra and that suppression of the activity of nigral neurons is anticonvulsant against a variety of seizures (including those evoked from AT), it is likely that the anticonvulsant action of bicuculline in SC is due to interference with the influence of a nigrotectal GABAergic projection.