Background Neuropeptide Y (NPY) is a potent neuromodulator that is expressed throughout the central nervous system. The sparing and persistence increase in NPY-expressing striatal interneurons with advancing disease have been implicated to correlate with striatal pathology in both Huntington’s disease (HD) patients and animal models of HD. However, the potential roles of intense expression of NPY in HD pathology still remain under-explored.

Aims To investigate whether activation of NPY-Y2 receptor using NPY and selective Y2 receptor ligands could ameliorate behavioural deficits and neuropathology in R6/2 mouse model of HD.

Methods/techniques NPY and selective Y2 receptor agonist NPY_13-36 were intranasally administered to R6/2 mice, five days in a week, beginning from 4 weeks of age until 12 weeks of age. In the second study, R6/2 mice received daily intraperitoneal administration of selective non-peptide Y2 receptor antagonist (SF-31) to selectively block Y2 receptor.

Results/outcome Intranasal application of NPY showed significant increase in rotarod performance compared to saline and SF-31 treated R6/2 mice (pp < 0.05 and **p < 0.01 at 8 and 12 weeks of age respectively, n = 10). However, treatment with NPY_13-36 showed a clear trend towards increased rotarod performance at 12 weeks of age compared with the saline and SF-31 treated R6/2 mice but the difference did not reach significance. Also, we found no statistically significant difference in body weight loss between the groups, contrasting with previous data obtained with single intracerebroventricular (ICV) injection of NPY in R6/2 mice. Furthermore, intranasal application NPY or NPY_13-36 led to decrease in mutant Huntingtin (Htt) aggregation and mediated increase in dopamine-and cAMP regulated phosphoprotein (DARPP-32) and brain derived neurotrophic factor (BDNF) levels. Additionally, we found that NPY and NPY_13-36 attenuate microglial activation and expression of interleukin-1beta mRNA expression.

Conclusion Taken together, our findings suggest that targeting NPY-Y2 receptor might be a potential neuroprotective therapy for HD and other neurodegenerative diseases.