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  • br Materials and methods br Results br Discussion Present st

    2021-10-23


    Materials and methods
    Results
    Discussion Present study demonstrated the ability of a GIP agonist, D-Ala2GIP, to protect against the QA-induced neurobehavioral phenotype of HD in rats, for the first time. D-Ala2GIP treatment significantly improved the behavioral deficits, biochemical and neurochemical alterations caused by QA administration. GIP receptor antagonist, (Pro3)GIP, significantly attenuated the protective effects of D-Ala2GIP, indicating the specific role of GIP signaling pathway in observed protective effects with GIP agonist in QA-induced HD in rats. Several lines of evidence indicate that mutant huntingtin protein (mHTT) causes microglial activation, neuroinflammation, and neurotoxicity, contributing to the HD pathogenesis (Yang et al., 2017). Activated microglia harbor hyperphysiological levels of the metabolites of the kyneurenine pathway, 3-hydroxykynurenine (3-HK) and QA under pathological conditions, and causally relate with HD pathology (Schwarcz et al., 2010). Congruently, in animal models, QA administration leads to increased striatal oxidative stress, reduced endogenous antioxidant levels, culminating in the striatal neuropathology and neurobehavioral phenotype of HD (Behan et al., 1999, Bjorklund et al., 1986). In the present study, bilateral QA administration to striatum showed increased ampa receptor lipid peroxidation, reduction in endogenous antioxidants, decreased striatal monoamine levels, characteristic deficits in, locomotor activity, motor coordination, neuromuscular coordination and short-term episodic memory. Single bilateral administration of QA to the striatal regions resulted in deficits in the locomotor activity, motor and neuromuscular coordination, as previously reported (Gill et al., 2017, Kalonia et al., 2010, Mishra and Kumar, 2014). Our results demonstrate that treatment with D-Ala2GIP for 14 days post QA-lesioning, attenuated the loss of the locomotor activity counts. Similarly, deficits in motor coordination were also mitigated after D-Ala2GIP treatment, indicating the potential of the GIP receptor stimulation to antagonize the striatal dysfunction caused by QA. D-Ala2GIP also improved the fine motor coordination in the beam walking test, where reduction in the duration to traverse the beam and reduction in number of slips was observed. Fine motor deviations and choreiform movements form an important part of clinical etiopathology of the striatal and basal ganglia dysfunctions in Huntington's disease (Leisman et al., 2014). Huntington's disease patients also exhibit hypertonicity, hemispasticity and velocity dependent resistance in the flexion movements (Homberg and Huttunen, 1994). In our study, QA lesioned animals displayed defective grip strength, possibly due to the increased muscle spasticity. The peak force exerted by the fore-limbs of rats was significantly lower to the sham-treated animals, which was attenuated by D-Ala2GIP treatment. Overall, stimulation of GIP receptor with D-Ala2GIP was found to attenuate the deficits of motor control and neuromuscular function, whereas (Pro3)GIP was ineffectual. Protective effects of D-Ala2GIP were evident only in QA-lesioned conditions, with no significant alterations when treated alone in the un-lesioned animals. These symptomatic improvements could potentially be attributed to either restoration of the dysregulated striatal monoamine levels or neuroprotective mechanisms, or both. Indeed, previous studies have shown involvement of both mechanisms with ampa receptor GIP receptor agonists (Li et al., 2016, Li et al., 2017, Verma et al., 2017). Further, we show that a selective GIP receptor antagonist, (Pro3)GIP, counteracts the effects of D-Ala2GIP, supporting the specific involvement of the GIP receptor pathway. We further explored mnemonic domains that are affected in Huntington's disease. Striatal atrophy results in cognitive deficits in working memory, attention span and executive functioning (Montoya et al., 2006). Short-term memory dysfunctions precede the motor impairments in Huntington's disease, as recapitulated in the animal models (Giralt et al., 2012). In our study, short-term episodic memory was impaired with QA administration in the novel object recognition task; rats failed to exhibit differential exploration of the familiar vs. novel objects, indicating deficits in memory acquisition and consolidation. D-Ala2GIP attenuated the decline of discrimination index, whereas (Pro3)GIP and per se treated groups had no significant effect.