Neurotoxicity of intrathecal Shiga toxin 2 and protection by intrathecal injection of anti-Shiga toxin 2 antiserum in rabbits.
The initial brain lesions in rabbits given intravenous Shiga toxin 2 (Stx2) were noted at 24 h in an area around the third ventricle (Fujii et al., Infect Immun 1996, 64: 5053-60). This result implied that Stx2 is present in the cerebrospinal fluid (CSF) despite the fact that the toxin was administered intravenously. We measured Stx2 activity in CSF by using a Vero cell cytotoxicity assay at various times after an intravenous injection of Stx2. Stx2 was detected from 2 h after the injection, and its concentration in CSF remained at a high level for a further 6 h. Fifty percent lethal doses (LD 50) of Stx2 were measured in rabbits after intravenous and intrathecal Stx2 injections; The LD 50 after an intrathecal injection of Stx2 was 0. 36 microg/kg, which was 9.2-fold lower than that of an intravenous injection of Stx2 (3.4 microg/kg). Magnetic resonance images obtained after an intrathecal Stx2 injection (5 microg/kg) were compared with those obtained after an intravenous Stx2 injection (5 microg/kg). At 48 h, the cerebellar lesions had spread from the area in contact with the CSF on a T2-weighted image, which suggests that the intrathecal Stx2 may invade the cerebellum directly. We then examined whether anti-Stx2 antiserum injected intrathecally protects rabbits against brain damage. Eighty percent of the rabbits infected with Stx2 at 5 microg/kg died within 8 days from brain damage. Rabbit anti-Stx2 sera (with titres of x16 and x64 by the Ouchterlony precipitation method) were administered into the CSF space through the cisterna magna. All the rabbits ( n=10) survived when they were given an intrathecal injection of rabbit anti-Stx2 antiserum 2 h before the intravenous injection of Stx2. Our results suggest that a leakage of Stx2 into the CSF from the choroid plexus causes brain damage, and that an intrathecal injection of anti-Stx2 antiserum could be a therapy for acute encephalopathy caused by Stx2-producing Escherichia coli.
Fujii
J
J
Department of Microbiology, University of Occupational and Environmental Health, Kitakyushu, 807-8555, Japan.
Kinoshita
Y
Y
Yamada
Y
Y
Yutsudo
T
T
Kita
T
T
Takeda
T
T
Yoshida
S
S
D000818:Animals; D000992:Antitoxins / Q000008:administration & dosage*; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000276:immunology / Q000493:pharmacokinetics / Q000633:toxicity*; D001812:Blood-Brain Barrier; D001921:Brain / Q000473:pathology*; D001927:Brain Diseases / Q000382:microbiology / Q000473:pathology* / Q000517:prevention & control*; D002531:Cerebellum / Q000473:pathology; D002555:Cerebrospinal Fluid / Q000737:chemistry; D004926:Escherichia coli / Q000378:metabolism*; D007275:Injections, Intravenous; D007278:Injections, Spinal; D007928:Lethal Dose 50; D008279:Magnetic Resonance Imaging; D008297:Male; D008854:Microscopy, Electron; D011817:Rabbits; D022603:Shiga Toxins
D000992:Antitoxins; D001427:Bacterial Toxins; D022603:Shiga Toxins