Maria Concetta Geloso

The S100B protein in biological fluids: more than a lifelong biomarker of brain distress

J. Neurochem. (2012) 120, 644–659.

Changes in open field behavior, spatial memory, and hippocampal parvalbumin immunoreactivity following enrichment in rats exposed to neonatal anoxia

Behavioral and neurochemical changes following enriched housing were studied in Wistar rats neonatally exposed to anoxia (100% N2 for 25 min at approximately 30 h after birth) or to sham treatment. Neonatal anoxia provoked transient hyperactivity during the P25-P40 period, and spatial memory disturbances persisting into adult life. Enriched housing, from P21, at weaning, to P60, improved behavior in open field and spatial memory abilities in a water maze, reducing the deficits that followed neonatal anoxia. Changes in the expression of the calcium binding protein parvalbumin were present in the CA1, CA3, and DG regions of the hippocampus in both sham-treated and anoxic rats exposed to enrichment. The present findings give further support to the evidence of a positive effect of enriched housing on behavior and learning of normal and lesioned animals, which is sustained by modifications in the neuronal activity, and suggest that modifications in the environment can be useful to counteract the development of some neurological disturbances that follow neonatal insults, e.g., perinatal asphyxia.

Elevated S100 blood level as an early indicator of intraventricular hemorrhage in preterm infants. Correlation with cerebral Doppler velocimetry.

The aim of this study was to assess the use of S100 protein in blood as a means of identifying preterm infants at risk of intraventricular hemorrhage. In 25 preterm newborns, S100 blood concentrations were measured by an immunoradiometric assay during the first 48 h. Cerebral Doppler velocimetry waveform patterns were also tested at the time the blood sample was taken, when clinical and cerebral ultrasound scanning were still normal. Of the 25 newborns studied, 14 were controls and 11 developed intraventricular hemorrhage as revealed by ultrasound scanning more than 72 h after birth, and clinically confirmed by neurological examination on the seventh day of follow-up. S100 blood concentrations were significantly higher (P<0.002) in infants with intraventricular hemorrhage than in control infants and also correlated significantly (r=0.81, P<0.003) with the grade of hemorrhage. A significant correlation (r=0.70, P<0.05) between the S100 blood concentration and the middle cerebral artery pulsatility index was also observed. The present data show that S100 blood concentrations offer a measurable parameter of brain lesion in preterm infants before a radiological assessment of hemorrhage can be performed, when clinical symptoms may be silent and preventive/therapeutic action could be especially useful.

Trimethyltin-induced hippocampal degeneration as a tool to investigate neurodegenerative processes.

Trimethyltin (TMT), an organotin compound with neurotoxicant effects selectively localised in the limbic system and especially marked in the hippocampus, is considered a useful tool to obtain an experimental model of neurodegeneration. Animals exposed to TMT develop behavioural alterations (hyperactivity and aggression), cognitive impairment (memory loss and learning impairment) and spontaneous seizures. TMT induces selective neuronal death involving the granular neurons of the Fascia Dentata and the pyramidal cells of the Cornu Ammonis, with a different pattern of severity and extension according to the various species studied and the dosage schedule. TMT-induced neurodegenerative events are associated with the activation of astrocytes and microglial cells and with the upregulation of proinflammatory cytokines. While the mechanisms by which TMT induces neurodegeneration are still not understood, many hypotheses seem to suggest that neuronal damage could be largely dependent on calcium overload. This review summarizes current data from in vivo and in vitro studies of the neurotoxic effects of TMT, focusing on the hypotheses regarding the mechanisms leading to neuronal death induced by the toxin.

Cyclooxygenase-2 and caspase 3 expression in trimethyltin-induced apoptosis in the mouse hippocampus

The neurotoxicant trimethyltin (TMT) induces massive neuronal loss in vivo in the hippocampus of rodents, accompanied by behavioral alterations. The present study investigates the pattern of cell death after in vivo administration of TMT to adult mice. In the granular cell layer of the Dentate Gyrus, TUNEL staining detected DNA fragmentation, and apoptotic bodies were also evident. In addition, a ladder pattern of internucleosomal DNA fragmentation was shown in agarose gel electrophoresis. We show that activated caspase-3, which is known to play a pivotal role in apoptotic processes, is clearly expressed by degenerating neurons. Inducible cyclooxygenase is also expressed at cytoplasmic level by degenerating granular neurons, suggesting that this enzyme may participate in TMT-induced neurodegeneration.

Calretinin-Containing Neurons in Trimethyltin-Induced Neurodegeneration in the Rat Hippocampus: An Immunocytochemical Study ☆

The present study uses immunocytochemistry to investigate the behavior of the calretinin (CR)-containing neuronal subpopulation (interneurons) of the rat hippocampus in neurodegenerative processes induced by the neurotoxicant trimethyltin. Cell counts of CR-immunolabeled interneurons indicated that these cells are spared by the neurotoxicant-induced degeneration, characterized by a generalized neuronal loss, as shown by quantitative analysis after cresyl violet staining.

The neuroprotective and neurogenic effects of neuropeptide Y administration in an animal model of hippocampal neurodegeneration and temporal lobe epilepsy induced by trimethyltin

J. Neurochem. (2012) 122, 415–426.

Expression of astrocytic nestin in the rat hippocampus during trimethyltin-induced neurodegeneration

In this study we used an immunocytochemical approach to study nestin expression in the rat hippocampus during trimethyltin-induced neurodegeneration at different time points (5, 10, 15, 21 and 50 days) after intoxication. Nestin is transiently expressed by a subpopulation of astroglial cells strictly associated with pyramidal neurons in those hippocampal areas severely affected by degeneration. This observation shows that cerebral tissue re-expresses this developmental protein during neurodegenerative diseases in early stages of astroglial activation.

γ-Aminobutyric acidergic interneuron vulnerability to aging in canine prefrontal cortex

The aged dog is considered a promising model for examining molecular and cellular processes involved in a variety of human neurological disorders. By using the canine counterpart of senile dementia of the Alzheimers type (ccSDAT), we investigated the specific vulnerability of the γ‐aminobutyric acid (GABA) cortical subset of interneurons, characterized by their calcium‐binding protein content, to neuronal death. Dogs representing a large variety of breeds were classified into three groups: young control, aged control, and ccSDAT. In all dogs, the general distribution and cell typology of parvalbumin‐, calretinin‐, and calbindin‐positive neurons were found to be similar to those in the human. As in Alzheimers disease patients, neurons displaying parvalbumin or calretinin immunoreactivity were resistant and the calbindin‐positive ones depleted. Together with aging, amyloid deposition in its early phase (stage II) participates in this specific neuronal death, but with a lower potency. In conclusion, our data provide evidence that preservation of GABAergic cortical interneurons has to be focused on the early stage of β‐amyloid deposition. We also demonstrate the usefulness of dogs of all breeds for investigating the early phases of human brain aging and Alzheimers disease.

Expression of EMAP-II by activated monocytes/microglial cells in different regions of the rat hippocampus after trimethyltin-induced brain damage.

Endothelial monocyte-activating polypeptide-II (EMAP-II), a novel cytokine with proinflammatory and antiangiogenic properties, has previously been shown to be expressed by activated monocytes/microglial cells in the rat brain and was therefore considered a useful marker to stage microglial activation in inflammatory lesions. The aim of the present immunohistochemical study was to investigate expression of EMAP-II in the rat hippocampus after intoxication with the organotin compound trimethyltin (TMT). Administration of this neurotoxicant is known to produce brain damage mainly affecting the hippocampal formation, with severe neuronal cell loss being observed predominantly in regions CA-1 and CA-3. The maximum severity of TMT-induced brain damage is observed 21 days after a single ip administration. In this well-characterized model of neurodegeneration, activated microglial cells have been described to occur mainly in the early stages of TMT-induced neurotoxicity. Following TMT intoxication, we observed a significant increase in EMAP-II(+) monocytes/microglial cells in the CA-1 and the CA-3 regions. The CA-2 region, however, was largely spared. While appearance of single EMAP-II(+) microglial cells was observed already after 5 days, EMAP-II immunoreactivity reached its maximum after 21 days and persisted in some of the rats up to 35 days. These findings show a close correlation to the temporal and spatial pattern of neuronal damage described in the rat hippocampus after TMT administration previously. Thus, upregulation of EMAP-II by activated monocytes/microglial cells may serve as a sensitive marker of neurotoxic lesions in the rat brain.