Deliryum patogenezinde astrositik glikojenin rolü

Background: Delirium is an acute neuropsychiatric syndrome that is very common in hospitalized patients. Also, a delirium episode independently increases the risk of post-discharge mortality and dementia. However, with this high prevalence and deleterious outcomes, the clear pathogenesis of delirium has not been explained yet. Systemic inflammation, hypoglycemia, and sleep deprivation can trigger delirium, among other causes, and the coexistence of multiple risk factors further increases the delirium risk. The brain astrocytic glycogen is a vital lactate donor for neurons under hypoglycemic conditions and glutamatergic excitation. And glycogen is necessary for synaptic plasticity and long-term memory formation. Sleep deprivation decreases the astrocytic glycogen content and is also a risk factor for delirium. Thus, the unavailability of astrocytic glycogen may induce or exacerbate a delirium episode. Aim: In this thesis project, we first aimed to investigate the role of astrocytic glycogen in delirium pathogenesis. Furthermore, we included a glucose treatment group to study if exogenous glucose replacement reverses the adverse effects of inhibition of glycogen degradation. Finally, we followed animals for one month to show if our model leads to late cognitive decline. Methods: Our study included 14 months old 74 male C57 mice. One week before the delirium model induction, an intracerebroventricular cannula was placed. The DAB+LPS group received 2µl of 5.9M DAB one hour before the intraperitoneal LPS (0.33mg/kg) challenge. The controls and LPS-only groups were injected with the same amount of sterile saline. Glucose treatment was done with 2mg/kg D-glucose with LPS injections and another dose after 2.5 hours. Open field, buried food, and Y-maze tests were conducted in the first 24 hours and repeated one month later with a novel object recognition test. Blood glucose, IL-1β, lactate, glucagon, insulin, amyloid β 1-41, and total and phosphorylated TAU levels were measured. Also, PAS staining was conducted to quantify glycogen, GFAP, and Neun immunofluorescence stainings for astrocyte and neuron numbers. Results: The DAB+LPS group show worse behavioral test performance at the first 3-6 hours of delirium model induction than the LPS-only group. And the glucose replacement mitigated the acute worsening due to DAB injection. The blood sugar was significantly lower in LPS treated groups than in controls in all the measurements up to 24 hours. Noteworthy, the solely DAB injection led to hyperglycemia in the 4th hour. The glucose replacement could not resolve but shortened the duration of LPS-induced hypoglycemia. The PAS-positive area was preserved in the DAB-only group. Moreover, not only the PAS-positive area was held, but the hippocampal lactic acid levels were also lower in the glucose treatment group. The plasma IL-1β levels were increased in the LPS-only group at the 24th hour. On the other hand, IL-1β levels were attenuated in all the DAB-received groups in the hippocampal homogenates. Finally, the GFAP expression in astrocytes was upregulated in the hippocampus and glia limitans except for controls. One month later, the DAB+LPS group showed cognitive impairments in memory tests compared to controls but not the LPS only or glucose treatment groups. We did not detect a significant decrease in the number of neurons (the percentage of Neun stained area), but they have a smaller hippocampus and an increased amount of Aβ 1-42 protein. Finally, the GFAP fluorescent intensity was still pronounced in the DAB+LPS group in glia limitans. Conclusion and Comment: This study demonstrated that inhibition of utilization of astrocytic glycogen increased the LPS-induced cognitive impairments in aged mice. One month later, the DAB+LPS group still had a worse cognitive profile than the controls, along with structural changes suggesting neurodegeneration. Glucose treatment reverses the DAB-induced cognition worsening in acute and chronic phases. Thus, the simultaneous presence of an inflammatory insult and glycogen-derived lactate insufficiency may lead to decompensation and permanent damage after a delirium episode.