Establishment of an intermittent cold stress model using <i>Tupaia belangeri</i> and evaluation of compound C737 targeting neuron-restrictive silencer factor

Abstract

Previous studies have shown that intermittent cold stress (ICS) induces depression-like behaviors in mammals. Tupaia belangeri (the tree shrew) is the only experimental animal other than the chimpanzee that has been shown to be susceptible to infection by hepatitis B and C viruses. Moreover, full genome sequence analysis has revealed strong homology between host proteins in Tupaia and in humans and other primates. Tupaia neuromodulator receptor proteins are also known to have a high degree of homology with their corresponding primate proteins. Based on these similarities, we hypothesized that induction of ICS in Tupaia would provide a useful animal model of stress responses. We exposed young adult Tupaia to ICS and observed decreases in body temperature and body weight in both female and male Tupaia, suggesting that Tupaia are an appropriate animal model for ICS studies. We further examined the efficacy of a new small-molecule compound, C737, against the effects of ICS. C737 mimics the helical structure of neuron-restrictive silencer factor (NRSF/REST), which regulates a wide range of target genes involved in neuronal function and pain modulation. Treatment with C737 significantly reduced stress-induced weight loss in female Tupaia; these effects were stronger than those elicited by the antidepressant agomelatine. These results suggest that Tupaia represents a useful non-rodent ICS model. Our data also provide new insights into the function of NRSF/REST in stress-induced depression and other disorders with epigenetic influences or those with high prevalence in women.

Construction of complete Tupaia belangeri transcriptome database by whole-genome and comprehensive RNA sequencing

“…Recently, tree shrew has been widely used for various biological studies, including investigations of viral infection 11,12,14 , depression 3 , the visual system 4 , and so on. However, research tools (e.g., antibody, PCR system) are limited for the establishment of tree shrew as an experimental animal model.…”

“…One of the appealing features of the tree shrew is its genetic closeness to human 2 . Thus, tree shrews are widely used as experimental animals in various research fields 3–6 . Recently, generation of a transgenic tree shrew has been reported 7 .…”

NRSF and Its Epigenetic Effectors: New Treatments for Neurological Disease

“…In a cold stress model, shrews were subjected to depression via exposure to cold temperature. Administration of C737 therapeutically protected against cold stress-induced weight loss and performed even better when compared against the antidepressant agomelatine [76]. These mimetics highlight a new strategy where specific epigenetic effectors that associate with transcription factor activity can be inhibited.…”

Pathological and genetic aspects of spontaneous mammary gland tumor in Tupaia belangeri (tree shrew)

“…In comparison with rodents, the genome sequence of tree shrew shows a higher homology with that of primates [4][5][6]. The tree shrew shows susceptibility to hepatitis viruses infections (hepatitis C virus [7,8], hepatitis B virus [9,10]) and can be used for the evaluation of anti-depressant drugs [11]. In addition, the development and physiological characters of the tree shrew's mammary gland are similar to those of human beings [12,13].…”