The orexigenic hormone ghrelin, a potential antagonist of the insulin system, ensures sufficient serum glucose in times of fasting. In the race for new therapeutics for diabetes, one focus of study has been antagonizing the ghrelin system in order to improve glucose tolerance. We provide evidence for a differential role of a ghrelin agonist on glucose homeostasis in an Alzheimer’s disease mouse model fed a high–glycemic index diet as a constant challenge for glucose homeostasis. The ghrelin agonist impaired glucose tolerance immediately after administration but not in the long term. At the same time, the ghrelin agonist improved spatial learning in the mice, raised their activity levels, and reduced their body weight and fat mass. Immunoassay results showed a beneficial impact of long-term treatment on insulin signaling pathways in hippocampal tissue. The present results suggest that ghrelin might improve cognition in Alzheimer’s disease via a central nervous system mechanism involving insulin signaling.

Huntington's disease (HD) is an incurable autosomal-dominant neurodegenerative disorder initiated by an abnormally expanded polyglutamine domain in the huntingtin protein. It is proposed that abnormal mitochondrial Ca2+ capacity results in an increased susceptibility to mitochondrial permeability transition (MPT) induction that may contribute significantly to HD pathogenesis. The in vivo contribution of these hypothesized defects remains to be elucidated. In this proof-of-principle study, we examined whether increasing mitochondrial Ca2+ capacity could ameliorate the well-characterized phenotype of the R6/2 transgenic mouse model. Mouse models lacking cyclophilin D demonstrate convincingly that cyclophilin D is an essential component and a key regulator of MPT induction. Mitochondria of cyclophilin D knockout mice are particularly resistant to Ca2+ overload. We generated R6/2 mice with normal, reduced or absent cyclophilin D expression and examined the effect of increasing mitochondrial Ca2+ capacity on the behavioral and neuropathological features of the R6/2 model. A predicted outcome of this approach was the finding that cyclophilin D deletion enhanced the R6/2 brain mitochondria Ca2+ capacity significantly. Increased neuronal mitochondrial Ca2+ capacity failed to ameliorate either the behavioral and neuropathological features of R6/2 mice. We found no alterations in body weight changes, lifespan, RotaRod performances, grip strength, overall activity and no significant effect on the neuropathological features of R6/2 mice. The results of this study demonstrate that increasing neuronal mitochondrial Ca2+-buffering capacity is not beneficial in the R6/2 mouse model of HD.

Background: Flavonoids, a group of natural dietary polyphenols, are known for their beneficial effects on human health. By virtue of their various pharmacological effects, like anti-oxidative, antiinflammatory, anti-carcinogenic and neuroprotective effects, flavonoids have now become an important component of herbal supplements, pharmaceuticals, medicinals and cosmetics. There has been enormous literature supporting neuroprotective effect of flavonoids. Recently their efficacy in various neurodegenerative diseases, like Alzheimer’s disease and Parkinson diseases, has received particular attention. Objective: The mechanism of flavanoids neuroprotection might include antioxidant, antiapoptotic, antineuroinflammatory and modulation of various cellular and intracellular targets. In in-vivo systems, before reaching to brain, they have to cross barriers like extensive first pass metabolism, intestinal barrier and ultimately blood brain barrier. Different flavonoids have varied pharmacokinetic characteristics, which affect their pharmacodynamic profile. Therefore, brain accessibility of flavonoids is still debatable. Methods: This review emphasized on current trends of research and development on flavonoids, especially in neurodegenerative diseases, possible challenges and strategies to encounter using novel drug delivery system. Results: Various flavonoids have elicited their therapeutic potential against neurodegenerative diseases, however by using nanotechnology and novel drug delivery systems, the bioavailability of favonoids could be enhanced. Conclusion: This study bridges a significant opinion on medicinal chemistry, ethanopharmacology and new drug delivery research regarding use of flavonoids in management of neurodegeneration.

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Identifying molecular drivers of pathology provides potential therapeutic targets. Differentiating between drivers and coincidental molecular alterations presents a major challenge. Variation unrelated to pathology further complicates transcriptomic, proteomic and metabolomic studies which measure large numbers of individual molecules. To overcome these challenges towards the goal of determining drivers of Huntington's disease (HD), we generated an allelic series of HD knock-in mice with graded levels of phenotypic severity for comparison with molecular alterations. RNA-sequencing analysis of this series reveals high numbers of transcripts with level alterations that do not correlate with phenotypic severity. These discorrelated molecular changes are unlikely to be drivers of pathology allowing an exclusion-based strategy to provide a short list of driver candidates. Further analysis of the data shows that a majority of transcript level changes in HD knock-in mice involve alteration of the rate of mRNA processing and/or degradation rather than solely being due to alteration of transcription rate. The overall strategy described can be applied to assess the influence of any molecular change on pathology for diseases where different mutations cause graded phenotypic severity.