Ellagic Acid Rescued Motor And Cognitive Deficits And Attenuated Neuropathology In The R6/2 Transgenic Mouse Model Of Huntington’s Disease

Huntington’s disease(HD)is a genetic autosomal dominant neurodegenerative disease caused by an extended polyglutamine(polyQ)tract at the N-terminus of huntingtin protein(HTT).The polyQ expansion induces a pathological conformational change in mutant HTT(mHTT),which forms aggregates in both nucleus and cytoplasm of affected neurons.The abnormal aggregation of mHTT plays key a role in the pathogenesis of HD,which leads to neuronal dysfunction and death through multiple mechanisms,including inflammation,oxidative stress,autophagy deficiency and metabolic dysfunction.Strategies to lower mHTT levels,enhance autophagy,inhibit neuroinflammation and oxidative stress may confer therapeutic potential to combat HD.Ellagic acid(EA)is a polyphenolic antioxidant,it can be found in numerous fruits and vegetables such as pomegranates.EA has been marketed as a dietary supplement with various claimed benefits and neuroprotective effects on several neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease,while its effect on mHTT pathology is still unknown.In present work,we reported that EA significantly inhibited mHTT aggregation,reduced mHTT-induced neurocytotoxicity and protected against mHTT-induced apoptosis in vitro.When applied EA to R6/2 mouse model of HD,EA significantly attenuated motor and cognitive deficits in R6/2 mice.Moreover,EA markedly lowered mHTT levels,reduced neuroinflammation,rescued synapse loss,decreased oxidative stress and enhanced autophagy in the brains of R6/2 mice.These findings indicated that EA has promising therapeutic potential for HD.