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PAN-811 prevents chemotherapy-induced cognitive impairment and preserves neurogenesis in the hippocampus of adult rats.
Jiang, Zhi-Gang; Winocur, Gordon; Wojtowicz, J Martin; Shevtsova, Olga; Fuller, Steven; Ghanbari, Hossein A.
Afiliación
  • Jiang ZG; Panacea Pharmaceuticals, Inc., Gaithersburg, Maryland, United States of America.
  • Winocur G; Department of Psychology, Trent University, Peterborough, Ontario, Canada.
  • Wojtowicz JM; Rotman Research Institute, Baycrest Centre, Toronto, Ontario, Canada.
  • Shevtsova O; Departments of Psychology and Psychiatry, University of Toronto, Toronto, Ontario, Canada.
  • Fuller S; Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
  • Ghanbari HA; Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
PLoS One ; 13(1): e0191866, 2018.
Article en En | MEDLINE | ID: mdl-29370277
Chemotherapy-induced cognitive impairment (CICI) occurs in a substantial proportion of treated cancer patients, with no drug currently available for its therapy. This study investigated whether PAN-811, a ribonucleotide reductase inhibitor, can reduce cognitive impairment and related suppression of neurogenesis following chemotherapy in an animal model. Young adult rats in Chemo and Chemo+PAN-811 groups received 3 intraperitoneal (i.p.) injections of methotrexate (MTX) and 5-fluorouracil (5-FU), and those in Saline and Saline+PAN-811 groups received equal volumes of physiological saline at 10-day intervals. PAN-811 in saline was delivered through i.p. injection, 10 min following each saline (Saline+PAN-811 group) or MTX/5-FU (Chemo+PAN-811 group) treatment, while equal volumes of saline were delivered to Saline and Chemo groups. Over Days 31-66, rats were administered tests of spatial memory, nonmatching-to-sample rule learning, and discrimination learning, which are sensitive to dysfunction in hippocampus, frontal lobe and striatum, respectively. On Day 97, neurogenesis was immnunohistochemically evaluated by counting doublecortin-positive (DCX+) cells in the dentate gyrus (DG). The results demonstrated that the Chemo group was impaired on the three cognitive tasks, but co-administration of PAN-811 significantly reduced all MTX/5-FU-induced cognitive impairments. In addition, MTX/5-FU reduced DCX+ cells to 67% of that in Saline control rats, an effect that was completely blocked by PAN-811 co-administration. Overall, we present the first evidence that PAN-811 protects cognitive functions and preserves neurogenesis from deleterious effects of MTX/5-FU. The current findings provide a basis for rapid clinical translation to determine the effect of PAN-811 on CICI in human.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piridinas / Tiosemicarbazonas / Fármacos Neuroprotectores / Neurogénesis / Disfunción Cognitiva Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piridinas / Tiosemicarbazonas / Fármacos Neuroprotectores / Neurogénesis / Disfunción Cognitiva Tipo de estudio: Prognostic_studies Límite: Animals / Female / Humans Idioma: En Revista: PLoS One Asunto de la revista: CIENCIA / MEDICINA Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos