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. 2012 Sep;18(9):BR337-45.
doi: 10.12659/msm.883342.

Atovaquone Ameliorate Gastrointestinal Toxoplasmosis Complications in a Pregnancy Model

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Free PMC article

Atovaquone Ameliorate Gastrointestinal Toxoplasmosis Complications in a Pregnancy Model

Helieh S Oz et al. Med Sci Monit. .
Free PMC article

Abstract

Background: Toxoplasma is an important source of foodborne hospitalization with no safe and effective therapy against chronic or congenital Toxopalsmosis. Atovaquone is a drug of choice but not approved for use in congenital Toxoplasmosis. We hypothesized atovaquone to be safe and effective against feto-maternal Toxoplasmosis.

Material/methods: Programmed pregnant mice were i.p. infected with 50-2400 Tachyzoites from Type II strain (clone PTG). Dams were treated daily with atovaquone or sham and monitored for pain, and complications.

Results: Dams developed pain related abdominal hypersensitivity (allodynia) to mechanical stimuli in a Tachyzoites dose dependent manner. Infected dams were anemic and exhibited ascities and severe hepatitis (score 3.6±0.01 on scale 0--normal to 4--severe) with influx of inflammatory and plasma cells, multinucleated dysplastic hepatocytes and necrosis. In addition, dams expressed mild to severe pancreatitis with mononuclear cell invasion, loss of islets and necrosis. This was consistent with splenomegaly (X3 Fold), and massive infiltration of epithelioid cells and loss of germinal structure. Colon became significantly shortened in length (p<0.01) with semi-normal content. Pathological manifestation included, shortening of crypts with numerous microabscess formations, infiltration of lymphocytes, and macrophages. The severe clinical complications led to abortion (50%), early birth (25%) or still birth (25%) consistent with the high dose of Tachyzoites inoculation. Atovaquone treatment partially but significantly protected the dams from the severity of hepatitis, splenomegaly, colitis, myocarditis, and pain related responses as well as fetal demise.

Conclusions: This is a valuable model for therapeutic evaluation of feto-maternal Toxoplasmosis and gastrointestinal complications. Atovaquone protects dams and their fetuses against some infectious/inflammatory aspects of the disease.

Figures

Figure 1
Figure 1
Percent pain related abdominal response to Von Frey mechanical stimuli to 0.166 GM force. (A) Dose dependent abdominal response from dams infected with Tachyzoites (T-600 to T-2400) compared to normal Controls demonstrating increased hypersensitivity to stimuli. (B) Atovaquone treatment ameliorated hypersensitivity to stimuli (allodynia) in infected dams (T-600).
Figure 2
Figure 2
Infected dams had pale mucosa and became anemic as demonstrated by significant decreases in hematocrit values in a dose dependent manner (controls vs. T-600 p<0.05, Controls vs. T-1200 and T-2400 p<0.01).
Figure 3
Figure 3
Splenic weight (A) and length (C) significantly increased in infected dams and partially but significantly improved in atovaquone treated animals (B, D, p<0.05).
Figure 4
Figure 4
H&E stained sections from hepatic tissues were scored from normal (0) to severe (4) hepatitis (A). Atovaquone treatment significantly ameliorated the lesions in dams and protected against hepatitis as consequences of Toxoplasmosis (B).
Figure 5
Figure 5
H&E stained cardiomyocytes from infected Dam and cardiac weight. Infected dams developed mild to moderate myocarditis (A) with infiltration of inflammatory cells (H&E staining). Cardiac weight increased in infected dams and atovaquone treatment attenuated pathological inflammatory response and excess weight (B).
Figure 6
Figure 6
Uteri from infected (red arrow) and uninfected (blue arrow) dams (A) similar to atovaquone treated ones (not shown here). Immunohistochemical staining demonstrating infected uteri. Arrows point at the organisms (B).
Figure 7
Figure 7
Fetal weight significantly decreased in a dose dependent response due to the infection (A). Atovaquone treatment returned the fetal weight to a normal value (B).

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