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  • notch pathway Gastric inhibitory polypeptide a hormone belon


    Gastric inhibitory polypeptide, a hormone belonging to the glucagon-secretin family of peptides, exhibits protection against the neurodegeneration and also stimulates neurogenesis in adult rats in a paracrine manner (Gault and Holscher, 2008, Nyberg et al., 2005, Usdin et al., 1993). The expression of GIP receptor in the human hippocampus, cerebral cortex and in the notch pathway regions relevant to the pathology of Parkinson's disease, viz., thalamus, substantia nigra, hypothalamus and lateral septal nucleus, suggests a potential neurotrophic role of GIP (Figueiredo et al., 2011, Nyberg et al., 2007). Several preclinical studies directed towards investigating neuroprotection and rescue of the behavioral sequalae of Parkinson's disease have employed MPTP-induced lesions of the nigrostriatal dopaminergic pathway in rodents (Jackson-Lewis and Przedborski, 2007). The metabolism of MPTP to its neurotoxic metabolite MPP+ results in oxidative stress, energy failure and neuronal cell death (Javitch et al., 1985, Ramsay and Singer, 1986). Faivre and Holscher (2013) demonstrated that brain penetrating GIP receptor agonists exhibit neuroprotection in the transgenic (APP/PS1) mouse model of Alzheimer's disease. GIP analogues like D-Ala2-GIP-glu-PAL have shown benefit in the MPTP-induced Parkinson's disease model by promoting cell survival and inhibiting apoptosis, when administered in a therapeutic regimen (Li et al., 2016b). Similar results were observed in the chronic treatment paradigm with D-Ala2-GIP-glu-PAL in a chronic Parkinson's disease model induced by MPTP in combination with probenecid (Li et al., 2016a). Unlike these earlier publications, in the present study, we aim to investigate the plausible symptomatic effects and neuroprotective actions of GIP receptor agonist, D-Ala2GIP, against MPTP-induced neurotoxicity by a pretreatment regimen.
    Materials and methods
    Discussion Expression of GIP and its receptor, GIP receptor, throughout the mammalian brain has been confirmed by several studies, indicative of its potential roles in brain functions (Usdin et al., 1993). A putative role of GIP as a neurotransmitter and a neurotrophic factor has thus been proposed considering the ample evidence of its role in maintenance and survival of the neuronal population in the brain regions (Faivre et al., 2011). Protease-resistant and brain penetrating GIP analogues, like D-Ala2GIP and N-Ac-GIP, demonstrably improve the LTP and rescue the phenotype of Alzheimer's disease in the APP/PS1 mouse (Faivre and Holscher, 2013). Novel GIP analogues like D-Ala2-GIP-glu-PAL, when administered therapeutically, promote dopaminergic cell survival through activation of cAMP/PKA/CREB pathway and protect against the MPTP-induced impairments in motor activity (Li et al., 2016b). Chronic treatment with D-Ala2-GIP-glu-PAL also reduced Parkinsonism-like motor disorders, neuroinflammation and oxidative stress in a MPTP-induced chronic Parkinson's disease model (Li et al., 2016a). Utilizing the classical MPTP-induced mouse model of Parkinson's disease, we further demonstrate the beneficial effect of D-Ala2GIP, on the associated biochemical and behavioral parameters in a pretreatment regimen. We tested the effects of pretreatment with D-Ala2GIP on MPTP-challenge by evaluating the motor function, tremor amplitude, oxidative stress and striatal levels of dopamine and its metabolites. Our results demonstrate that pretreatment with D-Ala2GIP, 7 days prior to the MPTP administration led to the significant attenuation of the MPTP behavioral sequalae. The total locomotor activity counts in the D-Ala2GIP group was significantly higher in comparison to the MPTP group, indicative of the protection against the acute neurotoxicity caused by MPTP. This observation is in agreement with the neuroprotective activity observed with another GIP analogue, D-Ala2-GIP-Glu-Pal, in the MPTP-induced motor impairments, when administered therapeutically (Li et al., 2016b). Under similar conditions, L-DOPA treatment also attenuated the hypoactivity caused by MPTP administration, as previously reported at these dose levels (Fredriksson et al., 1990). In agreement with the reported findings, pretreatment of selegiline, a monoamine oxidase B inhibitor, is also known to protect dopaminergic neurons against MPTP by inhibiting the early steps of MPTP conversion to MPP+ and the resultant toxicity of mitochondrial respiration in dopaminergic neurons (Ebadi et al., 2002, Magyar and Haberle, 1999). Further, we show that a specific GIP receptor antagonist, (Pro3)GIP, when administered prior to D-Ala2GIP, is able to antagonize the protection offered by D-Ala2GIP on the MPTP-induced hypolocomotion. This is indicative of specific involvement of GIP receptor and its downstream pathways. Indeed, earlier studies conducted on memory retention, have also shown the inhibitory role of (Pro3)GIP on the GIP-induced cyclic adenosine monophosphate production and attenuation of the memory function in the novel object recognition task (Faivre et al., 2012, Gault et al., 2007). Our results with the rotating rod test revealed that pretreatment with D-Ala2GIP also significantly attenuated the loss of motor coordination induced by MPTP administration. These protective effects, again, were found to be sensitive to blockade by (Pro3)GIP, and thus obviating the involvement of other signaling pathways or any non-specific activity.