title: Cerebellum neurotransmission during postnatal development: [Pt(O,O'-acac)(γ-acac)(DMS)] vs cisplatin and neurotoxicity.
abstract: 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. Since several drugs interact with neurotransmitters during neuronal maturation, we performed immunostainings with antibodies raised against markers of glutamate and GABA, the major neurotransmitters in the cerebellum. After a single injection of cisplatin at postnatal day 10 (PD10), the labelling of Purkinje cells with the neurotransmitter markers evidenced alterations between PD11 and PD30, i.e. atrophy of the dendrite tree, changes in the distribution of synaptic contacts of parallel and climbing fibres, delay in the elimination of transient synapses on cell soma and severely impaired pinceau formation at the axon hillock. After treatment with [Pt(O,O'-acac)(γ-acac)(DMS)], the sole relevant change concerned the timing of climbing fibres elimination; the transient synapses disappearance on the Purkinje cell soma was delayed in some cells; instead, the growth of Purkinje cell dendrite tree was normal as was the formation of inhibitory synaptic contacts on these neurons. These findings add new evidence not only on the lower neurotoxicity of [Pt(O,O'-acac)(γ-acac)(DMS)] vs cisplatin but also on the involvement of neurotransmitters and relative synaptic connections in the maturation of central nerve tissue.
authors.affiliation: Dipartimento di Biologia e Biotecnologie "L. Spallanzani" Università di Pavia, via Ferrata 9, 27100 Pavia, Italy; Istituto di Genetica Molecolare del CNR, Sezione di Istochimica e Citometria, via Ferrata 9, 27100 Pavia, Italy. Electronic address: valeria.piccolini@unipv.it.
authors.forename: Valeria Maria
authors.initials: VM
authors.lastname: Piccolini
authors.affiliation: Dipartimento di Biologia e Biotecnologie "L. Spallanzani" Università di Pavia, via Ferrata 9, 27100 Pavia, Italy. Electronic address: alessandra.esposito01@universitadipavia.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Esposito
authors.affiliation: Dipartimento di Biologia e Biotecnologie "L. Spallanzani" Università di Pavia, via Ferrata 9, 27100 Pavia, Italy. Electronic address: veronica.dalbo01@ateneopv.it.
authors.forename: Veronica
authors.initials: V
authors.lastname: Dal Bo
authors.affiliation: Dipartimento di Biologia e Biotecnologie "L. Spallanzani" Università di Pavia, via Ferrata 9, 27100 Pavia, Italy. Electronic address: violetta.isolia01@ateneopv.it.
authors.forename: Violetta
authors.initials: V
authors.lastname: Insolia
authors.affiliation: Dipartimento di Biologia e Biotecnologie "L. Spallanzani" Università di Pavia, via Ferrata 9, 27100 Pavia, Italy; Istituto di Genetica Molecolare del CNR, Sezione di Istochimica e Citometria, via Ferrata 9, 27100 Pavia, Italy. Electronic address: mariagrazia.bottone@unipv.it.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Bottone
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, 73100 Lecce, Italy. Electronic address: sandra.depascali@unisalento.it.
authors.forename: Sandra Angelica
authors.initials: SA
authors.lastname: De Pascali
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, 73100 Lecce, Italy. Electronic address: fp.fanizzi@unisalento.it.
authors.forename: Francesco Paolo
authors.initials: FP
authors.lastname: Fanizzi
authors.affiliation: Dipartimento di Biologia e Biotecnologie "L. Spallanzani" Università di Pavia, via Ferrata 9, 27100 Pavia, Italy. Electronic address: graziella.bernocchi@unipv.it.
authors.forename: Graziella
authors.initials: G
authors.lastname: Bernocchi
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D064026:Calbindins / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D002945:Cisplatin / Q000633:toxicity*; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005968:Glutamate Decarboxylase / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000209:etiology*; D009498:Neurotoxins / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000633:toxicity; D009435:Synaptic Transmission / Q000187:drug effects*; D050598:Vesicular Glutamate Transport Protein 1
chemical_list: D064026:Calbindins; D009498:Neurotoxins; D017470:Receptors, Glutamate; C493466:Slc17a7 protein, rat; D050598:Vesicular Glutamate Transport Protein 1; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C061800:N,N-dimethylsphingosine; D013110:Sphingosine; D002945:Cisplatin
keywords: GABA; Glutamate; Platinum compounds; Rat developing cerebellum