Abstract
Tolfenamic acid is a nonsteroidal anti-inflammatory drug with neuroprotective properties, and it alleviates learning and memory deficits in the APP transgenic mouse model of Alzheimer's disease. However, whether tolfenamic acid can prevent motor and memory dysfunction in transgenic animal models of Huntington's disease (HD) remains unclear. To this end, tolfenamic acid was orally administered to transgenic R6/1 mice from 10 to 20 weeks of age, followed by several behavioral tests to evaluate motor and memory function. Tolfenamic acid improved motor coordination in R6/1 mice as tested by rotarod, grip strength, and locomotor behavior tests and attenuated memory dysfunction as analyzed using the novel object recognition test and passive avoidance test. Tolfenamic acid decreased the expression of mutant huntingtin in the striatum of 20-week-old R6/1 mice by inhibiting specificity protein 1 expression and enhancing autophagic function. Furthermore, tolfenamic acid exhibited antioxidant effects in both R6/1 mice and PC12 cell models. Collectively, these results suggest that tolfenamic acid has a good therapeutic effect on R6/1 mice, and may be a potentially useful agent in the treatment of HD.
Highlights
Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder, the clinical hallmarks of which include motor dysfunction, psychiatric disturbance, and cognitive deficits
HD is caused by abnormal expansion of the cytosine-adenine-guanine repeat in the IT15 gene located on chromosome 4, resulting in the formation of a polyglutamine stretch in the N-terminus region of the Huntingtin protein (Htt) [1]
The body weights of R6/1 mice progressively decreased from 15 to 20 weeks of age (p < 0 01) (Figures 1(a) and 1(b)); tolfenamic acid treatment did not result in any differences
Summary
Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder, the clinical hallmarks of which include motor dysfunction, psychiatric disturbance, and cognitive deficits. HD is caused by abnormal expansion of the cytosine-adenine-guanine repeat in the IT15 gene located on chromosome 4, resulting in the formation of a polyglutamine stretch in the N-terminus region of the Huntingtin protein (Htt) [1]. Mutant Htt (mHtt) causes selective neuronal loss in the brain. Mouse models of HD, most commonly the R6 transgenic model that expresses a truncated form of human Htt, have been primarily used to examine several therapeutic strategies [2]. Specificity protein 1 (Sp1) is a transcription factor, the target genes of which include amyloid β precursor protein (APP), BACE1, Tau, and Htt, which all play vital roles in neurodegenerative diseases. Because Sp1 promotes human Htt gene transcription [3,4,5], we hypothesized that the downregulation of Sp1-mediated Htt transcription may alleviate the pathogenesis of HD
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