The Absence of Gastrointestinal Redox Dyshomeostasis in the Brain-First Rat Model of Parkinson’s Disease Induced by Bilateral Intrastriatal 6-Hydroxydopamine

Abstract

The gut-brain axis plays an important role in Parkinson’s disease (PD) by acting as a route for vagal propagation of aggregated α-synuclein in the gut-first endophenotype and as a mediator of gastrointestinal dyshomeostasis via the nigro-vagal pathway in the brain-first endophenotype of the disease. One important mechanism by which the gut-brain axis may promote PD is by regulating gastrointestinal redox homeostasis as overwhelming evidence suggests that oxidative stress plays a key role in the etiopathogenesis and progression of PD and the gastrointestinal tract maintains redox homeostasis of the organism by acting as a critical barrier to environmental and microbiological electrophilic challenges. The present aim was to utilize the bilateral intrastriatal 6-hydroxydopamine (6-OHDA) brain-first PD model to study the effects of isolated central pathology on redox homeostasis of the gastrointestinal tract. Three-month-old male Wistar rats were either not treated (intact controls; CTR) or treated bilaterally intrastriatally with vehicle (CIS) or 6-OHDA (6-OHDA). Motor deficits were assessed with the rotarod performance test, and the duodenum, ileum, and colon were dissected for biochemical analyses 12 weeks after the treatment. Lipid peroxidation, total antioxidant capacity, low-molecular-weight thiols, and protein sulfhydryls, the activity of total and Mn/Fe superoxide dismutases, and total and azide-insensitive catalase/peroxidase were measured. Both univariate and multivariate models analyzing redox biomarkers indicate that significant disturbances in gastrointestinal redox balance are not present. The findings demonstrate that motor impairment observed in the brain-first 6-OHDA model of PD can occur without concurrent redox imbalances in the gastrointestinal system.

Insights into Gastrointestinal Redox Dysregulation in a Rat Model of Alzheimer’s Disease and the Assessment of the Protective Potential of D-Galactose

“…For instance, in the context of mimicking Parkinson’s disease through intrastriatal administration of 6-hydroxydopamine, central neurodegeneration does not seem to lead to pronounced redox dyshomeostasis in the gut . Although GI changes have been observed in this model, − they cannot be solely attributed to the absence of responsiveness to stimuli as a common factor.…”

“…Activity of SODs was determined with a modified 1,2,3-trihydroxybenzene (THB) autoxidation inhibition assay. − Reaction buffer contained 0.05 M Tris-HCl and 1 mM Na 2 EDTA (pH 8.2), and the final concentration of THB was 1.2 mM. Reaction buffer was modified by adding 2 mM KCN to discriminate between Cu/Zn- and Mn/Fe-SOD . THB autoxidation was monitored at 450 nm with a multimodal microplate reader (Tecan, Switzerland).…”

“…Baseline interference was ruled out by reacting the samples with stop solution before adding the substrate. , Carbonato-cobaltate (III) complex ([Co­(CO 3 ) 3 ]­Co) absorbance was measured at 450 nm with a microplate reader (Tecan, Switzerland) and compared to the H 2 O 2 standard model to determine the H 2 O 2 concentration. The same procedure was repeated in the presence of 25 μM NaN 3 to discriminate between the activity of catalase and peroxidases. , Reaction conditions were optimzied in pilot experiments. Lipid peroxidation was assessed with the thiobarbituric acid reactive substances (TBARS) assay .…”

“…In transgenic animal models of AD, it is common to observe physiological changes in the GI tract before observing any pathological changes in the brain. − This sequence of events makes it difficult to study the GI consequences of localized neurodegeneration in the CNS. On the other hand, brain-first nontransgenic animal models, which involve the targeted delivery of toxic substances (e.g., amyloid β, streptozotocin (STZ), colchicine, and okadaic acid) that mimic AD-related neuropathology to the CNS, provide an opportunity to investigate the one-way disruption of the gut–brain axis. − These models offer invaluable insights into how localized neurodegeneration impacts the structural and functional integrity of the gut. One of the most extensively studied and well-established brain-first models of sporadic AD is the rat model generated by intracerebroventricular administration of the diabetogenic toxin streptozotocin (STZ-icv). , Based on the evidence accumulated over the last 30 years, the STZ-icv model recapitulates key behavioral and neuropathological hallmarks of AD .…”

“…On the other hand, brain-first nontransgenic animal models, which involve the targeted delivery of toxic substances (e.g., amyloid β, 18 streptozotocin (STZ), 19 colchicine, 20 and okadaic acid 21 ) that mimic AD-related neuropathology to the CNS, provide an opportunity to investigate the one-way disruption of the gut–brain axis. 22 − 25 These models offer invaluable insights into how localized neurodegeneration impacts the structural and functional integrity of the gut. One of the most extensively studied and well-established brain-first models of sporadic AD is the rat model generated by intracerebroventricular administration of the diabetogenic toxin streptozotocin (STZ-icv).…”