Angiotensin-(1-7) protects from brain damage induced by shiga toxin 2-producing enterohemorrhagic Escherichia coli.
Shiga toxin 2 (Stx2)-producing enterohemorrhagic induced brain damage. Since a cerebroprotective action was reported for angiotensin (Ang)-(1-7), our aim was to investigate whether Ang-(1-7) protects from brain damage induced by Stx2-producing enterohemorrhagic Escherichia coli The anterior hypothalamic area of adult male Wistar rats was injected with saline solution or Stx2 or Stx2 plus Ang-(1-7) or Stx2 plus Ang-(1-7) plus A779. Rats received a single injection of Stx2 at the beginning of the experiment, and Ang-(1-7), A779, or saline was administered daily in a single injection for 8 days. Cellular ultrastructural changes were analyzed by transmission electron microscopy. Stx2 induced neurodegeneration, axonal demyelination, alterations in synapse, and oligodendrocyte and astrocyte damage, accompanied by edema. Ang-(1-7) prevented neuronal damage triggered by the toxin in 55.6 ± 9.5% of the neurons and the Stx2-induced synapse dysfunction was reversed. In addition, Ang-(1-7) blocked Stx2-induced demyelination in 92 ± 4% of the axons. Oligodendrocyte damage caused by Stx2 was prevented by Ang-(1-7) but astrocytes were only partially protected by the peptide (38 ± 5% of astrocytes were preserved). Ang-(1-7) treatment resulted in 50% reduction in the number of activated microglial cells induced by Stx2, suggesting an anti-inflammatory action. All these beneficial effects elicited by Ang-(1-7) were blocked by the Mas receptor antagonist and thus it was concluded that Ang-(1-7) protects mainly neurons and oligodendrocytes, and partially astrocytes, in the central nervous system through Mas receptor stimulation.
Laboratorio de Neurofisiopatología, Instituto de Fisiología y Biofísica "Houssay"-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
Jorge
J
Goldstein
Departamento de Química Biológica, Instituto de Química y Fisicoquímica Biológicas-CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina; and.
Tomás R
TR
Carden
Departamento de Química Biológica, Instituto de Química y Fisicoquímica Biológicas-CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina; and.
María J
MJ
Perez
Departamento de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
Carlos A
CA
Taira
Departamento de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
Christian
C
Höcht
Departamento de Química Biológica, Instituto de Química y Fisicoquímica Biológicas-CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina; and mariela@qb.ffyb.uba.ar.
Mariela M
MM
Gironacci
D000803:Angiotensin I / Q000008:administration & dosage*; D000818:Animals; D004927:Escherichia coli Infections / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D007031:Hypothalamus / Q000187:drug effects / Q000473:pathology*; D000069544:Infectious Encephalitis / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage; D010446:Peptide Fragments / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D022641:Shiga Toxin 2 / Q000633:toxicity*; D054323:Shiga-Toxigenic Escherichia coli / Q000378:metabolism; D016896:Treatment Outcome
D018696:Neuroprotective Agents; D010446:Peptide Fragments; D022641:Shiga Toxin 2; D000803:Angiotensin I; C118790:angiotensin I (1-7)
Mas receptor; angiotensin-(1-7); astrocyte; neuron; oligodendrocyte