Modifications of local cerebral glucose utilization in thalamic structures following injection of a dopaminergic agonist in the nucleus accumbens--involvement in antiepileptic effects?

Dopaminergic transmission in the nucleus accumbens (NAcc) is implicated in different aspects of reward and motivational mechanisms. More recently, it has been suggested that this nucleus could also be involved in the modulation of generalized epileptic seizures. In particular, microinjection of dopaminergic agonists in the NAcc suppresses the occurrence of epileptic seizures in a model of absence seizures, the GAERS (generalized absence epileptic rats from Strasbourg). The aim of this study was to identify the structures involved in this effect. Local cerebral metabolic rates for glucose utilization (LCMRglc) were measured in different parts of the basal ganglia and output structures after apomorphine injection in the NAcc in GAERS and in the inbred non-epileptic rats (NE), concomitantly with seizure suppression. Apomorphine injection in the NAcc induced a significant increase of glucose intake in the anteromedial, mediodorsal and ventrolateral nuclei of the thalamus in NE rats, while no significant changes were observed in the basal ganglia structures (globus pallidus, subthalamic nucleus, substantia nigra). Furthermore, microinjections of muscimol (100 and 200 pmol/side) in the mediodorsal nucleus of the thalamus in GAERS rats suppressed seizures. These results suggest that the mediodorsal nucleus of the thalamus could be involved in absence seizures modulation. Along with data from the literature, our data suggest that this nucleus could participate in the control of the basal ganglia over generalized epileptic seizures.     

Effects of methoxychlor, dieldrin and lindane on sea urchin fertilization and early development

We have studied the effects of methoxychlor (MXC), dieldrin, and lindane on fertilization and early development of sea urchin egg. These organochlorine pesticides have often been found in polluted ground and water near agricultural sites, and have therefore been detected from time to time in the food chain and in drinking water. They have been reported to alter various reproduction functions in various animals including marine populations. We observed that the rate of fertilization decreased when the sperm was incubated with dieldrin or lindane. Treatment of eggs with each pesticide did not prevent fertilization, but increased the rate in polyspermy, delayed or blocked the first mitotic divisions, and altered early embryonic development. Moreover, all pesticides could alter several intracellular biochemical pathways that control first mitotic divisions and early development, including intracellular calcium homeostasis, MPF (mitosis promoting factor) activity and formation of the bipolar mitotic spindle. We found that lindane was the most potent of the three pesticides to alter all biochemical events. All these effects were observed at relatively high concentrations. However, bio-accumulation in sediments and aquatic organisms have been reported. Sea urchin eggs may then be in contact with very high concentrations of these pesticides in areas where these pesticides are not handled or stocked properly, and then develop into abnormal embryos.     

Embryotoxicity in vitro with extract of Indigofera suffruticosa leaves

Aqueous extract of leaves of Indigofera suffruticosa (AELIs) were studied for adverse effects in preimplantation mouse embryos. Two-cell mouse embryos were cultured for 94 h in human tubal fluid medium (HTF), and AELIs at a concentration of 5 or 10 mg/ml. On Day 4 of culture, morulae and blastocysts were collected for morphological analysis of blastomeres. We found that embryos exposed to the higher concentration of AELIs (10 mg/ml) did not develop and all embryos persisted at the two-cell stage. Those embryos exposed to the lower concentration (5 mg/ml) showed development until morula, blastocyst and hatched blastocyst stages that were similar to the controls. These results suggest that use of AELIs may be hazardous to humans who make use of it in folk medicine.     

Acute pulmonary inflammation induced by lung overloading with selenium particles: leukocyte response and in situ detection of selenium at high resolution

The kinetics of the acute inflammatory response of the lung was triggered in CD-1 mice by a single intratracheal instillation of a large amount of Se (10 mg); it was studied by quantitative cytology of bronchoalveolar lavage samples, light microscopy, and scanning electron microscopy coupled with x-ray elemental microanalysis. Bronchoalveolar lavage leukocytes were mostly neutrophils and increased from 12 to 24 h of Se treatment and decreased at 72 h. Only less than half of the granulocytes showed ingested Se particles; in contrast, virtually all BAL macrophages contained Se particles. Scanning electron microscopy coupled with X-ray elemental microanalysis revealed that the intracellular Se particles were heterogeneous in size (diameters from 0.4 and up to 14 microm), and that Se inclusions were sometimes accumulated at a pole of the cell. At 72 h after instillation of the particles, Se-loaded alveolar macrophages were migrated in the interstitial space of the alveoli. Se-positive regions had a focal distribution in the lung; accumulation of inflammatory cells erased the alveolar architecture of these areas of the deep lung. Our data indicates that Se overloading of the lung results in: (1) an acute inflammatory response that is dominated by neutrophils; (2) early removal of Se done mostly by alveolar macrophages, and (3) formation of focal areas of invasion of the lung parenchyma by inflammatory infiltrates.     

Metabotropic glutamate 1 receptor distribution and occupancy in the rat brain: a quantitative autoradiographic study using [3H]R214127

We used the selective metabotropic glutamate (mGlu) 1 receptor antagonist [3H]1-(3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-2-phenyl-1-ethanone ([3H]R214127) to investigate the distribution of mGlu1 receptor binding sites in rat brain. We found high mGlu1 receptor binding in the cerebellum, thalamus, dentate gyrus and medial central gray, moderate binding within the CA3 of the hippocampus and hypothalamus, and low mGlu1 receptor binding in the basal ganglia and cortex. The mGlu1 receptor is also present in variable degree in the dorsal lateral septal nucleus, amygdala, interpeduncular nucleus and median raphe nucleus. Additionally, we employed [3H]R214127 autoradiography as a means of investigating the occupancy of central mGlu1 receptors following in vivo administration of mGlu1 receptor antagonists that prevent binding of this radioligand. We found that the mGlu1 receptor antagonist (3aS,6aS)-6a-naphtalan-2-ylmethyl-5-methyliden-hexahydro-cyclopenta[c]furan-1-on (BAY 36-7620), administered subcutaneously (s.c.) at 10 mg/kg, only occupied about 30% of cerebellar and thalamic mGlu1 receptors. The mGlu1/5 receptor antagonist 2-quinoxaline-carboxamide-N-adamantan-1-yl (NPS 2390) exhibited a relatively high potency in occupying mGlu1 receptors in rat cerebellum (ED50 = 0.75 mg/kg, s.c.) and thalamus (ED50 = 0.63 mg/kg, s.c). In the future, this method can be employed to gain more insight into the in vivo profile and central activity of potential therapeutic agents that act upon the mGlu1 receptor.     

JNJ16259685, a highly potent, selective and systemically active mGlu1 receptor antagonist

We examined the pharmacological profile of (3,4-dihydro-2H-pyrano[2,3]b quinolin-7-yl) (cis-4-methoxycyclohexyl) methanone (JNJ16259685). At recombinant rat and human metabotropic glutamate (mGlu) 1a receptors, JNJ16259685 non-competitively inhibited glutamate-induced Ca2+ mobilization with IC50 values of 3.24+/-1.00 and 1.21+/-0.53 nM, respectively, while showing a much lower potency at the rat and human mGlu5a receptor. JNJ16259685 inhibited [3H]1-(3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-2-phenyl-1-ethanone ([3H]R214127) binding to membranes prepared from cells expressing rat mGlu1a receptors with a Ki of 0.34+/-0.20 nM. JNJ16259685 showed no agonist, antagonist or positive allosteric activity toward rat mGlu2, -3, -4 or -6 receptors at concentrations up to 10 microM and did not bind to AMPA or NMDA receptors, or to a battery of other neurotransmitter receptors, ion channels and transporters. In primary cerebellar cultures, JNJ16259685 inhibited glutamate-mediated inositol phosphate production with an IC50 of 1.73+/-0.40 nM. Subcutaneously administered JNJ16259685 exhibited high potencies in occupying central mGlu1 receptors in the rat cerebellum and thalamus ( ED50=0.040 and 0.014 mg/kg, respectively). These data show that JNJ16259685 is a selective mGlu1 receptor antagonist with excellent potencies in inhibiting mGlu1 receptor function and binding and in occupying the mGlu1 receptor after systemic administration.     

Effect of perinatal asphyxia on thyroid-stimulating hormone and thyroid hormone levels

AIM: To compare serum concentrations of thyroid hormones--T4, T3, free T4 (FT4) and reverse T3 (rT3)--and thyroid-stimulating hormone (TSH) found in the umbilical cord blood of term newborns with and without asphyxia and those found in their arterial blood collected between 18 and 24 h after birth. A further aim of the study was to assess the association between severity of hypoxic-ischemic encephalopathy and altered thyroid hormone and TSH levels, and between mortality and FT4 levels in the arterial blood of newborns between 18 and 24 h of life. METHODS: A case-control study was carried out. The case group comprised 17 term newborns (Apgar score < or = 3 and < or = 5 at the first and fifth minutes; umbilical cord blood pH < or = 7.15) who required bag and mask ventilation for at least one minute immediately after birth. The control group consisted of 17 normal, term newborns (Apgar score > or = 8 and > or = 9 at the first and fifth minutes; umbilical cord blood pH > or = 7.2). Cord blood and arterial blood samples were collected immediately after birth and 18 to 24 h after birth, respectively, and were used in the blood gas analysis and to determine serum concentrations of T4, T3, FT4, rT3 and TSH by radioimmunoassay. All newborns were followed-up until hospital discharge or death. RESULTS: Gestational age, birthweight, sex, size for gestational age, mode of delivery and skin color (white and non-white) were similar for both groups. No differences were found in mean levels of cord blood TSH, T4, T3 and FT4 between the groups. In the samples collected 18 to 24 h after birth, mean levels of TSH, T4, T3 and FT4 were significantly lower in the asphyxiated group than in the control group. Mean concentrations of arterial TSH, T4 and T3 between 18 and 24 h of life were lower than concentrations found in the cord blood analysis in asphyxiated newborns, but not in controls. In addition, asphyxiated newborns with moderate/severe hypoxic-ischemic encephalopathy presented significantly lower mean levels of TSH, T4, T3 and FT4 than those of controls. None of the asphyxiated newborns with FT4 > or = 2.0 ng/dl died; 6 out of the 11 asphyxiated newborns with FT4 < 2.0 ng/dl died. CONCLUSIONS: Serum concentrations of TSH, T4, T3 and FT4 are lower in asphyxiated newborns than in normal newborns between 18 and 24 h of life; this suggests central hypothyroidism secondary to asphyxia. Asphyxiated newborns with moderate/severe hypoxic-ischemic encephalopathy present a greater involvement of the thyroid function and consequently a greater risk of death.