Biomedical subjects

Stefania Bassanini

Publications and source records attributed to Stefania Bassanini.

7 recordsLinked to original sources

PubMed2006

Determinants of drug brain uptake in a rat model of seizure-associated malformations of cortical development.

We examined the blood-brain barrier (BBB) function in methylazoxymethanol acetate (MAM)-treated rats, a model of human developmental brain malformations. We found aberrant vessels morphology and serum albumin leakage in the heterotopic (malformed) hippocampus; these changes were associated with a significant increase in endothelial P-glycoprotein (P-gp) expression. Seizures exacerbated BBB leakage and greatly augmented P-gp expression in vessels and additionally in perivascular/parenchymal astrocytes. The effects of seizures were observed to a much larger extent in malformed than in normal brain tissue. The intrinsic changes in BBB function in MAM-exposed rats were associated with increased blood-to-brain penetration of ondansetron, a P-gp substrate. However, a marked reduction in drug brain levels was provoked by seizures, and this effect was reversed by selective blockade of P-gp activity with tariquidar. Changes in BBB function may critically contribute to determine the brain uptake and distribution of P-gp substrates in epileptic tissue associated with developmental malformations.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

NMDA receptor composition differs among anatomically diverse malformations of cortical development.

Altered excitatory synaptic activity is likely a key factor in the neuronal hyperexcitability of developmental cerebral malformations. Using a combined morphologic and molecular approach, we investigated the NMDA receptor and related protein composition in human epileptic patients affected by periventricular nodular heterotopia, subcortical band heterotopia, or focal cortical dysplasia. Our results indicate that expression levels of specific NMDA receptor subunits are altered in both cerebral heterotopia and cortical dysplasia. A selective increase in the NR2B subunit was present in all cortical dysplasia, whereas the expression level of NR2A and NR2B subunits was significantly downregulated in all patients with heterotopia. NR2B upregulation in cortical dysplasia was greater in the total homogenate than the postsynaptic membrane fraction, suggesting that mechanisms other than increased ionic influx through the postsynaptic membrane may sustain hyperexcitability in dysplastic neurons. In cerebral heterotopia, the NR2A and NR2B downregulation was accompanied by less evident reduction of the SAP97 and PSD-95 proteins of the MAGUK family, thus suggesting that NMDA impairment was associated with altered molecular structure of the postsynaptic membrane. Our results demonstrate that diverse human developmental malformations are associated with different alterations of the NMDA receptor, which may contribute to the genesis of epileptic phenomena.

Adolescent↗

PubMed2006

Periventricular nodular heterotopia: classification, epileptic history, and genesis of epileptic discharges.

PURPOSE: Periventricular nodular heterotopia (PNH) is among the most common malformations of cortical development, and affected patients are frequently characterized by focal drug-resistant epilepsy. Here we analyzed clinical, MRI, and electrophysiologic findings in 54 PNH patients to reevaluate the classification of PNH, relate the anatomic features to epileptic outcome, and ascertain the contribution of PNH nodules to the onset of epileptic discharges. METHODS: The patients were followed up for a prolonged period at the Epilepsy Center of our Institute. In all cases, we related MRI findings to clinical and epileptic outcome and analyzed interictal and ictal EEG abnormalities. In one patient, EEG and stereo-EEG (SEEG) recordings of seizures were compared. RESULTS: We included cases with periventricular nodules, also extending to white matter and cortex, provided that anatomic continuity was present between nodules and malformed cortex. Based on imaging and clinical data, patients were subdivided into five PNH groups: (a) bilateral and symmetrical; (b) bilateral single-noduled; (c) bilateral and asymmetrical; (d) unilateral; and (e) unilateral with extension to neocortex. The latter three groups were characterized by worse epileptic outcome. No differences in outcome were found between unilateral PNH patients regardless the presence of cortical involvement. Interictal as well as ictal EEG abnormalities were always related to PNH location. CONCLUSIONS: The distinctive clinical features and epileptic outcomes in each group of patients confirm the reliability of the proposed classification. Ictal EEG and SEEG recordings suggest that seizures are generated by abnormal anatomic circuitries including the heterotopic nodules and adjacent cortical areas.

Adolescent↗

PubMed2005

Electroencephalographic recordings of focal seizures in patients affected by periventricular nodular heterotopia: role of the heterotopic nodules in the genesis of epileptic discharges.

Patients affected by periventricular nodular heterotopia are frequently characterized by focal drug-resistant epilepsy. To investigate the role of periventricular nodules in the genesis of seizures, we analyzed the electroencephalographic (EEG) features of focal seizures recorded by means of video-EEG in 10 patients affected by different types of periventricular nodular heterotopia and followed for prolonged periods of time at the epilepsy center of our institute. The ictal EEG recordings with surface electrodes revealed common features in all patients: all seizures originated from the brain regions where the periventricular nodular heterotopia were located; EEG patterns recorded on the leads exploring the periventricular nodular heterotopia were very similar both at the onset and immediately after the seizure's end in all patients. Our data suggest that seizures are generated by abnormal anatomic circuitries, including the heterotopic nodules and adjacent cortical areas. The major role of heterotopic neurons in the genesis and propagation of epileptic discharges must be taken into account when planning surgery for epilepsy in patients with periventricular nodular heterotopia.

Adolescent↗

PubMed2003

Neurogenesis in cerebral heterotopia induced in rats by prenatal methylazoxymethanol treatment.

We have previously demonstrated that the antiproliferative agent methylazoxymethanol acetate (MAM) is able to induce in rats cerebral heterotopia that share striking similarities with those observed in human periventricular nodular heterotopia (PNH), a cerebral dysgenesis frequently observed in human patients affected by drug-resistant focal epilepsy. In this study, we investigated the time-course of neurogenesis in the cerebral heterotopia of MAM-treated rats, with the idea of understanding why PNH develop in human patients. For these goals, we analyzed the cytoarchitectural features, the time of neurogenesis and the cellular phenotype of the heterotopia, by means of BrdU immunocytochemistry and confocal immunofluorescence experiments. Our data demonstrate that the different types of heterotopia in MAM-treated rats are formed through the same altered neurogenetic process, which follows quite organized neurogenetic gradients. The MAM-induced ablation of an early wave of cortical neurons is sufficient to alter per se the migration and differentiation of subsequently generated neurons, which in turn set the base for the formation of the different heterotopic structures. The neurogenesis of MAM-induced heterotopia may explain the origin and intrinsic epileptogenicity of periventricular nodular heterotopia in human patients.

Animals↗

PubMed2003

The NMDA receptor complex is altered in an animal model of human cerebral heterotopia.

Double intraperitoneal injections of methylazoxymethanol (MAM) in pregnant rats induce developmental brain dysgenesis with nodular heterotopia similar to human periventricular nodular heterotopia (PNH) and composed of hyperexcitable neurons. Here we analyzed the NMDA receptor complex and associated proteins in the heterotopic neurons of 2- to 3-month-old MAM-treated rats by means of a combined immunocytochemical/molecular approach. Our data demonstrated a clear reduction of p286-active form of alphaCaMKII and a selective impairment of both the targeting and the CaMKII-dependent phosphorylation of NR2A/B subunits in the postsynaptic membranes of the MAM-induced heterotopia. The reduced NR2A/B immunofluorescence of the cellular membrane was not due to reduced expression since it was decreased only in postsynaptic fractions but not in the homogenate. NMDA-NR1 and AMPA-GluR2/3 subunits, as well as PSD-95 and total alphaCaMKII protein levels, were not affected in MAM-treated rats, thus revealing that the overall composition of the postsynaptic fraction was not altered. These data clearly suggest that the molecular organization of the NMDA/alphaCaMKII complex is selectively altered in the postsynaptic compartment of heterotopic neurons. This alteration can play a role in determining the hyperexcitability of brain heterotopia in MAM rats as well as in human patients affected by PNH.

Animals↗

PubMed2003

The genesis of epileptogenic cerebral heterotopia: clues from experimental models.

The pre-natal administration of methylazoxymethanol acetate (MAM) in rats is able to induce cerebral heterotopia that share striking similarities with those observed in human periventricular nodular heterotopia, a cerebral dysgenesis frequently associated with drug-resistant focal seizures. In the present study, we investigated the mode of neurogenesis in cerebral heterotopia of MAM-treated rats, by analyzing post-natal cytoarchitectural features and time of neurogenesis using bromodeoxyuridine immunocytochemistry. The cytoarchitectural analysis demonstrated the existence, in the early post-natal period, of white matter cellular bands in close anatomical relationship with the heterotopia, which most likely serve as a reservoir of young, migrating neurons for the newly forming heterotopia. The birth dating analysis demonstrated that the period of generation of neurons within the heterotopia and adjacent white matter bands, was extended in comparison to corticogenesis in normal rat brains. In addition, it demonstrated that the heterotopia were formed through a rather precise outside-in (for cortical and periventricular heterotopia) and dorso-ventral (for intra-hippocampal heterotopia) neurogenetic pattern. We hypothesize that the MAM-induced ablation of an early wave of cortical neurons is sufficient to alter per se the migration and differentiation of subsequently generated neurons, which in turn set the base for the formation of the different types of heterotopia. On this basis, we suggest a neurogenetic scheme for MAM-induced heterotopia that can also explain the origin and intrinsic epileptogenicity of periventricular nodular heterotopia in humans.

Animals↗