Delivery of Antihuman African Trypanosomiasis Drugs Across the Blood–Brain and Blood–CSF Barriers

Sekhar, Gayathri Nair; Watson, Christopher P.; Fidanboylu, Mehmet; Sanderson, Lisa; Thomas, Sarah

doi:10.1016/bs.apha.2014.06.003

Cited by 20 publications

(19 citation statements)

References 95 publications

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“…Of note, PTM is suitable for a rapid translation for clinical use, being an already-approved drug. Although PTM has limited capacity to permeate the BBB [53], and although a proportion is retained within the capillary endothelium [54], the BBB damage occurring during demyelinating diseases [55], as also shown by evidences of tracer leakage into the CNS [56], suggests that this drug may be easily available within the inflamed CNS, also when administered systemically, as in this work. Finally, the identification of S100B as a putative therapeutic target of MS pathogenetic processes might likely open novel perspectives for even more efficacious treatments.…”

Section: Discussionmentioning

confidence: 63%

The S100B Inhibitor Pentamidine Ameliorates Clinical Score and Neuropathology of Relapsing—Remitting Multiple Sclerosis Mouse Model

Sante

Amadio

Sampaolese³

et al. 2020

Cells

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S100B is an astrocytic protein acting either as an intracellular regulator or an extracellular signaling molecule. A direct correlation between increased amount of S100B and demyelination and inflammatory processes has been demonstrated. The aim of this study is to investigate the possible role of a small molecule able to bind and inhibit S100B, pentamidine, in the modulation of disease progression in the relapsing–remitting experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. By the daily evaluation of clinical scores and neuropathologic-molecular analysis performed in the central nervous system, we observed that pentamidine is able to delay the acute phase of the disease and to inhibit remission, resulting in an amelioration of clinical score when compared with untreated relapsing–remitting experimental autoimmune encephalomyelitis mice. Moreover, we observed a significant reduction of proinflammatory cytokines expression levels in the brains of treated versus untreated mice, in addition to a reduction of nitric oxide synthase activity. Immunohistochemistry confirmed that the inhibition of S100B was able to modify the neuropathology of the disease, reducing immune infiltrates and partially protecting the brain from the damage. Overall, our results indicate that pentamidine targeting the S100B protein is a novel potential drug to be considered for multiple sclerosis treatment.

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Section: Discussionmentioning

confidence: 63%

The S100B Inhibitor Pentamidine Ameliorates Clinical Score and Neuropathology of Relapsing—Remitting Multiple Sclerosis Mouse Model

Sante

Amadio

Sampaolese³

et al. 2020

Cells

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“…Originally developed as a drug against cancer, it was subsequently repurposed for use against T . brucei gambiense , as well as female hirsutism [15]. Similarly the drug tamoxifen, which is effective against estrogen receptor-positive breast cancer, also has efficacy against Leishmania [16, 17].…”

Section: Introductionmentioning

confidence: 99%

Selective inhibition of RNA polymerase I transcription as a potential approach to treat African trypanosomiasis

et al. 2017

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Trypanosoma brucei relies on an essential Variant Surface Glycoprotein (VSG) coat for survival in the mammalian bloodstream. High VSG expression within an expression site body (ESB) is mediated by RNA polymerase I (Pol I), which in other eukaryotes exclusively transcribes ribosomal RNA genes (rDNA). As T. brucei is reliant on Pol I for VSG transcription, we investigated Pol I transcription inhibitors for selective anti-trypanosomal activity. The Pol I inhibitors quarfloxin (CX-3543), CX-5461, and BMH-21 are currently under investigation for treating cancer, as rapidly dividing cancer cells are particularly dependent on high levels of Pol I transcription compared with nontransformed cells. In T. brucei all three Pol I inhibitors have IC50 concentrations for cell proliferation in the nanomolar range: quarfloxin (155 nM), CX-5461 (279 nM) or BMH-21 (134 nM) compared with IC50 concentrations in the MCF10A human breast epithelial cell line (4.44 μM, 6.89 μM or 460 nM, respectively). T. brucei was therefore 29-fold more sensitive to quarfloxin, 25-fold more sensitive to CX-5461 and 3.4-fold more sensitive to BMH-21. Cell death in T. brucei was due to rapid inhibition of Pol I transcription, as within 15 minutes treatment with the inhibitors rRNA precursor transcript was reduced 97-98% and VSG precursor transcript 91-94%. Incubation with Pol I transcription inhibitors also resulted in disintegration of the ESB as well as the nucleolus subnuclear structures, within one hour. Rapid ESB loss following the block in Pol I transcription argues that the ESB is a Pol I transcription nucleated structure, similar to the nucleolus. In addition to providing insight into Pol I transcription and ES control, Pol I transcription inhibitors potentially also provide new approaches to treat trypanosomiasis.

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“…Eflornithine, commonly known as the 'resurrection drug', is the first-line anti-parasitic treatment, as it is able to pass through the blood-brain barrier and is an effective drug recommended by the World Health Organization for the treatment of late-stage HAT (Anon, 2018;Eperon et al, 2014;Kennedy, 2013;Sekhar et al, 2014). The patient was treated with a standard regimen and a half course regimen of eflornithine (Kennedy, 2013;Pépin et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Human African trypanosomiasis caused by Trypanosoma brucei gambiense: The first case report in China

Nian

Jin

et al. 2019

International Journal of Infectious Diseases

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Delivery of Antihuman African Trypanosomiasis Drugs Across the Blood–Brain and Blood–CSF Barriers

Cited by 20 publications

References 95 publications

The S100B Inhibitor Pentamidine Ameliorates Clinical Score and Neuropathology of Relapsing—Remitting Multiple Sclerosis Mouse Model

The S100B Inhibitor Pentamidine Ameliorates Clinical Score and Neuropathology of Relapsing—Remitting Multiple Sclerosis Mouse Model

Selective inhibition of RNA polymerase I transcription as a potential approach to treat African trypanosomiasis

Human African trypanosomiasis caused by Trypanosoma brucei gambiense: The first case report in China

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