Prolidase enzyme is required for extracellular matrix integrity and impacts on postnatal cerebellar cortex development.

The extracellular matrix is essential for brain development, lamination, and synaptogenesis. In particular, the basement membrane below the pial meninx (pBM) is required for correct cortical development. The last step in the catabolism of the most abundant protein in pBM, collagen Type IV, requires prolidase, an exopeptidase cleaving the imidodipeptides containing pro or hyp at the C-terminal end.

Calcium-Binding Proteins in the Nervous System during Hibernation: Neuroprotective Strategies in Hypometabolic Conditions?

Calcium-binding proteins (CBPs) can influence and react to Ca transients and modulate the activity of proteins involved in both maintaining homeostatic conditions and protecting cells in harsh environmental conditions. Hibernation is a strategy that evolved in vertebrate and invertebrate species to survive in cold environments; it relies on molecular, cellular, and behavioral adaptations guided by the neuroendocrine system that together ensure unmatched tolerance to hypothermia, hypometabolism, and hypoxia. Therefore, hibernation is a useful model to study molecular neuroprotective adaptations to extreme conditions, and can reveal useful applications to human pathological conditions.

Long-term effects after treatment with platinum compounds, cisplatin and [Pt(O,O'-acac)(γ-acac)(DMS)]: Autophagy activation in rat B50 neuroblastoma cells.

Cisplatin (cisPt), among the best known components of multi-drug front-line therapies used for the treatments of solid tumors, such as the childhood neuroblastoma, acts through DNA linking. Nevertheless, the cisPt effectiveness is compromised by the onset of severe side effects, including neurotoxicity that results in neurodegeneration, cell death, and drug-resistance. In the field of experimental oncology, aimed at overcoming cytotoxicity and chemoresistance, great efforts are devoted to the synthesis of new platinum-based drugs, such as [Pt(O,O'-acac)(γ-acac)(DMS)] (PtAcacDMS), which shows a specific reactivity with sulfur residues of enzymes involved in apoptosis.

Hibernation induces changes in the metacerebral neurons of Cornu aspersum: distribution and co-localization of cytoskeletal and calcium-binding proteins.

Pulmonate gastropods provide unique opportunities to examine physiological and biochemical adaptation strategies when cellular metabolic activity is reduced. In this study, cytochemical changes in metacerebral neurons of the cerebral ganglia were investigated in the garden snail Cornu aspersum during the hibernation phase. The immunocytochemical expression of three cytoskeletal markers: microtubule-associate protein 2-like (MAP-2-li), phosphorylated form of tau-like (P-Tau-li) and heavy subunit of neurofilaments-like (NF-H-li), and of two calcium-binding proteins: calmodulin-like (CaM-li) and parvalbumin-like (PV-li) was compared in active and hibernated snails.

[Pt(O,O'-acac)(γ-acac)(DMS)] versus cisplatin: apoptotic effects in B50 neuroblastoma cells.

Cisplatin is one of the most active chemotherapeutic agents used in the treatment of childhood and adult malignancies. Cisplatin induces cell death through different pathways. Despite its effectiveness, the continued clinical use of cisplatin is limited by onset of severe side effects (nephrotoxicity, ototoxicity and neurotoxicity) and drug resistance.

Neurotoxic Effects of Platinum Compounds: Studies on Intracellular Calcium Homeostasis in the Immature Central Nervous System.

Platinum compounds cause significant clinical neurotoxicity. Several studies highlight neurological complications especially in paediatric oncology patients with Central Nervous System (CNS) and non-CNS malignancies. To understand the toxicity mechanisms of platinum drugs at cellular and molecular levels in the immature brain, which appears more vulnerable to injury than in the adult one, we compared the effects of the most used platinum compounds, , cisdichlorodiammineplatinum (cisplatin, cisPt), and the new [Pt(,'-acac)(γ-acac)(DMS)] (PtAcacDMS).

Renal fibrogenesis and platinum compounds in a rat model: a novel Pt (II) complex vs. cisplatin.

Background/aim: A new platinum compound, (Pt(O,O'-acac)(γ-acac)(DMS)) (PtAcacDMS), has been shown to possess higher cytotoxic activity than cisplatin on several cancer and chemoresistant cell lines. The aim of the present study was to compare the nephrotoxic effects - particularly renal fibrogenesis- of PtAcacDMS and cisplatin in rats after the subcutaneous administration of a single dose (5 mg/Kg b.w.

Cerebellum neurotransmission during postnatal development: [Pt(O,O'-acac)(γ-acac)(DMS)] vs cisplatin and neurotoxicity.

Several chemotherapeutic drugs are known to cause neurotoxicity. Platinum-based agents in use or in clinical trials display neurotoxic potential accompanied by neurological complications; recent studies have identified a large number of behavioural issues in paediatric oncology patients. To understand the toxicity of platinum drugs at the molecular and cellular levels, this study compares the possible cytotoxic effects of an older platinum compound, cisplatin and a new platinum compound, [Pt(O,O'-acac)(γ-acac)(DMS)], on the CNS of postnatally developing rats, which is much more vulnerable to injury than the CNS of adult rats.

Blood-brain barrier (BBB) toxicity and permeability assessment after L-(4-¹⁰Boronophenyl)alanine, a conventional B-containing drug for boron neutron capture therapy, using an in vitro BBB model.

Since brain tumours are the primary candidates for treatment by Boron Neutron Capture Therapy, one major challenge in the selective drug delivery to CNS is the crossing of the blood-brain barrier (BBB). The present pilot study investigated (i) the transport of a conventional B-containing product (i.e.

Platinum drugs and neurotoxicity: effects on intracellular calcium homeostasis.

[Pt(O,O'-acac)(γ-acac)(DMS)] (PtAcacDMS) is a new platinum compound showing low reactivity with nucleobases and specific reactivity with sulfur ligands intracellularly. It induces apoptosis in breast cancer cells, but appears to be less neurotoxic to the developing cerebellum than cisplatin (cisPt). The aim of this study was to assess the neurotoxicity of platinum compounds on calcium homeostasis in the dentate gyrus and Cornu Ammonis regions of the hippocampal formation during rat postnatal development.

Morphological Features of Organelles during Apoptosis: An Overview.

An apoptotic program leading to controlled cell dismantling implies perturbations of nuclear dynamics, as well as changes affecting the organelle structure and distribution. In human cancer cells driven to apoptosis by different stimuli, we have recently investigated the morphological properties of several organelles, including mitochondria, lysosomes, endoplasmic reticulum and Golgi apparatus. In this review, we will discuss the body of evidence in the literature suggesting that organelles are generally relocated and/or degraded during apoptosis, irrespectively of the apoptogenic stimulus and cell type.

Mitochondrial fusion: a mechanism of cisplatin-induced resistance in neuroblastoma cells?

Cisplatin induces apoptosis through different pathways. The intrinsic apoptotic pathway is mediated by mitochondria, which, as a result of cisplatin treatment, undergo morphological alterations. The aim of this study was to investigate cisplatin-induced mitochondrial functional and morphological long-term effects in neuroblastoma B50 rat cells.

Developmental expression of cellular prion protein and apoptotic molecules in the rat cerebellum: effects of platinum compounds.

Programmed cell death is regulated by prototypes of a large family of Bcl-2-like proteins such as Bax and Bcl-2. A neuroprotective role for cellular prion protein (PrPc) on programmed cell death has been reported, although the cytosolic accumulation of PrPc correlates with toxicity and death of some neurons by apoptosis. In order to understand the signalling function of PrPc in promoting survival or suppressing cell death, we analyzed the expression and co-localization of PrPc, Bax and Bcl-2 proteins in the developing cerebellum of rats treated at PD10 (postnatal day 10) with the chemotherapeutic drug cisplatin (cisPt) or the new platinum (Pt) compound [Pt(O,O'-acac)(γ-acac)(DMS)] (PtAcacDMS).

Cisplatin induces changes in the matrix metalloproteinases and their inhibitors in the developing rat cerebellum.

The role of matrix metalloproteinases (MMP-3 and MMP-9), tissue inhibitor of MMP (TIMP-2), and GAP-43 (growth-associated-protein) in neocerebellar vermis lobules during postnatal histogenesis was studied after challenge with cisplatin (cisPt). CisPt is one of the most effective and widely used cytotoxic agents in the treatment of a variety of malignancies, in both children and adult patients. A single injection of cisPt to 10-day-old rats altered the spatiotemporal MMP/TIMP expression balance and provoked a decrease in GAP43 immunoreactivity.

Effects of Cisplatin in neuroblastoma rat cells: damage to cellular organelles.

Cisplatin (cisPt) is a chemotherapy agent used as a treatment for several types of cancer. The main cytotoxic effect of cisplatin is generally accepted to be DNA damage. Recently, the mechanism by which cisPt generates the cascade of events involved in the apoptotic process has been demonstrated.

Developing central nervous system and vulnerability to platinum compounds.

Comparative studies on the effects of the platinum complexes in use or in clinical trials are carried out in order to discover differences in the neurotoxic potential and the reversibility of neurotoxicity. In this paper, we summarized the current literature on neurotoxicity and chemoresistance of cisplatin (cisPt) and discussed our recent efforts on the interference of cisPt and a new platinum compound [Pt(O,O'-acac)(γ-acac)(DMS)] (PtAcacDMS), with high specific reactivity with sulphur ligands instead of nucleobases as cisPt, on some crucial events of rat postnatal cerebellum development. The acute effects of drug treatments on cell proliferation and death in the external granular layer and granule cell migration and the late effects on the dendrite growth of Purkinje cells were evaluated.

Interactions of neurotransmitter systems during postnatal development of the rat hippocampal formation: effects of cisplatin.

The distribution of neuroimmunohistochemical markers for the serotoninergic, noradrenergic, glutamatergic and GABAergic systems (respectively, 5HT(2A)R, β1AR, GluR 2/3 and GAD65/67) was determined in the hippocampal formation at stages PD11, PD17 and PD30 of postnatal development of untreated rats and cisplatin-treated rats after a single injection of the drug at 10days of life. In the different time points the neurons of the dentate gyrus and Cornu Ammonis progressively acquire mature morphological characteristics, and cell genesis, migration of interneurons and differentiation of mossy cells occur. Cisplatin induced decrease in immunoreactivity for most of the selected neurotransmitter markers, thereby altering the postnatal development of circuits in the hippocampal formation.

Different patterns of apoptosis in response to cisplatin in B50 neuroblastoma rat cells.

Cisplatin (cisPt) is a chemotherapeutic drug used for several human malignancies. CisPt cytotoxicity is primarily mediated by its ability to cause DNA damage and subsequent apoptotic cell death. DNA is the primary target of cisPt; however, recent data have shown that cisPt may have important direct interactions with mitochondria, which can induce apoptosis and may account for a significant part of the clinical activity associated with this drug.

The developmental neurotoxicity study of platinum compounds. Effects of cisplatin versus a novel Pt(II) complex on rat cerebellum.

In the field of experimental oncology, many efforts are being carried out to search new platinum-based drugs overcoming the CNS toxicity and drug resistance. One of the adopted strategies is the synthesis of platinum compounds able to form Pt-DNA adducts different from the cisplatin ones or to react with other subcellular targets. In this context a novel Pt(II) complex, [Pt(O,O'-acac)(γ-acac)(DMS)](PtAcacDMS), was synthesized which reacts preferentially with protein thiols or thioethers.

Postnatal development of the central nervous system: anomalies in the formation of cerebellum fissures.

A natural defect in rat cerebellum postnatal development has been found in the fissura prima, consisting in various complex configurations of the cerebellar layers. We investigated the genesis of fissure malformations through immunoreactions for PCNA, GFAP, GABAA alpha6, and calbindin to label proliferating cells of the external granular layer (egl), radial glial fibers, mature granule cells, and Purkinje cells, respectively. Results on critical stages of rat postnatal development provided interesting evidences on how the malformation develops in fissures prima and secunda.

Cell proliferation and death in the brain of active and hibernating frogs.

'Binomial' cell proliferation and cell death have been studied in only a few non-mammalian vertebrates, such as fish. We thought it of interest to map cell proliferation/apoptosis in the brain of the frog (Rana esculenta L.) as this animal species undergoes, during the annual cycle, physiological events that could be associated with central nervous system damage.

Perineuronal glial system in the cerebral ganglion of active and hibernating Helix aspersa.

The electron microscopical changes in the glial lacunar network that surrounds the large neurons of meso- and metacerebrum of land snail cerebral ganglia were considered, in order to get an insight into the functional role of this peculiar structure in invertebrates. Compared with snails during the active period, in the hibernating animals the extension of glial processes was reduced and the glial processes appeared more regular and stacked around neurons. Moreover, they did not form deep, long interdigitations with neuronal infoldings as during the active period.

Cell proliferation, apoptosis and mitochondrial damage in rat B50 neuronal cells after cisplatin treatment.

Objectives: Cisplatin (cisPt) is used as a chemotherapeutic agent for the treatment of a variety of human tumours; more recently, it has been demonstrated that tumour cell exposure to cisPt ultimately results in apoptosis, but the mechanism by which nuclear cisPt/DNA generates the cytoplasmic cascade of events involved has not been clarified. We have investigated the effects of cisPt on proliferation in the neuronal cell line B50, with particular attention being given to understand whether mitochondria are a target of cisPt and their involvement in the apoptotic process.

Materials And Methods: Rat neuronal B50 cells were used to investigate the mechanisms of cisPt-induced cytotoxicity; this line has been used as a model system for neurotoxicity in vivo.

Cerebellum cholinergic muscarinic receptor (subtype-2 and -3) and cytoarchitecture after developmental exposure to methylmercury: an immunohistochemical study in rat.

The developing central nervous system (CNS) is a target of the environmental toxicant methylmercury (MeHg), and the cerebellum seems the most susceptible tissue in response to this neurotoxicant. The cholinergic system is essential for brain development, acting as a modulator of neuronal proliferation, migration and differentiation processes; its muscarinic receptors (MRs) play pivotal roles in regulating important basic physiologic functions. By immunohistochemistry, we investigated the effects of perinatal (GD7-PD21) MeHg (0.

Perinatal co-exposure to methylmercury and PCB153 or PCB126 in rats alters the cerebral cholinergic muscarinic receptors at weaning and puberty.

In the last few decades, combined exposure to methylmercury (MeHg) and polychlorinated biphenyls (PCBs) from fish and seafood, and their potentially interactive effects on neurodevelopment, have been giving increasing cause for concern. We examined the combined effects of MeHg and either a non-dioxin PCB (PCB153) or a dioxin-like PCB (PCB126) congener on the developing brain cholinergic muscarinic receptors (MRs). These receptors are known to play a major role in many central functions including higher cognitive processes and the modulation of extrapyramidal motor activity.