The growth of glioblastoma orthotopic xenografts in nude mice is directly correlated with impaired object recognition memory

Abstract

Cognitive dysfunction is found in patients with brain tumors and there is a need to determine whether it can be replicated in an experimental model. In the present study, the object recognition (OR) paradigm was used to investigate cognitive performance in nude mice, which represent one of the most important animal models available to study human tumors in vivo. Mice with orthotopic xenografts of the human U87MG glioblastoma cell line were trained at 9, 14, and 18days (D9, D14, and D18, respectively) after implantation of 5×10(5) cells. At D9, the mice showed normal behavior when tested 90min or 24h after training and compared to control nude mice. Animals at D14 were still able to discriminate between familiar and novel objects, but exhibited a lower performance than animals at D9. Total impairment in the OR memory was observed when animals were evaluated on D18. These alterations were detected earlier than any other clinical symptoms, which were observed only 22-24days after tumor implantation. There was a significant correlation between the discrimination index (d2) and time after tumor implantation as well as between d2 and tumor volume. These data indicate that the OR task is a robust test to identify early behavior alterations caused by glioblastoma in nude mice. In addition, these results suggest that OR task can be a reliable tool to test the efficacy of new therapies against these tumors.

Disruption of prion protein–HOP engagement impairs glioblastoma growth and cognitive decline and improves overall survival

“…26 We found that in human GBM cells in vitro, HOP binds specifically to PrP C and modulates proliferation through extracellular-signal-regulated kinase (ERK1/2) and phosphatidylinositide 3-kinase (PI3K) pathways, 7 suggesting that HOP-PrP C binding could be an important therapeutic target in GBMs. It is noteworthy that we demonstrated that mice bearing orthotopic xenograft GBM exhibit early cognitive decline, 27 consistent with the brain dysfunction and cognitive decline described for human patients with brain tumors. 28 Herein, the expression of HOP and PrP C was evaluated in human glioma specimens, grades I-IV, and correlated with tumor proliferation and patient survival.…”

“…This beneficial effect was probably due to inhibition of tumor growth as demonstrated previously. 27 This is particularly important since cognitive performance is increasingly valued as secondary end point in clinical trials. 46 On the other hand, a few years ago, we demonstrated that HOP 230-245 peptide had trophic properties 13 and was able to improve memory formation when infused directly into the hippocampus.…”

“…27 The tumors were fixed in 4% paraformaldehyde, sectioned (10 μm) and processed for immunofluorescence. Animals bearing U251 tumors have their brains removed, fixed, paraffin-embedded and hematoxylin and eosin stained.…”

“…27 They were habituated to an open-field polyvinyl chloride plastic arena (30 × 25 × 20 cm 3 ) with 20 min per day free exploration for 4 days. Then, they were placed in the arena with two identical objects on day 9, 12, 17 or 25 p.i.…”

Humulus japonicus inhibits the progression of Alzheimer's disease in a APP/PS1 transgenic mouse model

“…The time spent exploring both objects was calculated. A discrimination index was calculated for each animal and expressed by the ratio of time spent exploring the novel object − time spent exploring the familiar object/(time spent exploring the novel object + time spent exploring the familiar object) on day 2, as previously described (28). …”