Sylvie Bodard

Serotoninergic neurotransmission is affected by n-3 polyunsaturated fatty acids in the rat

We explored the effects of chronic α‐linolenic acid dietary deficiency on serotoninergic neurotransmission. In vivo synaptic serotonin (5‐HT) levels were studied in basal and pharmacologically stimulated conditions using intracerebral microdialysis in the hippocampus of awake 2‐month‐old rats. We also studied the effects of reversion of the deficient diet on fatty acid composition and serotoninergic neurotransmission. A balanced (control) diet was supplied to deficient rats at different stages of development, i.e. from birth, 7, 14 or 21 days of age. We demonstrated that chronic n‐3 polyunsaturated fatty acid dietary deficiency induced changes in the synaptic levels of 5‐HT both in basal conditions and after pharmacological stimulation with fenfluramine. Higher levels of basal 5‐HT release and lower levels of 5‐HT‐stimulated release were found in deficient than in control rats. These neurochemical modifications were reversed by supply of the balanced diet provided at birth or during the first 2 weeks of life through the maternal milk, whereas they persisted if the balanced diet was given from weaning (at 3 weeks of age). This suggests that provision of essential fatty acids is durably able to affect brain function and that this is related to the developmental stage during which the deficiency occurs.

Maternal Exposure to LPS Induces Hypomyelination in the Internal Capsule and Programmed Cell Death in the Deep Gray Matter in Newborn Rats

Epidemiologic and experimental findings implicate maternal infection in the etiology of injury to brain white matter, which may lead to cerebral palsy in preterm newborns. In the present study, inflammation and brain damage in 1- and 7-d-old rats were investigated after maternal inflammation. Intraperitoneal injection of 300 μg/kg of Escherichia coli lipopolysaccharide was administered to pregnant Wistar rats at d 19 and 20 of gestation (LPS group). Control females received a saline injection. Proinflammatory cytokines IL-1β, tumor necrosis factor-α, and IL-6 expression in the fetal brain were determined by reverse transcription quantitative polymerase chain reaction. Brain injury was examined in 16-μm coronal brain sections by GFAP, MBP, caspase-3 immunohistochemistry, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Expression of IL-1β was significantly increased 3 d after maternal administration (P1). A significant increase in cell death occurred at P1 and P7 in specific brain areas, i.e. in the subventricular striatal zone at P1, and in 1) the periventricular striatum, 2) the periventricular white matter, and 3) the germinative ventricular zone at P7. We also observed typical astrogliosis and strong hypomyelination in the external and internal capsule in the LPS group at P7. These results demonstrate that maternal LPS treatment induces persistent fetal inflammatory reactions associated with significant white matter injury in progeny at P1 and P7. This model should be relevant for the study of the pathophysiological mechanisms involved in cerebral white matter damage in preterm human newborns and in the development of therapeutic strategies.

Partial recovery of dopaminergic pathway after graft of adult mesenchymal stem cells in a rat model of Parkinson's disease

Cellular therapy with adult stem cells appears as an opportunity for treatment of Parkinsons disease. To validate this approach, we studied the effects of transplantation of rat adult bone-marrow mesenchymal stem cells in a rat model of Parkinsons disease. Animals were unilaterally lesioned in the striatum with 6-hydroxydopamine. Two weeks later, group I did not undergo grafting, group II underwent sham grafting, group III was intra-striatal grafted with cells cultured in an enriched medium and group IV was intra-striatal grafted with cells cultured in a standard medium. Rotational amphetamine-induced behavior was measured weekly until animals were killed 6 weeks later. One week after graft, the number of rotations/min was stably decreased by 50% in groups III and IV as compared with groups I and II. At 8 weeks post-lesion, the density of dopaminergic markers in the nerve terminals and cell bodies, i.e. immunoreactive tyrosine hydroxylase, membrane dopamine transporter and vesicular monoamine transporter-2 was significantly higher in group III as compared with group I. Moreover, using microdialysis studies, we observed that while the rate of pharmacologically induced release of dopamine was significantly reduced in lesioned versus intact striatum in no grafted rats, it was similar in both sides in animals transplanted with mesemchymal stem cells. These data demonstrate that graft of adult mesemchymal stem cells reduces behavioral effects induced by 6-hydroxydopamine lesion and partially restores the dopaminergic markers and vesicular striatal pool of dopamine. This cellular approach might be a restorative therapy in Parkinsons disease.

Behavior and serotonergic disorders in rats exposed prenatally to valproate: A model for autism

In order to explore whether some aspects of the autistic phenotype could be related to impairment of the serotonergic system, we chose an animal model which mimics a potential cause of autism, i.e. rats exposed to valproate (VPA) on the 9th embryonic day (E9). Previous studies have suggested that VPA exposure in rats at E9 caused a dramatic shift in the distribution of serotonergic neurons on postnatal day 50 (PND50). Behavioral studies have also been performed but on rats that were exposed to VPA later (E12.5). Our aim was to test whether VPA exposure at E9 induces comparable behavioral impairments than at E12.5 and causes serotonergic impairments which could be related to behavioral modifications. The results showed significant behavioral impairments such as a lower tendency to initiate social interactions and hyperlocomotor activity in juvenile male rats. The serotonin levels of these animals at PND50 were decreased (-46%) in the hippocampus, a structure involved in social behavior. This study suggests that VPA could have a direct or indirect action on the serotonergic system as early as the progenitor cell stage. Early embryonic exposure to VPA in rats provides a good model for several specific aspects of autism and should help to continue to explore pathophysiological hypotheses.

Antidepressant-like effect of tramadol in the unpredictable chronic mild stress procedure: possible involvement of the noradrenergic system.

Tramadol, which inhibits the reuptake of noradrenaline and serotonin, is effective in animal models of depression. Its antidepressant-like effects may be mediated mainly by the noradrenergic system. This study investigated the role of the noradrenergic system in the antidepressant-like effects of tramadol and desipramine in the unpredictable chronic mild stress model. We assessed the involvement of &bgr;-adrenoreceptors, particularly &bgr;2-receptors in the activity of these drugs. In addition, we measured the level of noradrenaline and its metabolite 3-methoxy-4-hydroxy-phenylglycol (MHPG) in the locus coeruleus, hypothalamus, hippocampus and cerebellum in stressed mice. Unpredictable chronic mild stress induced a degradation of coat state and decreased grooming behaviour in the splash test, which was reversed by the chronic administration of tramadol (20 mg/kg) and desipramine (10 mg/kg). The nonselective &bgr;-adrenoreceptor antagonist propranolol (5 mg/kg, intraperitoneally) and the selective &bgr;2-receptor antagonist ICI 118,551 (2 mg/kg, intraperitoneally) reversed the antidepressant-like effects of tramadol and desipramine. Moreover, chronic tramadol and desipramine treatment increased the level of noradrenaline (NA) and MHPG in the locus coeruleus but not in the cerebellum, whereas only MHPG level was increased in the hypothalamus. Tramadol, however, increased the levels of MHPG and NA in the hippocampus, whereas desipramine only increased NA level. These data support the view that the noradrenergic system plays an important role in the antidepressant-like action of tramadol.

TIME COURSE OF CHANGES IN STRIATAL DOPAMINE TRANSPORTERS AND D2 RECEPTORS WITH SPECIFIC IODINATED MARKERS IN A RAT MODEL OF PARKINSON'S DISEASE

The time course of the loss in presynaptic dopamine transporters (DAT) and of the increase in postsynaptic dopamine D2 receptors (D2R) was studied in a rat model of Parkinsons disease. For this, in vitro autoradiographic experiments were performed in the striatum using (E)‐N‐(3‐iodoprop‐2‐enyl)‐2β‐carbomethoxy‐3β‐(4′‐methylphenyl) nortropane (PE2I), a new single photon emission tomography (SPET) ligand for DAT, and iodobenzamide (IBZM), a SPET ligand for D2R. A significant decrease in [125I]PE2I binding was observed as early as 24 h after 6‐hydroxydopamine lesion, whereas no change occurred in [125I]IBZM binding. At 48 h postlesion, PE2I binding was 50% decreased, while IBZM binding was 30% increased. Between 3 and 14 days postlesion, PE2I binding had almost totally disappeared and IBZM binding remained increased by around 40–50%. From these animal experiments, it can be assumed that PE2I would be very efficient for the detection of a reduction in the number of DAT reflecting neuronal loss, thus allowing early diagnosis of Parkinsons disease. The exploration of both DAT and D2R would improve follow‐up of this disease. Synapse 31:134–139, 1999.

Hypoxic preconditioning reduces apoptosis in a rat model of immature brain hypoxia-ischaemia

Hypoxic events are common in newborns but their consequences on brain development have not been demonstrated. It has been reported that in newborn animal models of cerebral hypoxic-ischaemic insult, short-term hypoxia before the insult completely prevented brain damage. The mechanisms of this brain tolerance have not been fully elucidated. Using a rat model of hypoxic preconditioning at day 6 followed by carotid ligation and hypoxic insult at day 7, we found a decrease in the number of apoptotic cells 24 and 48 h after the insult in the striatum, hippocampus and cortex. We demonstrated here that regulation of apoptotic cell death is one of the mechanisms involved in tolerance to hypoxia-ischaemia induced by hypoxic preconditioning.

Oxidative Stress Is Related to the Deleterious Effects of Heme Oxygenase-1 in an In Vivo Neuroinflammatory Rat Model

Heme oxygenase-1 (HO-1) induction is associated with beneficial or deleterious effects depending on the experimental conditions adopted and the neurodegenerative rodent models used. The present study aimed first to evaluate the effects of cerebral HO-1 induction in an in vivo rat model of neuroinflammation by intrastriatal injection of quinolinic acid (QA) and secondly to explore the role played by reactive oxygen species (ROS) and free iron (Fe2+) derived from heme catabolism promoted by HO-1. Chronic I.P. treatment with the HO-1 inductor and substrate hemin was responsible for a significant dose-related increase of cerebral HO-1 production. Brain tissue loss, microglial activation, and neuronal death were significantly higher in rats receiving QA plus hemin (H-QA) versus QA and controls. Significant increase of ROS production in H-QA rat brain was inhibited by the specific HO-1 inhibitor ZnPP which supports the idea that ROS level augmentation in hemin-treated animals is a direct consequence of HO-1 induction. The cerebral tissue loss and ROS level in hemin-treated rats receiving the iron chelator deferoxamine were significantly decreased, demonstrating the involvement of Fe2+in brain ROS production. Therefore, the deleterious effects of HO-1 expression in this in vivo neuroinflammatory model were linked to a hyperproduction of ROS, itself promoted by free iron liberation.

Longitudinal and parallel monitoring of neuroinflammation and neurodegeneration in a 6-hydroxydopamine rat model of Parkinson's disease

As neuroinflammatory processes are involved in the pathogenesis of Parkinsons disease (PD), we achieved the longitudinal evaluation of them in parallel with the modifications of dopaminergic function at several time‐points after 6‐hydroxydopamine (6‐OHDA) lesion in the rat mimicking an early stage of PD. After unilateral intrastriatal 6‐OHDA administration, we quantified the temporal evolution of the 18 kDa translocator protein (TSPO), TH‐immunoreactivity and dopamine transporters in the striatum and substantia nigra pars compacta (SNc) from 3‐ to 56‐days postlesion (dpl). Increased binding of TSPO ligands used, i.e., [3H]PK11195 and [125I]CLINDE, was observed in the lesioned striatum at 3, 7, and 14 dpl, followed by a progressive return to the basal level at 56 dpl. The binding profile in the SNc showed progressive binding beginning at 3 dpl, peaking at 14 dpl, and progressively decreasing until 56 dpl. In this model, the neuroinflammatory and neurodegenerative processes occurred concomitantly. The transitory occurrence of microglial activation could be involved in the lasting installation of dopaminergic neuron loss. Synapse, 2012.

Lamotrigine Is Neuroprotective in the Energy Deficiency Model of MPTP Intoxicated Mice

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) inhibits the mitochondrial complex I of the respiratory chain. This results in ATP and ion homeostasis disturbances, which lead to selective death of the substantia nigra dopaminergic neurons. Well known as a Parkinsons disease model, the MPTP animal model also provides a potential paradigm of the energy deficiencies found in childhood. In these conditions, anticonvulsants may provide neuroprotection by limiting cellular energy consumption. We tested valproate, topiramate and lamotrigine in the MPTP mouse model. Dopamine transporter (DAT) density was assessed by quantitative autoradiography, tyrosine hydroxylase (TH) was evaluated by immunohistochemistry and dopamine (DA) levels by HPLC-ED whereas neuronal apoptosis was monitored through active caspase-3. Expectedly, the DAT density, TH immunoreactive neurons and DA content in the MPTP group were respectively reduced to 51%, 40% and 26% versus control animals. Unlike valproate and topiramate, lamotrigine provided a significant neuroprotection against MPTP in maintaining these levels at 99%, 74% and 58% respectively and reducing the induced apoptosis. Altogether, the data indicate that lamotrigine limits dopaminergic neuronal death in the substantia nigra and promotes striatal dendrites sprouting. Lamotrigine, a widely used and well-tolerated molecule in young patients, could represent a valuable adjuvant therapy in various energy deficiency conditions during childhood.