Model systems for investigating disease processes in neurocysticercosis

Lange, Ann-Marie G. de; Mahanty, Siddhartha; Raimondo, Joseph V.

doi:10.1017/s0031182018001932

Cited by 26 publications

(33 citation statements)

References 87 publications

(131 reference statements)

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“…They are very rare in human infections, which make its handling very safe. In addition, its capability of asexual reproduction through budding provides a great source of biological material 28 .…”

Section: Discussionmentioning

confidence: 99%

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Demyelination in experimental intraventricular neurocysticercosis

Moura

Milhomem

Lima

et al. 2020

Arq. Neuro-Psiquiatr.

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Neurocysticercosis (NCC) is classified as a neglected tropical disease, which affects mainly Latin America and Africa in spite of some reports in North America and Europe. NCC represents the cause of up to 30% of the reported cases of epilepsy in endemic countries. The NCC injuries present direct relation to the development stage, location, and number of parasites as well as to the host immune response. This study aimed the characterization of the inflammatory response and tissue injuries by means of the analyses of the periventricular and parenchymatous demyelination through the experimental intraventricular NCC infection. Therefore, BALB/c mice were submitted to experimental NCC inoculation with Taenia crassiceps cysticerci. Their brains were removed at 7, 30, 60, and 90 days after the inoculation (DAI), and analyzed after staining with hematoxylin and eosin (HE), Luxol Fast Blue, and Nissl. It was possible to observe ventriculomegaly, inflammatory infiltration composed by polymorphonuclear and mononuclear cells, and foamy macrophages. The presence of inflammatory cells was associated with neurodegeneration detected by the areas with demyelination observed initially in the periventricular area and lately in the parenchyma. In conclusion, the presence of cysticerci and the consequent inflammation were able to promote initial periventricular demyelination followed by parenchymatous demyelination as the infection progressed.

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Section: Discussionmentioning

confidence: 99%

“…The use of female mice is indicated because estradiol and progesterone stimulate reproduction and infectivity of the cysticerci. Initial stage T. crassiceps cysticerci 27 were removed from one intraperitoneal infected mouse, washed twice with PBS for posterior intracranial inoculation 28 .…”

Section: Experimental Designmentioning

confidence: 99%

Demyelination in experimental intraventricular neurocysticercosis

Moura

Milhomem

Lima

et al. 2020

Arq. Neuro-Psiquiatr.

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“…It is also easily cultured and is regarded as non-infective for humans [50,51]. This model has been used to identify new cestocidal compounds in pharmacological studies [39,[52][53][54][55][56]. Using M. vogae TTy to screen HDAC inhibitors as cestocidal compounds allowed us to select candidates to be later tested in experimental animal models of the zoonotic parasites, such as E. granulosus.…”

Section: Plos Neglected Tropical Diseasesmentioning

confidence: 99%

The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs

et al. 2021

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Background Echinococcosis and cysticercosis are neglected tropical diseases caused by cestode parasites (family Taeniidae). Not only there is a small number of approved anthelmintics for the treatment of these cestodiases, but also some of them are not highly effective against larval stages, such that identifying novel drug targets and their associated compounds is critical. Histone deacetylase (HDAC) enzymes are validated drug targets in cancers and other diseases, and have been gaining relevance for developing new potential anti-parasitic treatments in the last years. Here, we present the anthelmintic profile for a panel of recently developed HDAC inhibitors against the model cestode Mesocestoides vogae (syn. M. corti). Methodology/Principal findings Phenotypic screening was performed on M. vogae by motility measurements and optical microscopic observations. Some HDAC inhibitors showed potent anthelmintic activities; three of them -entinostat, TH65, and TH92- had pronounced anthelmintic effects, reducing parasite viability by ~100% at concentrations of ≤ 20 μM. These compounds were selected for further characterization and showed anthelmintic effects in the micromolar range and in a time- and dose-dependent manner. Moreover, these compounds induced major alterations on the morphology and ultrastructural features of M. vogae. The potencies of these compounds were higher than albendazole and the anthelmintic effects were irreversible. Additionally, we evaluated pairwise drug combinations of these HDAC inhibitors and albendazole. The results suggested a positive interaction in the anthelmintic effect for individual pairs of compounds. Due to the maximum dose approved for entinostat, adjustments in the dose regime and/or combinations with currently-used anthelmintic drugs are needed, and the selectivity of TH65 and TH92 towards parasite targets should be assessed. Conclusion, significance The results presented here suggest that HDAC inhibitors represent novel and potent drug candidates against cestodes and pave the way to understanding the roles of HDACs in these parasites.

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“…Since T. solium larvae invade the central nervous system in neurocysticercosis, it is important to determine potential AChE activity expressed by these larvae, as such activity could conceivably interfere with endogenous cholinergic signalling in the brain by breaking acetylcholine down into neurologically inactive products [26]. Taenia crassiceps (T. crassiceps) is a related cestode, which has also been known to invade the human nervous system, and is widely utilised as a model parasite for T. solium in animal models of cysticercosis and neurocysticercosis [27][28][29]. It is therefore also important to ascertain how AChE activity might compare between the larvae of these two Taenia species.…”

Section: Introductionmentioning

confidence: 99%

Taenia larvae possess distinct acetylcholinesterase profiles with implications for host cholinergic signalling

Lange

Prodjinotho²,

Tomes

et al. 2020

PLoS Negl Trop Dis

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Larvae of the cestodes Taenia solium and Taenia crassiceps infect the central nervous system of humans. Taenia solium larvae in the brain cause neurocysticercosis, the leading cause of adult-acquired epilepsy worldwide. Relatively little is understood about how cestode-derived products modulate host neural and immune signalling. Acetylcholinesterases, a class of enzyme that breaks down acetylcholine, are produced by a host of parasitic worms to aid their survival in the host. Acetylcholine is an important signalling molecule in both the human nervous and immune systems, with powerful modulatory effects on the excitability of cortical networks. Therefore, it is important to establish whether cestode derived acetylcholinesterases may alter host neuronal cholinergic signalling. Here we make use of multiple techniques to profile acetylcholinesterase activity in different extracts of both Taenia crassiceps and Taenia solium larvae. We find that the larvae of both species contain substantial acetylcholinesterase activity. However, acetylcholinesterase activity is lower in Taenia solium as compared to Taenia crassiceps larvae. Further, whilst we observed acetylcholinesterase activity in all fractions of Taenia crassiceps larvae, including on the membrane surface and in the excreted/secreted extracts, we could not identify acetylcholinesterases on the membrane surface or in the excreted/secreted extracts of Taenia solium larvae. Bioinformatic analysis revealed conservation of the functional protein domains in the Taenia solium acetylcholinesterases, when compared to the homologous human sequence. Finally, using whole-cell patch clamp recordings in rat hippocampal brain slice cultures, we demonstrate that Taenia larval derived acetylcholinesterases can break down acetylcholine at a concentration which induces changes in neuronal signalling. Together, these findings highlight the possibility that Taenia larval acetylcholinesterases can interfere with cholinergic signalling in the host, potentially contributing to pathogenesis in neurocysticercosis.

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Model systems for investigating disease processes in neurocysticercosis

Cited by 26 publications

References 87 publications

Demyelination in experimental intraventricular neurocysticercosis

Demyelination in experimental intraventricular neurocysticercosis

The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs

Taenia larvae possess distinct acetylcholinesterase profiles with implications for host cholinergic signalling

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