Prevention of Huntington’s Disease-Like Behavioral Deficits in R6/1 Mouse by Tolfenamic Acid Is Associated with Decreases in Mutant Huntingtin and Oxidative Stress

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.

Drug repositioning as a therapeutic strategy for neurodegenerations associated with OPA1 mutations

“…Thus, the positive effect of ORM14 on mitochondrial morphology in OPA1 mutant cells may depend on a decrease in mitochondrial fission due to reduced CDK5 protein levels and, in turn, inhibition of DRP1. Recently, ORM14 treatment in a Huntington’s disease mouse model showed antioxidant properties, increasing the expression of NRF2, NQO1 and HO1, and also a pro-autophagic effect ( 66 ), as we also observed in R445H MEFs, suggesting that ORM14 may increase autophagic function in models of different diseases.…”

No symphony without bassoon and piccolo: changes in synaptic active zone proteins in Huntington’s disease

“…Of note, the association between Bassoon and huntingtin inclusions was apparent already at the age of 16 weeks (Fig. 5a, b second panels) when the first motor symptoms appear in the R6/1 mouse model [10,17,22,25,46], implying the effect of colocalization induced the presynaptic dysfunction and led to locomotor impairment. At 40 weeks of age, the normal Bassoon signal was drastically reduced and the Bassoon protein seemed to be predominantly present in the mutant huntingtin aggregates (Fig.…”

Fenamates as Potential Therapeutics for Neurodegenerative Disorders

“…Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder caused by the abnormal expansion of the cytosine–adenine–guanine (CAG) repeat in the IT15 gene located on chromosome 4 [ 70 ]. This results in the production of mutant huntingtin (mHtt) protein with a long polyglutamine stretch in the N-terminus region of the Huntingtin protein (Htt) [ 70 , 71 ]. Individuals with greater than 39 CAG repeats develop HD, while those with 36–39 have reduced penetrance [ 71 ].…”

“…The most common mouse model of HD is the R6 transgenic model that expresses a truncated form of the human Htt and has been used to examine therapeutic strategies [ 70 ]. The human htt gene is among many that are regulated by Sp1, which suggests that TA may be an effective treatment to attenuate motor and cognitive deficits for HD patients [ 74 ].…”