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Preclinical assessment of the treatment of second-stage African trypanosomiasis with cordycepin and deoxycoformycin.

Vodnala SK, Ferella M, Lundén-Miguel H, Betha E, van Reet N, Amin DN, Oberg B, Andersson B, Kristensson K, Wigzell H, Rottenberg ME - PLoS Negl Trop Dis (2009)

Bottom Line: Oral, intraperitoneal or subcutaneous administrations of the compounds were successful for treatment.Incubation with cordycepin resulted in programmed cell death followed by secondary necrosis of the parasites.Altogether, our data strongly support testing of treatment with a combination of cordycepin and deoxycoformycin as an alternative for treatment of second-stage and/or melarsoprol-resistant HAT.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.

ABSTRACT

Background: There is an urgent need to substitute the highly toxic compounds still in use for treatment of the encephalitic stage of human African trypanosomiasis (HAT). We here assessed the treatment with the doublet cordycepin and the deaminase inhibitor deoxycoformycin for this stage of infection with Trypanosoma brucei (T.b.).

Methodology/principal findings: Cordycepin was selected as the most efficient drug from a direct parasite viability screening of a compound library of nucleoside analogues. The minimal number of doses and concentrations of the drugs effective for treatment of T.b. brucei infections in mice were determined. Oral, intraperitoneal or subcutaneous administrations of the compounds were successful for treatment. The doublet was effective for treatment of late stage experimental infections with human pathogenic T.b. rhodesiense and T.b. gambiense isolates. Late stage infection treatment diminished the levels of inflammatory cytokines in brains of infected mice. Incubation with cordycepin resulted in programmed cell death followed by secondary necrosis of the parasites. T.b. brucei strains developed resistance to cordycepin after culture with increasing concentrations of the compound. However, cordycepin-resistant parasites showed diminished virulence and were not cross-resistant to other drugs used for treatment of HAT, i.e. pentamidine, suramin and melarsoprol. Although resistant parasites were mutated in the gene coding for P2 nucleoside adenosine transporter, P2 knockout trypanosomes showed no altered resistance to cordycepin, indicating that absence of the P2 transporter is not sufficient to render the trypanosomes resistant to the drug.

Conclusions/significance: Altogether, our data strongly support testing of treatment with a combination of cordycepin and deoxycoformycin as an alternative for treatment of second-stage and/or melarsoprol-resistant HAT.

No MeSH data available.


Related in: MedlinePlus

Levels of pro-inflammatory cytokine transcripts in brains of T.b. rhodesiense and T.b. gambiense-infected, cordycepin and deoxycoformycin-treated mice.Total RNA was extracted from brain tissues of mice 30 days after inoculation with T.b. rhodesiense A–D) or 80 days after inoculation with T.b. gambiense E–H), treated or not with 2 mg/kg/d cordycepin and 0.2 mg/kg/d deoxycoformycin starting 20 or 30 days after infection respectively, converted into cDNA and pro-inflammatory mRNA accumulation was measured by real time PCR. The number of moles of cytokine per mole of HPRT in samples from individual mice (4–6 per group) was calculated and the fold increase of IL-1 A, E), IL-6 B, F), IFN−γ C, G), TNF-α D, H) in cordycepin and deoxycoformycin treated or untreated infected mice with respect to levels in brains of one of the uninfected mice depicted. *Differences with untreated, infected group are significant (p<0.05 Student t test).
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pntd-0000495-g006: Levels of pro-inflammatory cytokine transcripts in brains of T.b. rhodesiense and T.b. gambiense-infected, cordycepin and deoxycoformycin-treated mice.Total RNA was extracted from brain tissues of mice 30 days after inoculation with T.b. rhodesiense A–D) or 80 days after inoculation with T.b. gambiense E–H), treated or not with 2 mg/kg/d cordycepin and 0.2 mg/kg/d deoxycoformycin starting 20 or 30 days after infection respectively, converted into cDNA and pro-inflammatory mRNA accumulation was measured by real time PCR. The number of moles of cytokine per mole of HPRT in samples from individual mice (4–6 per group) was calculated and the fold increase of IL-1 A, E), IL-6 B, F), IFN−γ C, G), TNF-α D, H) in cordycepin and deoxycoformycin treated or untreated infected mice with respect to levels in brains of one of the uninfected mice depicted. *Differences with untreated, infected group are significant (p<0.05 Student t test).

Mentions: Brains from T.b. rhodesiense-infected mice treated with cordycepin and deoxycoformycin starting 20 days after infection contained diminished levels of IFN-γ, IL-1β, IL-6 and TNF-α mRNA compared to untreated infected controls when measured 10 days after treatment (Figure 6A–D). Likewise, brains from mice infected with T.b. rhodesiense and treated with cordycepin and deoxycoformycin starting 20 days after infection with T.b rhodesiense contained lower levels of pro-inflammatory cytokine transcripts when studied after 80 days after infection, as compared to non-treated infected groups. Cytokine mRNA levels in infected and cordycepin and deoxycoformycin-treated mice and in uninfected mice were similar. (Figure 6E–H).


Preclinical assessment of the treatment of second-stage African trypanosomiasis with cordycepin and deoxycoformycin.

Vodnala SK, Ferella M, Lundén-Miguel H, Betha E, van Reet N, Amin DN, Oberg B, Andersson B, Kristensson K, Wigzell H, Rottenberg ME - PLoS Negl Trop Dis (2009)

Levels of pro-inflammatory cytokine transcripts in brains of T.b. rhodesiense and T.b. gambiense-infected, cordycepin and deoxycoformycin-treated mice.Total RNA was extracted from brain tissues of mice 30 days after inoculation with T.b. rhodesiense A–D) or 80 days after inoculation with T.b. gambiense E–H), treated or not with 2 mg/kg/d cordycepin and 0.2 mg/kg/d deoxycoformycin starting 20 or 30 days after infection respectively, converted into cDNA and pro-inflammatory mRNA accumulation was measured by real time PCR. The number of moles of cytokine per mole of HPRT in samples from individual mice (4–6 per group) was calculated and the fold increase of IL-1 A, E), IL-6 B, F), IFN−γ C, G), TNF-α D, H) in cordycepin and deoxycoformycin treated or untreated infected mice with respect to levels in brains of one of the uninfected mice depicted. *Differences with untreated, infected group are significant (p<0.05 Student t test).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2713411&req=5

pntd-0000495-g006: Levels of pro-inflammatory cytokine transcripts in brains of T.b. rhodesiense and T.b. gambiense-infected, cordycepin and deoxycoformycin-treated mice.Total RNA was extracted from brain tissues of mice 30 days after inoculation with T.b. rhodesiense A–D) or 80 days after inoculation with T.b. gambiense E–H), treated or not with 2 mg/kg/d cordycepin and 0.2 mg/kg/d deoxycoformycin starting 20 or 30 days after infection respectively, converted into cDNA and pro-inflammatory mRNA accumulation was measured by real time PCR. The number of moles of cytokine per mole of HPRT in samples from individual mice (4–6 per group) was calculated and the fold increase of IL-1 A, E), IL-6 B, F), IFN−γ C, G), TNF-α D, H) in cordycepin and deoxycoformycin treated or untreated infected mice with respect to levels in brains of one of the uninfected mice depicted. *Differences with untreated, infected group are significant (p<0.05 Student t test).
Mentions: Brains from T.b. rhodesiense-infected mice treated with cordycepin and deoxycoformycin starting 20 days after infection contained diminished levels of IFN-γ, IL-1β, IL-6 and TNF-α mRNA compared to untreated infected controls when measured 10 days after treatment (Figure 6A–D). Likewise, brains from mice infected with T.b. rhodesiense and treated with cordycepin and deoxycoformycin starting 20 days after infection with T.b rhodesiense contained lower levels of pro-inflammatory cytokine transcripts when studied after 80 days after infection, as compared to non-treated infected groups. Cytokine mRNA levels in infected and cordycepin and deoxycoformycin-treated mice and in uninfected mice were similar. (Figure 6E–H).

Bottom Line: Oral, intraperitoneal or subcutaneous administrations of the compounds were successful for treatment.Incubation with cordycepin resulted in programmed cell death followed by secondary necrosis of the parasites.Altogether, our data strongly support testing of treatment with a combination of cordycepin and deoxycoformycin as an alternative for treatment of second-stage and/or melarsoprol-resistant HAT.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden.

ABSTRACT

Background: There is an urgent need to substitute the highly toxic compounds still in use for treatment of the encephalitic stage of human African trypanosomiasis (HAT). We here assessed the treatment with the doublet cordycepin and the deaminase inhibitor deoxycoformycin for this stage of infection with Trypanosoma brucei (T.b.).

Methodology/principal findings: Cordycepin was selected as the most efficient drug from a direct parasite viability screening of a compound library of nucleoside analogues. The minimal number of doses and concentrations of the drugs effective for treatment of T.b. brucei infections in mice were determined. Oral, intraperitoneal or subcutaneous administrations of the compounds were successful for treatment. The doublet was effective for treatment of late stage experimental infections with human pathogenic T.b. rhodesiense and T.b. gambiense isolates. Late stage infection treatment diminished the levels of inflammatory cytokines in brains of infected mice. Incubation with cordycepin resulted in programmed cell death followed by secondary necrosis of the parasites. T.b. brucei strains developed resistance to cordycepin after culture with increasing concentrations of the compound. However, cordycepin-resistant parasites showed diminished virulence and were not cross-resistant to other drugs used for treatment of HAT, i.e. pentamidine, suramin and melarsoprol. Although resistant parasites were mutated in the gene coding for P2 nucleoside adenosine transporter, P2 knockout trypanosomes showed no altered resistance to cordycepin, indicating that absence of the P2 transporter is not sufficient to render the trypanosomes resistant to the drug.

Conclusions/significance: Altogether, our data strongly support testing of treatment with a combination of cordycepin and deoxycoformycin as an alternative for treatment of second-stage and/or melarsoprol-resistant HAT.

No MeSH data available.


Related in: MedlinePlus