Measures of striatal insulin resistance in a 6-hydroxydopamine model of Parkinson's disease

Abstract

Clinical evidence has shown a correlation between Parkinson’s Disease (PD) and Type 2 Diabetes (T2D), as abnormal glucose tolerance has been reported in >50% of PD patients. The development of insulin resistance and the degeneration of nigrostriatal dopamine (DA) neurons are both mediated by oxidative mechanisms, and oxidative stress is likely a mechanistic link between these pathologies. Although glucose uptake in neuronal tissues is primarily non-insulin dependent, proteins involved in insulin signaling, such as insulin receptor substrate 2 (IRS2) and glucose transporter 4 (GLUT4), are present in the basal ganglia. The purpose of this study was to determine whether nigrostriatal DA depletion affects measures of insulin resistance in the striatum. Six weeks after 6-hydroxydopamine (6-OHDA) infusion into the medial forebrain bundle, rats were classified as having either partial (20–65%) or severe (90–99%) striatal DA depletion. Increased IRS-2 serine phosphorylation, a marker of insulin resistance, was observed in the DA depleted striatum. Additionally, severe depletion resulted in decreased total IRS-2, indicating possible degradation of the protein. Decreased phosphorylation of AKT and expression of the kinase glycogen synthase kinase-3 alpha (GSK3-α) was also measured in the striatum of severely DA depleted animals. Finally, expression of heat shock protein 25 (hsp25), which is protective against oxidative damage and can decrease stress kinase activity, was decreased in the striatum of lesioned rats. Together, these results support the hypothesis that nigrostriatal DA depletion impairs insulin signaling in the basal ganglia.

Neurodegeneration in an animal model of Parkinson's disease is exacerbated by a high-fat diet

“…Three days prior to surgery, animals were administered an intraperitoneal glucose tolerance test (IPGTT), as described previously (39). Animals were fasted overnight (ϳ12 h), at which time they were anesthetized with Nembutal (50 mg/ml) at 1 ml/kg body wt.…”

“…Five weeks after beginning the diet, all animals received a unilateral 6-OHDA lesion in the medial forebrain bundle. This procedure was modified from previous studies published by our laboratory (39). Anesthesia was induced with 5% isoflurane.…”

“…Tail blood was harvested for fasting blood glucose and insulin measurements at the end of the experiment. Glucose measurements were made using a glucometer, while serum samples were collected as previously described (39) and analyzed using a rat insulin ELISA (Alpco). Serum samples were also analyzed for total cholesterol levels using a Cholesterol E kit (Wako Diagnostics) and low-density lipoprotein cholesterol (LDL-C) levels using an L-type LDL-C kit (Wako Diagnostics).…”

The Gut Microflora and its Metabolites Regulate the Molecular Crosstalk between Diabetes and Neurodegeneration

“…In the 6-OHDA model of PD in rats, there is severe striatal dopamine depletion manifesting in PD symptoms. In this model, there is a strong depletion of IRS coupled with increased inhibitory phosphorylation of the remaining receptors [112]. Also, silencing of PINK1 and Parkin, two key loss-of-function mutations in familial PD, increases the phosphorylation levels of the IGF-1 receptor impacting the downstream Akt and GSK3β signaling and aggravating PD pathology [113].…”

Moieties in antidiabetic drugs as a target of insulin receptors in association with common neurological disorders

“…Reduction in the clearance of Aβ in brain regions is possibly due to the action of insulin, for the fact that the two share a common and depurative mechanism: The insulin-degrading enzyme (IDE). IDE is more selective for insulin than for Aβ, hence, brain hyperinsulinism may exclude Aβproof from its principal clearance mechanism (26).…”