L22 Intranasal application of NPY and NPY13–36 ameliorate disease pathology in R6/2 mouse model of huntington’s disease

Abstract

BackgroundNeuropeptide 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.AimsTo 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/techniquesNPY and selective Y2 receptor agonist NPY13-36 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/outcomeIntranasal 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 NPY13-36 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 NPY13-36 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 NPY13-36 attenuate microglial activation and expression of interleukin-1beta mRNA expression.ConclusionTaken together, our findings suggest that targeting NPY-Y2 receptor might be a potential neuroprotective therapy for HD and other neurodegenerative diseases.

A multi-staged neuropeptide response to traumatic brain injury

“…Therefore, reinforcing NPY's response is a potential therapeutic strategy, possibly along with SP modulation [14], in Neurotrauma, considering previously mentioned NPY's pro-neurogenic, pro-migratory and neuroprotective properties [61]. Neuropeptide Y supplementation protocols (namely by intranasal delivery) are underway in phase II/phase III clinical trials concerning other clinical contexts [62,63]. Some issues can be raised concerning this research protocol.…”

Intranasal Peptide Therapeutics: A Promising Avenue for Overcoming the Challenges of Traditional CNS Drug Development

“…IN-NPY significantly improved motor performance on rotarod testing at the end for treatment, but IN-NPY 13–36 and saline did not. Both NPY and NPY 13–36 decreased mutant Htt aggregation, increased dopamine, cAMP regulated phosphoprotein and BDNF levels, and attenuated microglial activation and IL-1β expression [ 136 ]. These results indicate that while the Y2 receptor of NPY is involved in both the role of NPY in developing HD pathology and in the therapeutic efficacy of NPY, its activation does not restore HD-deficits, indicating a role for other receptors, such as Y1, which has been shown in preclinical PTSD models to be responsible for the therapeutic benefits of IN-NPY [ 130 ].…”