title: Histological changes in the rat brain and spinal cord following prolonged intracerebroventricular infusion of cerebrospinal fluid from amyotrophic lateral sclerosis patients are similar to those caused by the disease.
abstract: BACKGROUND
  Cerebrospinal fluid (CSF) from amyotrophic lateral sclerosis (ALS) patients induces cytotoxic effects in in vitro cultured motor neurons.
  
  
  METHODS
  We selected CSF with previously reported cytotoxic effects from 32 ALS patients. Twenty-eight adult male rats were intracerebroventricularly implanted with osmotic mini-pumps and divided into 3 groups: 9 rats injected with CSF from non-ALS patients, 15 rats injected with cytotoxic ALS-CSF, and 4 rats injected with a physiological saline solution. CSF was intracerebroventricularly and continuously infused for periods of 20 or 43days after implantation. We conducted clinical assessments and electromyographic examinations, and histological analyses were conducted in rats euthanised 20, 45, and 82days after surgery.
  
  
  RESULTS
  Immunohistochemical studies revealed tissue damage with similar characteristics to those found in the sporadic forms of ALS, such as overexpression of cystatinC, transferrin, and TDP-43 protein in the cytoplasm. The earliest changes observed seemed to play a protective role due to the overexpression of peripherin, AKTpan, AKTphospho, and metallothioneins; this expression had diminished by the time we analysed rats euthanised on day 82, when an increase in apoptosis was observed. The first cellular changes identified were activated microglia followed by astrogliosis and overexpression of GFAP and S100B proteins.
  
  
  CONCLUSIONS
  Our data suggest that ALS could spread through CSF and that intracerebroventricular administration of cytotoxic ALS-CSF provokes changes similar to those found in sporadic forms of the disease.
authors: Laboratorio de Neurobiología, Instituto de Neurociencias, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, España. Electronic address: ulisesalfonso.gomez@salud.madrid.org.
authors: U
authors: U
authors: Gómez-Pinedo
authors: Servicio de Neurología, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, España.
authors: L
authors: L
authors: Galán
authors: Servicio de Neurocirugía, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, España.
authors: M
authors: M
authors: Yañez
authors: Servicio de Neurología, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, España.
authors: J
authors: J
authors: Matias-Guiu
authors: Servicio de Neurología, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, España.
authors: C
authors: C
authors: Valencia
authors: Servicio de Neurología, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, España.
authors: A
authors: A
authors: Guerrero-Sola
authors: Laboratorio de Neurobiología, Instituto de Neurociencias, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, España.
authors: F
authors: F
authors: Lopez-Sosa
authors: Servicio de Neurocirugía, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, España.
authors: J R
authors: JR
authors: Brin
authors: Laboratorio de Neurobiología, Instituto de Neurociencias, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, España.
authors: M S
authors: MS
authors: Benito-Martin
authors: Laboratorio de Neurobiología, Instituto de Neurociencias, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, España.
authors: G
authors: G
authors: Leon-Espinosa
authors: Servicio de Neurología, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, España.
authors: A
authors: A
authors: Vela-Souto
authors: Servicio de Neurocirugía, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, España.
authors: C
authors: C
authors: Lendinez
authors: Laboratorio de Neurobiología, Instituto de Neurociencias, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, España.
authors: T
authors: T
authors: Guillamon-Vivancos
authors: Laboratorio de Neurobiología, Instituto de Neurociencias, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, España; Servicio de Neurología, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, España.
authors: J A
authors: JA
authors: Matias-Guiu
authors: Instituto Teófilo Hernando, Departamento de Farmacología Terapéutica, Universidad Autónoma de Madrid, Madrid, España.
authors: J A
authors: JA
authors: Arranz-Tagarro
authors: Servicio de Neurocirugía, IdISSC, Hospital Clínico San Carlos, Universidad Complutense de Madrid, Madrid, España.
authors: J A
authors: JA
authors: Barcia
authors: Instituto Teófilo Hernando, Departamento de Farmacología Terapéutica, Universidad Autónoma de Madrid, Madrid, España.
authors: A G
authors: AG
authors: Garcia
mesh_terms: D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000134:cerebrospinal fluid* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000473:pathology*; D002478:Cells, Cultured; D002555:Cerebrospinal Fluid / Q000737:chemistry / Q000378:metabolism*; D003603:Cytotoxins / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D057967:Infusions, Intraventricular; D008297:Male; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D013116:Spinal Cord / Q000473:pathology*
chemical_list: D003603:Cytotoxins
keywords: ALS experimental model; Amyotrophic lateral sclerosis; Citotoxicidad; Cytotoxicity; Enfermedades neurodegenerativas; Esclerosis lateral amiotrófica; Modelo experimental ELA; Neurodegenerative diseases; Periferina; Peripherin; TDP-43