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  • We speculated modulation of redox balance in

    2021-09-16

    We speculated modulation of redox balance in brain, by activation of GIP receptor pathway. QA is known to mediate production of ROS, lipid peroxidation by its interactions with Fe2+ and formation of QA-Fe2+ complex (Braidy et al., 2010, Rios and Santamaria, 1991, Stipek et al., 1997). QA induces NOS activity in neurons Torcetrapib and astrocytes, causing oxidative stress, increased lipid peroxidation, and decreased mitochondrial function in striatal slices (Perez-De La Cruz et al., 2010). Damage due to QA to neuronal tissues in part may also be mediated through gliosis, an inflammatory reaction in microglial cells, further accentuating the oxidative stress by free radical production (Behan et al., 1999, Bjorklund et al., 1986). Further, QA alters the endogenous antioxidants, reduced glutathione and copper and zinc –dependent superoxide dismutase activity (Cu, Zn-SOD), leading to reduced antioxidant capacity (Leipnitz et al., 2005, Rodriguez-Martinez et al., 2000). In the present study, bilateral administration to striatum led to increased MDA levels, indicating increased lipid peroxidation, and lowered antioxidant levels (GSH), potentially contributing to striatal oxidative stress. D-Ala2GIP reduced the MDA levels in whole Torcetrapib samples, which indicates reduced lipid peroxidation providing neuroprotective effects due to reduced oxidative stress. Further, D-Ala2GIP enhanced the endogenous antioxidant levels; GSH levels were restored after treatment in the QA lesioned animals, but not elevated in the un-lesioned animals. Under oxidative stress, GIP receptor stimulation may mediate up-regulation of prosurvival genes, antioxidant and antiapoptotic proteins through cAMP/PKA/CREB pathway (Ryu et al., 2005). Moreover, incretin hormones like GLP-1 and GIP, are known to reduce oxidative stress, upregulate neurotrophic factors and endogenous antioxidants in microglial cells in a PKA-dependent manner (Spielman et al., 2017). Activation of the cAMP/PKA/CREB pathway by GIP receptor pathway modulates key neurotrophic factors like BDNF, and antiapoptotic protein like Bcl-2 (Li et al., 2016, Li et al., 2017). Indeed, GIP agonists, D-Ala2-GIP-glu-PAL and D-Ala2GIP, have earlier demonstrated augmented CREB mediated prosurvival responses (Li et al., 2016, Li et al., 2017, Verma et al., 2017). Thus, GIP receptor stimulation may mediate a broad-based neuroprotection through reduced oxidative stress, anti-inflammatory, antiapoptotic and neurotrophic actions on striatal neurons. Modulation of the monoamine levels may also underlie the observed symptomatic improvements. Changes in striatal dopamine and serotonin levels represent one of the earliest alterations at onset of the neuropsychological symptoms in Huntington's disease (Bedard et al., 2011, Mochel et al., 2011). QA administration leads to reduction in striatal levels of epinephrine, serotonin, GABA, dopamine and their metabolites in rats (Gill et al., 2017). We observed significant depletion of dopamine and its metabolites, DOPAC and HVA by QA injections, possibly causing impaired locomotor functions. D-Ala2GIP restored striatal dopamine and its metabolites, in part attenuating the motor dysfunction. Dopamine to DOPAC, HVA ratios were not appreciably changed by D-Ala2GIP, indicating normal patterns of dopamine catabolism, precluding effects on the MAO and COMT pathways. However, (Pro3)GIP potentiated the QA-induced loss of monoamines and reduced monoamines to metabolite ratios, possibly due to a direct antagonism at striatal dopaminergic afferents or blocking of the residual GIP receptor mediated neurotrophic support. Altered 5-HT receptor expression, diminished 5-HT and 5-HIAA levels also associate with Huntington's symptomatology (Jamwal et al., 2015, Reynolds et al., 1999, Singh and Kumar, 2016). In our studies, D-Ala2GIP attenuated the loss of striatal 5-HT and 5-HIAA levels with potential implications on the motor control. Arguably, the antioxidant effects associated with D-Ala2GIP treatment, could potentially relieve the sensitivity of tryptophan hydroxylase towards oxidative stress and restore 5-HT levels (Yohrling et al., 2002). Furthermore, loss of norepinephrine has also been linked to motor and non-motor dysfunctions (Beskid and Finkiewicz-Murawiejska, 1992, Delaville et al., 2011, Rommelfanger et al., 2007). We show that D-Ala2GIP is able to attenuate the QA-induced loss of striatal NE, potentially contributing to the restoration motor functions as well. Overall, GIP receptor stimulation with D-Ala2GIP was associated with restoration of the complex interplay of monoamine levels essential for normal motor control and coordination.