RESUMO
Neurocysticercosis (NCC) is a helminth infection affecting the central nervous system caused by the larval stage (cysticercus) of Taenia solium. Since vascular alteration and blood-brain barrier (BBB) disruption contribute to NCC pathology, it is postulated that angiogenesis could contribute to the pathology of this disease. This study used a rat model for NCC and evaluated the expression of two angiogenic factors called vascular endothelial growth factor (VEGF-A) and fibroblast growth factor (FGF2). Also, two markers for BBB disruption, the endothelial barrier antigen and immunoglobulin G, were evaluated using immunohistochemical and immunofluorescence techniques. Brain vasculature changes, BBB disruption, and overexpression of angiogenesis markers surrounding viable cysts were observed. Both VEGF-A and FGF2 were overexpressed in the tissue surrounding the cysticerci, and VEGF-A was overexpressed in astrocytes. Vessels showed decreased immunoreactivity to endothelial barrier antigen marker and an extensive staining for IgG was found in the tissues surrounding the cysts. Additionally, an endothelial cell tube formation assay using human umbilical vein endothelial cells showed that excretory and secretory antigens of T. solium cysticerci induce the formation of these tubes. This in vitro model supports the hypothesis that angiogenesis in NCC might be caused by the parasite itself, as opposed to the host inflammatory responses alone. In conclusion, brain vasculature changes, BBB disruption, and overexpression of angiogenesis markers surrounding viable cysts were observed. This study also demonstrates that cysticerci excretory-secretory processes alone can stimulate angiogenesis.
Assuntos
Barreira Hematoencefálica/fisiopatologia , Fatores de Crescimento de Fibroblastos/metabolismo , Neovascularização Patológica/metabolismo , Neurocisticercose/fisiopatologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Vasos Sanguíneos/parasitologia , Vasos Sanguíneos/patologia , Barreira Hematoencefálica/parasitologia , Barreira Hematoencefálica/patologia , Encéfalo/parasitologia , Células Endoteliais/metabolismo , Células Endoteliais/parasitologia , Células Endoteliais/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Imunoglobulina G/metabolismo , Neovascularização Patológica/parasitologia , Neurocisticercose/parasitologia , Ratos , Ratos Sprague-Dawley , Taenia soliumRESUMO
BACKGROUND: The parasite Taenia solium causes neurocysticercosis (NCC) in humans and is a common cause of adult-onset epilepsy in the developing world. Hippocampal atrophy, which occurs far from the cyst, is an emerging new complication of NCC. Evaluation of molecular pathways in brain regions close to and distant from the cyst could offer insight into this pathology. METHODS: Rats were inoculated intracranially with T. solium oncospheres. After 4 months, RNA was extracted from brain tissue samples in rats with NCC and uninfected controls, and cDNA was generated. Expression of 38 genes related to different molecular pathways involved in the inflammatory response and healing was assessed by RT-PCR array. RESULTS: Inflammatory cytokines IFN-γ, TNF-α, and IL-1, together with TGF-ß and ARG-1, were overexpressed in tissue close to the parasite compared to non-infected tissue. Genes for IL-1A, CSF-1, FN-1, COL-3A1, and MMP-2 were overexpressed in contralateral tissue compared to non-infected tissue. CONCLUSIONS: The viable cysticerci in the rat model for NCC is characterized by increased expression of genes associated with a proinflammatory response and fibrosis-related proteins, which may mediate the chronic state of infection. These pathways appear to influence regions far from the cyst, which may explain the emerging association between NCC and hippocampal atrophy.
Assuntos
Citocinas/metabolismo , Expressão Gênica , Hipocampo/patologia , Neurocisticercose/veterinária , Animais , Atrofia , Citocinas/genética , Hipocampo/parasitologia , Inflamação/metabolismo , Neurocisticercose/genética , Neurocisticercose/metabolismo , Neurocisticercose/patologia , Ratos , Taenia solium/imunologiaRESUMO
Neurocysticercosis is a parasitic brain disease caused by the larval form (Cysticercus cellulosae) of Taenia solium and is the leading cause of preventable epilepsy worldwide. However, the pathophysiology and relation to the wide range of clinical features remains poorly understood. Axonal swelling is emerging as an important early pathological finding in multiple neurodegenerative diseases and as a cause of brain injury, but has not been well described in neurocysticercosis. Histological analysis was performed on human, rat and porcine NCC brain specimens to identify axonal pathology. Rat infection was successfully carried out via two routes of inoculation: direct intracranial injection and oral feeding. Extensive axonal swellings, in the form of spheroids, were observed in both humans and rats and to a lesser extent in pigs with NCC. Spheroids demonstrated increased immunoreactivity to amyloid precursor protein and neurofilament indicating probable impairment of axonal transport. These novel findings demonstrate that spheroids are present in NCC which is conserved across species. Not only is this an important contribution toward understanding the pathogenesis of NCC, but it also provides a model to analyze the association of spheroids with specific clinical features and to investigate the reversibility of spheroid formation with antihelminthic treatment.