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IFN-gamma-dependent CXCL10 is critical for accumulation of T cells and trypanosomes in the brain during experimental African trypanosomiasis. Data suggest CXCL10 as a candidate marker for late stage human African trypanosomiasis.

There is an urgent need to discontinue the use of highly toxic compounds still in use for treatment of the encephalitic stage of human African trypanosomiasis (HAT). We show here that intraperitoneal injection of the adenosine analogue cordycepin (3 -deoxyadenosine), together with an adenosine deaminase (ADA) inhibitor (coformycin or deoxycoformycin), cures Trypanosoma brucei brucei infection in mice. Treatment was also effective at a stage when the trypanosomes had penetrated into the brain parenchyma, as determined by double immunolabeling of parasites and cerebral vessel endothelial cells in brain sections. At this stage, the parasites were eliminated not only from the blood but also from the brain parenchyma. In parallel with the elimination of parasites, in treated mice, the number of CD45 + inflammatory cells in the brain parenchyma was reduced. Treatment was not immunosuppressive. In vitro incubation with cordycepin reduced the growth of T. brucei brucei and T. cruzi, as well as Leishmania major and L. amazonensis. Administration of cordycepin plus deoxycofomycin to T. cruzi-infected mice also significantly reduced parasitemia. Accordingly, we propose nucleoside analogues resistant to ADA as candidates for treatment of late-stage HAT.The causative agent of African trypanosomiasis, the protozoan parasite Trypanosoma brucei, is transmitted to humans and domestic farm animals through the bite of the tsetse fly. There are an estimated 500,000 people infected with T. brucei, almost all of whom live in subSaharan Africa, and infections are fatal if not treated [1]. There are 2 recognized stages in the clinical presentation of human African trypanosomiasis (HAT): (1) the early hemolymphatic stage and (2) cephalitic stage, when the central nervous system (CNS) is involved. Successful treatment of the latter stage of the disease has been limited for several reasons: treatment relies on arsenic compounds (melarsoprol), which are associated with a high degree of toxicity [2], and the relatively new drug difluoromethylornithine (DFMO), which is effective against the West African form of HAT (caused by T. brucei gambiense) but not against the East African form (caused by T. brucei rhodesiense) [3]. Melarsoprol treatment is followed by posttreatment encephalitis in up to 10% of cases, with a fatality rate of ∼50% [1]. Moreover, there is evidence of increasing resistance to this drug, with reported rates of treatment failure of 30% [4].In the present study, we present data from a series of definitive experiments, which show that a purine analogue, 3 -deoxyadenosine (also known as "cordycepin"), is effective at curing both early stage and latestage (CNS involvement) T. brucei infection in mice when cordycepin is protected from the enzyme adenoDownloaded from https://academic.oup.

BackgroundThe CatWalk system, a video based automated gait analysis system developed to evaluate footfall and gait changes in rodents, has been used for studying rodent models of arthritis, mainly the rat model. However, it has not been used to study static and dynamic gait parameters in mice with Complete Freund’s adjuvant (CFA). CFA is used extensively to induce arthritis in rodents including mice.MethodsThe CatWalk system was used to study gait of freely moving mice with CFA-induced monoarthritis and evaluate pharmacological pain relief in this model of arthritis. CFA (20 μl) was injected intra-articularly into the right hind (RH) limb ankle joint through the Achilles tendon of C57BL/6 mice.ResultsMice had less regularity in their walking patterns after CFA inoculation compared to baseline walking patterns, which was significant at 2 days post inoculation (dpi). The mice also showed changes in static parameters (paw pressure (light intensity) and print area) as well as dynamic parameters (stance phase duration, swing phase duration and speed, and duty cycle). The ratio of the RH limb (ipslateral) to the left hind (LH) limb (contralateral) for paw pressure, print area, stance phase duration, duty cycle (stance phase duration/sum of stance and swing phase duration), and swing speed were significantly reduced compared to baseline ratios at 1–6 and/or 7 dpi. On the other hand, RH/LH limb ratio of the swing phase duration increased at 3 dpi compared to baseline values. Treatment with indomethacin (10 mg/kg) improved or restored the gait parameters of CFA inoculated mice i.e. similar to baseline values or LH limb.ConclusionsThese data show that the CatWalk system can be used to assess static and dynamic gait changes and pharmacological pain relief in freely moving mice with CFA-induced monoarthritis.

The blood-brain barrier (BBB) is a structural and functional barrier that protects the central nervous system (CNS) from invasion by blood-borne pathogens including parasites. However, some intracellular and extracellular parasites can traverse the BBB during the course of infection and cause neurological disturbances and/or damage which are at times fatal. The means by which parasites cross the BBB and how the immune system controls the parasites within the brain are still unclear. In this review we present the current understanding of the processes utilized by two human neuropathogenic parasites, Trypanosoma brucei spp and Toxoplasma gondii, to go across the BBB and consequences of CNS invasion. We also describe briefly other parasites that can invade the brain and how they interact with or circumvent the BBB. The roles played by parasite-derived and host-derived molecules during parasitic and white blood cell invasion of the brain are discussed.

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Our data indicate that innate immune TLR signals stimulate the expression of TNF-α and IFN-α/β that initiate brain invasion of T cells and trypanosomes, and control T. brucei brucei load in the brain by molecules distinct from these.

Neuropathic pain associated with nucleoside reverse transcriptase inhibitors (NRTIs), therapeutic agents for human immunodeficiency virus (HIV), responds poorly to available drugs. Smoked cannabis was reported to relieve HIV-associated neuropathic pain in clinical trials. Some constituents of cannabis (Cannabis sativa) activate cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptors. However, activation of the CB1 receptor is associated with side effects such as psychosis and physical dependence. Therefore, we investigated the effect of β-caryophyllene (BCP), a CB2-selective phytocannabinoid, in a model of NRTI-induced neuropathic pain. Female BALB/c mice treated with 2′-3′-dideoxycytidine (ddC, zalcitabine), a NRTI, for 5 days developed mechanical allodynia, which was prevented by cotreatment with BCP, minocycline or pentoxifylline. A CB2 receptor antagonist (AM 630), but not a CB1 receptor antagonist (AM 251), antagonized BCP attenuation of established ddC-induced mechanical allodynia. β-Caryophyllene prevented the ddC-induced increase in cytokine (interleukin 1 beta, tumor necrosis factor alpha and interferon gamma) transcripts in the paw skin and brain, as well as the phosphorylation level of Erk1/2 in the brain. In conclusion, BCP prevents NRTI-induced mechanical allodynia, possibly via reducing the inflammatory response, and attenuates mechanical allodynia through CB2 receptor activation. Therefore, BCP could be useful for prevention and treatment of antiretroviral-induced neuropathic pain.