title: Low-doses of cisplatin injure hippocampal synapses: a mechanism for 'chemo' brain?
abstract: Chemotherapy-related cognitive deficits are a major neurological problem, but the underlying mechanisms are unclear. The death of neural stem/precursor cell (NSC) by cisplatin has been reported as a potential cause, but this requires high doses of chemotherapeutic agents. Cisplatin is frequently used in modern oncology, and it achieves high concentrations in the patient's brain. Here we report that exposure to low concentrations of cisplatin (0.1μM) causes the loss of dendritic spines and synapses within 30min. Longer exposures injured dendritic branches and reduced dendritic complexity. At this low concentration, cisplatin did not affect NSC viability nor provoke apoptosis. However, higher cisplatin levels (1μM) led to the rapid loss of synapses and dendritic disintegration, and neuronal-but not NSC-apoptosis. In-vivo treatment with cisplatin at clinically relevant doses also caused a reduction of dendritic branches and decreased spine density in CA1 and CA3 hippocampal neurons. An acute increase in cell death was measured in the CA1 and CA3 neurons, as well as in the NSC population located in the subgranular zone of the dentate gyrus in the cisplatin treated animals. The density of dendritic spines is related to the degree of neuronal connectivity and function, and pathological changes in spine number or structure have significant consequences for brain function. Therefore, this synapse and dendritic damage might contribute to the cognitive impairment observed after cisplatin treatment.
authors.affiliation: Department of Anatomy & Neurobiology, University of California-Irvine, Irvine, CA, USA.
authors.forename: Adrienne L
authors.initials: AL
authors.lastname: Andres
authors.affiliation: Department of Neurology, University of California-Irvine, Irvine, CA, USA; Chao Family Comprehensive Cancer Center, University of California-Irvine, Irvine, CA, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Gong
authors.affiliation: Department of Neurological Surgery, University of California-Irvine, Irvine, CA, USA; Chao Family Comprehensive Cancer Center, University of California-Irvine, Irvine, CA, USA.
authors.forename: Kaijun
authors.initials: K
authors.lastname: Di
authors.affiliation: Department of Neurology, University of California-Irvine, Irvine, CA, USA; Department of Neurological Surgery, University of California-Irvine, Irvine, CA, USA; Chao Family Comprehensive Cancer Center, University of California-Irvine, Irvine, CA, USA. Electronic address: dbota@uci.edu.
authors.forename: Daniela A
authors.initials: DA
authors.lastname: Bota
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage* / Q000009:adverse effects; D003072:Cognition Disorders / Q000139:chemically induced* / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D002945:Cisplatin
keywords: Annexin V; Chemotherapy; Cisplatin; Hippocampal dendritic spines; Neural stem/precursor cells (NSCs); Neuronal apoptosis; Postsynaptic density-95 protein (PSD95)