In summary our findings provide the evidence and the mechani

In summary, our findings provide the evidence and the mechanistic understanding of the protective effects of GIP receptor agonist, D-Ala2GIP, in the MPTP-induced neurotoxicity in mice. The observed protective effects are potentially due to reduced oxidative stress and attenuation of dopamine loss in dopaminergic neurons without affecting its catabolism. Based on these observations we speculate that GIP receptor modulation could be a potential strategy for the treatment of Parkinson's disease.
Acknowledgements This work was fully supported by Lupin Limited.
Introduction Huntington's disease (HD) is an inherited autosomal dominant progressive neurodegenerative disorder, triggered by neurotoxic mutant Huntingtin (mHTT) protein. Polyglutamine tract expansion, encoded by cysteine-adenosine-guanine (CAG) repeats in the Huntingtin (HTT) gene, generates mHTT and results in toxicity to neurons (Ross and Tabrizi, 2011). HD symptoms include motor impairments (bradykinesia, chorea, gait abnormalities), cognitive dysfunction (dementia, lack of attention) and psychiatric symptoms (depression, apathy, mania), primarily an outcome of massive degeneration (80–90%) of striatal medium spiny neurons (Bates et al., 2002, Folstein, 1989, Heinsen et al., 1994). mHTT aggregation associates with neuroinflammation, microglial activation, neuronal oxidative stress and excitotoxicity-induced corticostriatal dysfunction (Rotblat et al., 2014, Yang et al., 2017). mHTT engenders reactive oxygen species (ROS), increases lipid peroxidation, and with reduced glutathione levels, associates with severe HD phenotype (Klepac et al., 2007). Oxidative stress interferes with electron transport chain, causing mitochondrial dysfunction in symptomatic HD patients (Duran et al., 2010, Lee et al., 2012). Further, striatal excitotoxicity due to mHTT-NMDA receptor interactions and loss of trophic support contribute to HD pathogenesis (Gu et al., 2005, Shimojo, 2008). Neurobehavioral symptomatology of HD has been modeled in experimental animals utilizing intrastriatal injections of kainic acid, ibotenic KY02111 and QA (Isacson et al., 1985, Schwarcz et al., 1977). Metabolite of the kynurenine pathway, QA, closely links exitotoxic potential of mHTT with HD in histological selectivity (Sanberg et al., 1989, Schwarcz et al., 2010). Neurochemical and histological characteristics of QA-induced lesions bear close resemblance to HD (Beal et al., 1991, Beal et al., 1986). Further, cognitive features, and chorea-like symptoms of HD are recapitulated in rodents and nonhuman primates by bilateral striatal lesioning with QA (Popoli et al., 1994, Roitberg et al., 2002). HD therapeutics are predominantly symptomatic, long-term disease modification still remains elusive (Coppen and Roos, 2017, Roos, 2010). Vesicular monoamine transporter-2 (VMAT2) inhibitors, tetrabenazine and deutetrabenazine, are approved for treatment of Huntington's chorea. Modulation of the brain kynurenine pathway represents an active area of research in HD (Schwarcz et al., 2010). Hormones belonging to glucagon-secretin family, e.g., GIP, promote neurogenesis and protect against experimental neurodegeneration (Faivre et al., 2011, Nyberg et al., 2005). GIP and GIP receptor are widely expressed in the brain, in the regions relevant to the neuropathology of HD, e.g., striatum, basal ganglia and cerebral cortex (Nyberg et al., 2007, Usdin et al., 1993). GIP expression colocalizes with neuronal marker NeuN in the hippocampal neurons (Nyberg et al., 2005). Further, GIP immunoreactivity in the Ki-67 positive neurons correlates to proliferation of the adult hippocampal progenitor cell and release of growth hormones (Kaplan and Vigna, 1994, Nyberg et al., 2005). GIP receptor agonists ameliorate neurobehavioral phenotype of Alzheimer's and Parkinson's disease in preclinical studies (Faivre and Holscher, 2013, Li et al., 2016, Li et al., 2017, Verma et al., 2017). Systematic explorations studying the effects of GIP receptor agonists in models of HD are hitherto unknown. Present studies were designed to test the potential of a GIP receptor agonist to attenuate the QA-induced neurobehavioral phenotype of HD in rats in a therapeutic regimen.