Disbalance of the Duodenal Epithelial Cell Turnover and Apoptosis Accompanies Insensitivity of Intestinal Redox Homeostasis to Inhibition of the Brain Glucose-Dependent Insulinotropic Polypeptide Receptors in a Rat Model of Sporadic Alzheimer’s Disease

Abstract

<b><i>Introduction:</i></b> Gastrointestinal dyshomeostasis is investigated in the context of metabolic dysfunction, systemic, and neuroinflammation in Alzheimer’s disease. Dysfunctional gastrointestinal redox homeostasis and the brain-gut incretin axis have been reported in the rat model of insulin-resistant brain state-driven neurodegeneration induced by intracerebroventricular streptozotocin (STZ-icv). We aimed to assess whether (i) the structural epithelial changes accompany duodenal oxidative stress; (ii) the brain glucose-dependent insulinotropic polypeptide receptor (GIP-R) regulates redox homeostasis of the duodenum; and (iii) the STZ-icv brain-gut axis is resistant to pharmacological inhibition of the brain GIP-R. <b><i>Methods:</i></b> GIP-R inhibitor [Pro<sup>3</sup>]-GIP (85 μg/kg) was administered intracerebroventricularly to the control and the STZ-icv rats 1 month after model induction. Thiobarbituric acid reactive substances (TBARSs) were measured in the plasma and duodenum, and the sections were analyzed morphometrically. Caspase-3 expression and activation were assessed by Western blot and multiplex fluorescent signal amplification. <b><i>Results:</i></b> Intracerebroventricular [Pro<sup>3</sup>]-GIP decreased plasma TBARSs in the control and STZ-icv animals and increased duodenal TBARSs in the controls. In the controls, inhibition of brain GIP-R affected duodenal epithelial cells, but not villus structure, while all morphometric parameters were altered in the STZ-icv-treated animals. Morphometric changes in the STZ-icv animals were accompanied by reduced levels of caspase-3. Suppression of brain GIP-R inhibited duodenal caspase-3 activation. <b><i>Conclusion:</i></b> Brain GIP-R seems to be involved in the regulation of duodenal redox homeostasis and epithelial cell turnover. Resistance of the brain-gut GIP axis and morphological changes indicative of abnormal epithelial cell turnover accompany duodenal oxidative stress in the STZ-icv rats.

The absence of gastrointestinal redox dyshomeostasis in the brain-first rat model of Parkinson’s disease induced by bilateral intrastriatal 6-hydroxydopamine

“…The presented results provide solid evidence against the existence of pronounced gastrointestinal redox dyshomeostasis in a brain-first rat model of PD induced by bilateral intrastriatal administration of 6-OHDA 12 weeks after model induction. Although the possibility that redox dyshomeostasis was present but too subtle to be estimated with a high degree of certainty using the current experimental design and methodological approach cannot be completely excluded, a substantial dropout rate and pronounced motor deficits ( administration of the 200 mg/kg D-galactose solution) [37] and in other neurotoxin-based models of brain-first-induced neurodegeneration [31,32].…”

“…The latter is further supported by the fact that the same biomarkers have been shown to be sufficiently sensitive to detect redox-related alterations induced by relatively mild stimuli (e.g. single orogastric administration of the 200 mg/kg D-galactose solution)[37] and in other neurotoxin-based models of brain-first-induced neurodegeneration [31, 32].…”

“…Considering that other neurotoxin-based „brain-first“models of neurodegeneration (e.g. the streptozotocin-induced rat model of sporadic Alzheimer’s disease [29] with some resemblance to the 6-OHDA models of PD [30]) demonstrate pronounced redox dyshomeostasis that may contribute to the progression of the disease phenotype [31, 32], we hypothesized that intrastriatal administration of 6-OHDA may produce similar alterations and promote systemic and neuro-inflammation in the rat model of PD contributing to the progression of neuropathology.…”

The Effect of Acute Oral Galactose Administration on the Redox System of the Rat Small Intestine

“…The possibility that the gastrointestinal tract mediates the protective effects of galactose is especially interesting given the increasingly recognized importance of gut homeostasis in the context of etiopathogenesis of neurodegeneration [ 21 ]. As different pathophysiological alterations of the gastrointestinal tract have been recently reported in the STZ-icv rat of sAD (e.g., redox dyshomeostasis [ 22 ], dysfunctional cell turnover and suppressed apoptosis of the intestinal epithelium [ 23 ], altered function of the brain–gut GLP-1 [ 22 ] and glucose-dependent insulinotropic polypeptide (GIP) [ 23 ] axes), it is possible that oral d -galactose treatment is able to exert neuroprotective effects by alleviating intestinal dyshomeostasis.…”

The effect of acute oral galactose administration on the redox system of the rat small intestine

“…Importantly, in contrast to the majority of studies utilizing galactose for the induction of agingrelated pathophysiological processes in which galactose was standardly administered via the parenteral route, health-promoting effects of galactose in the rat model of sAD have been repeatedly observed following long-term administration of galactose dissolved in drinking water (200 mg/kg/day) and available ad libitum [20,21] indicating that i) the gastrointestinal tract might be a critical factor mediating the observed beneficial effects, and ii) galactose might be beneficial only in small "tolerable" doses when tissue galactose metabolic capacity is not saturated. The possibility that the gastrointestinal tract mediates the protective effects of galactose is especially interesting in the context of recent findings of intestinal redox dyshomeostasis [23], dysfunctional cell turnover and suppressed apoptosis of the intestinal epithelium [24], and altered function of the brain-gut GLP-1 [23] and glucose-dependent insulinotropic polypeptide (GIP) [24] axes in the STZ-icv rat model of sAD. Considering the increasingly recognized importance of the gastrointestinal tract in the etiopathogenesis of neurodegeneration [25][26][27][28], the relevance of gut redox homeostasis for the maintenance of intestinal barrier and function [29][30][31], and a unique biochemical role of galactose in the context of redox regulation [5], the present aim was to explore the effects of acute oral administration of D-galactose on the individual mediators of redox homeostasis and their relationships in the rat small intestine.…”