Diisopropylfluorophosphate-induced status epilepticus drives complex glial cell phenotypes in adult male mice.

Organophosphate pesticides and nerve agents (OPs), are characterized by cholinesterase inhibition. In addition to severe peripheral symptoms, high doses of OPs can lead to seizures and status epilepticus (SE). Long lasting seizure activity and subsequent neurodegeneration promote neuroinflammation leading to profound pathological alterations of the brain. The aim of this study was to characterize neuroinflammatory responses at key time points after SE induced by the OP, diisopropylfluorophosphate (DFP). Immunohistochemistry (IHC) analysis and RT-qPCR on cerebral tissue are often insufficient to identity and quantify precise neuroinflammatory alterations. To address these needs, we performed RT-qPCR quantification after whole brain magnetic-activated cell-sorting (MACS) of CD11B (microglia/infiltrated macrophages) and GLAST (astrocytes)-positive cells at 1, 4, 24 h and 3 days post-SE. In order to compare these results to those obtained by IHC, we performed, classical Iba1 (microglia/infiltrated macrophages) and GFAP (astrocytes) IHC analysis in parallel, focusing on the hippocampus, a brain region affected by seizure activity and neurodegeneration. Shortly after SE (1-4 h), an increase in pro-inflammatory (M1-like) markers and A2-specific markers, proposed as neurotrophic, were observed in CD11B and GLAST-positive isolated cells, respectively. Microglial cells successively expressed immuno-regulatory (M2b-like) and anti-inflammatory (M2a-like) at 4 h and 24 h post-SE induction. At 24 h and 3 days, A1-specific markers, proposed as neurotoxic, were increased in isolated astrocytes. Although IHC analysis presented no modification in terms of percentage of marked area and cell number at 1 and 4 h after SE, at 24 h and 3 days after SE, microglial and astrocytic activation was visible by IHC as an increase in Iba1 and GFAP-positive area and Iba1-positive cells in DFP animals when compared to the control. Our work identified sequential microglial and astrocytic phenotype activation. Although the role of each phenotype in SE cerebral outcomes requires further study, targeting specific markers at specific time point could be a beneficial strategy for DFP-induced SE treatment.

Imaging Cerebral Arteries Tortuosity and Velocities by Transcranial Doppler Ultrasound Is a Reliable Assessment of Brain Aneurysm in Mouse Models.

Background: During the past few decades, several pathophysiological processes contributing to intracranial aneurysm (IA) rupture have been identified, including irregular IA shape, altered hemodynamic stress within the IA, and vessel wall inflammation. The use of preclinical models of IA and imaging tools is paramount to better understand the underlying disease mechanisms. Methods: We used 2 established mouse models of IA, and we analyzed the progression of the IA by magnetic resonance imaging, transcranial Doppler, and histology. Results: In both models of IA, we observed, by transcranial Doppler, a significant decrease of the blood velocities and wall shear stress of the internal carotid arteries. We also observed the formation of tortuous arteries in both models that were correlated with the presence of an aneurysm as confirmed by magnetic resonance imaging and histology. A high grade of tortuosity is associated with a significant decrease of the mean blood flow velocities and a greater artery dilation. Conclusions: Transcranial Doppler is a robust and convenient imaging method to evaluate the progression of IA. Detection of decreased blood flow velocities and increased tortuosity can be used as reliable indicators of IA.

Imaging Modalities for Intracranial Aneurysm: More Than Meets the Eye.

Intracranial aneurysms (IA) are often asymptomatic and have a prevalence of 3 to 5% in the adult population. The risk of IA rupture is low, however when it occurs half of the patients dies from subarachnoid hemorrhage (SAH). To avoid this fatal evolution, the main treatment is an invasive surgical procedure, which is considered to be at high risk of rupture. This risk score of IA rupture is evaluated mainly according to its size and location. Therefore, angiography and anatomic imaging of the intracranial aneurysm are crucial for its diagnosis. Moreover, it has become obvious in recent years that several other factors are implied in this complication, such as the blood flow complexity or inflammation. These recent findings lead to the development of new IA imaging tools such as vessel wall imaging, 4D-MRI, or molecular MRI to visualize inflammation at the site of IA in human and animal models. In this review, we will summarize IA imaging techniques used for the patients and those currently in development.