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    • Ability of D Ala GIP to attenuate the

    2021-09-09

    Ability of D-Ala2GIP to attenuate the neurobehavioral sequelae in QA-induced Huntington's disease model by reduction in lipid peroxidation, restoration of endogenous antioxidants and decreased striatal monoamine levels is of potential interest. Considerable preclinical evidence now exists of the potential of GIP receptor agonists to ameliorate the symptomatology of neurodegenerative disorders; this study contributes further to extended our understanding of xa inhibitor GIP receptor signaling in models of Huntington's disease. In summary, we report the mechanistic underpinnings of the ability of GIP receptor agonist, D-Ala2GIP, to protect against the QA-induced neurobehavioral deficits in rats. This study shows that the protective effects are mediated by modulation of lipid peroxidation, endogenous antioxidants and restoration of decreased monoamine levels in striatal regions. Thus, these data together suggest that GIP receptor agonists could be a potential therapeutic strategy for the management of symptoms of Huntington's disease.
    Acknowledgements Authors sincerely express gratitude to Dr. Raj Kamboj and Dr. Venkata Palle, for their guidance, continuous support and encouragement in accomplishment of the studies leading towards this manuscript. Authors also gratefully acknowledge the steadfast guidance and support from Dr. Mandar Bhonde, Dr. Sharad Sharma, Dr. Jayasagar Gundu and Dr. Lakshmi Narasimham for their several scientific inputs regarding study design, study execution and the employed analytical methods. This work was fully supported by Lupin Limited, under ASCENT program.
    Introduction Parkinson disease (PD) is a progressive neurodegenerative disorder, and due to the increase of life expectancy in the industrialized countries, patient numbers are on the increase (Schapira, 2013). PD presents with symptoms such as resting tremor, bradykinesia, rigidity and others (Langston, 2002). The main cause of this appears to be a reduction in striatal dopamine levels, which is caused by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) (Moore et al., 2005, Wakamatsu et al., 2008). Importantly, type II diabetes has been identified as a risk factor for PD (Hu et al., 2007, Schernhammer et al., 2011, Sun et al., 2012, Wahlqvist et al., 2012). Insulin signalling in the brain plays a key role in neuronal metabolism, repair and synaptic efficacy (Freiherr et al., 2013, Ghasemi et al., 2013, van der Heide et al., 2006). It has been shown that insulin signalling is desensitized in the brains of patients with PD (Aviles-Olmos et al., 2013b, Moroo et al., 1994, Morris et al., 2011). Analogues of incretin hormones have been developed to treat type II diabetes (Campbell and Drucker, 2013, Holst, 2004). The incretin hormones are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (Baggio and Drucker, 2007, Campbell and Drucker, 2013, Doyle and Egan, 2003). Protease-resistant analogues of GLP-1 and GIP have shown neuroprotective effects in animal models of Alzheimer's disease (Bomfim et al., 2012, Duffy and Holscher, 2013, Faivre and Holscher, 2013a, Faivre and Holscher, 2013b, Li et al., 2010, McClean et al., 2011) and re-sensitize insulin signalling in the brain (Long-Smith et al., 2013, Shi et al., 2017). Furthermore, previous studies found that GLP-1 receptor agonists also have neuroprotective effects in animal models of PD (Bertilsson et al., 2008, Harkavyi et al., 2008, Li et al., 2009, Liu et al., 2015a, Zhang et al., 2015). The GLP-1 mimetic exendin-4 showed impressive effects in a pilot clinical study and in a phase II double blind, placebo controlled study in PD patients (Athauda et al., 2017, Aviles-Olmos et al., 2013a, Aviles-Olmos et al., 2014). We have shown that GLP-1 and also GIP analogues are neuroprotective in the 1-methyl-4-phenyl 1,2,3,6-tetrahydropypridine (MPTP) mouse model of PD, demonstrating that both incretin signalling pathways protect the brain from the MPTP induced pathology such as motor impairment, an increase of α synuclein levels in the brain, development of chronic inflammation in the brain, loss of dopamine synthesis, and reduced growth factor expression (Ji et al., 2016a, Li et al., 2016, Li et al., 2017, Liu et al., 2015a, Liu et al., 2015b, Zhang et al., 2015).