Iron dysregulation in vascular dementia: Focused on the AMPK/autophagy pathway.

Recent researches suggested that iron dysregulation play an important role in the pathogenesis of vascular dementia (VD). Iron deposition had been found in hippocampus in vascular dementia model in recent research. Nevertheless, the underlying mechanisms of iron deposition and its neurotoxicity in vascular dementia was still unclear. Thus, our research was aimed at whether the neurotoxicity of iron was associated with autophagy regulation. We established a chronic cerebral hypoperfusion model in the rat brain in order to mimic the vascular dementia using permanent bilateral common carotid artery occlusion (2VO). The preparation of iron overloaded rats model by intraperitoneal injection of iron dextran. Following, we tested the learning and memory function of each group using Morris Water Maze. Consequently, we analyzed the iron content and iron transport related molecules (TFR1, DMT1) in hippocampus. Furthermore, we examined the effect of iron deposition on autophagy-related molecules including AMPK, Beclin1 and LC3 and the number of autophagosomes in hippocampus. Last, we tested the apoptosis of neurons in hippocampus. We found that iron deposition in hippocampus in model groups which accompanied the decline of learning and memory function. And the expression of TFR1 and DMT1 were up-regulated in model groups. Moreover, iron deposition up-regulated the expression of AMPK, Beclin1 and LC3 and increase the number of autophagosomes in hippocampus. And the expression of Bax was up-regulated and Bcl-2 was down-regulated in iron deposition groups. To sum up, our data suggested that iron deposition increased AMPK/autophagy pathway associated molecules in the hippocampus and promoted neuronal apoptosis, which might be a new pathogenesis in vascular dementia.

Ischemia-induced depolarizations and associated hemodynamic responses in incomplete global forebrain ischemia in rats.

Spontaneous depolarizations around the core are a consistent feature of focal cerebral ischemia, but the associated regional hemodynamic changes are heterogeneous. We determined how the features of depolarizations relate to subsequent cerebral blood flow (CBF) changes in global forebrain ischemia. Forebrain ischemia was produced in halothane-anesthetized rats (n=13) by common carotid artery occlusion and hypovolemic hypotension. Mean arterial blood pressure (MABP) was monitored via a femoral catheter. Specific illuminations allowed the capture of image sequences through a cranial window to visualize: changes in membrane potential (voltage-sensitive dye method); CBF (laser speckle contrast imaging); cerebral blood volume (intrinsic optical signal, IOS at 540-550nm); and hemoglobin deoxygenation (IOS at 620-640nm). A depolarization occurred (n=9) when CBF fell below 43.4±5% of control (41±4mmHg MABP), and propagated with a distinct wave front at a rate of 2.8mm/min. Depolarizations were either persistent (n=4), intermediate (n=3) or short, transient depolarization (n=2). Persistent and intermediate depolarizations were associated with sustained hypoperfusion (-11.7±5.1%) and transient hypoperfusion (-17.4±5.2, relative to CBF before depolarization). Short, transient depolarizations did not generate clear CBF responses. Depolarizations during incomplete global ischemia occurred at the lower limit of CBF autoregulation, propagated similar to spreading depolarization (SD), and the hemodynamic responses indicated inverse neurovascular coupling. Similar to SDs associated with focal stroke, the propagating event can be persistent or transient.

High dose infusion of activated protein C (rhAPC) fails to improve neuronal damage and cognitive deficit after global cerebral ischemia in rats.

PURPOSE: Recent studies demonstrated anticoagulatory, antiinflammatory, antiapoptotic, and neuroprotective properties of activated protein C (APC) in rodent models of acute neurodegenerative diseases, suggesting APC as promising broad acting therapeutic agent. Unfortunately, continuous infusion of recombinant human APC (rhAPC) failed to improve brain damage following cardiac arrest in rats. The present study was designed to investigate the neuroprotective effect after global cerebral ischemia (GI) with an optimized infusion protocol. METHODS: Rats were subjected to bilateral clip occlusion of the common carotid arteries (BCAO) and controlled hemorrhagic hypotension to 40 mm Hg for 14 min and a subsequent 5h-infusion of rhAPC (2mg/kg bolus+6 mg/kg/h continuous IV) or vehicle (0.9% NaCl). The dosage was calculated to maintain plasma hAPC activity at 150%. Cerebral inflammation, apoptosis and neuronal survival was determined at day 10. RESULTS: rhAPC infusion did not influence cortical cerebral perfusion during reperfusion and failed to reduce neuronal cell loss, microglia activation, and caspase 3 activity. CONCLUSION: Even an optimized rhAPC infusion protocol designed to maintain a high level of APC plasma activity failed to improve the sequels following GI. Despite positive reports about protective effects of APC following, e.g., ischemic stroke, the present study supports the notion that infusion of APC during the early reperfusion phase does not result in sustained neuroprotection and fails to improve outcome after global cerebral ischemia.

Oclusión dental: ¿doctrina mecanicista o lógica morfofisiológica? / Dental occlusion: mechanistic doctrine or morphophysiological logical?

Las escuelas de oclusión han creado un constructo mecanicista que busca explicar, bajo un modelo reduccionista y determinista, una dinámica cráneo-cervical y estomatognática compleja. Estos modelos de oclusión le dedican más importancia a la morfología dental y sus geometrías interpretativas que a la morfofisiología estomatognática. La configuración musculo-esquelética cráneo-cervical tiene el poder ganado de influir concomitantemente en la ubicación espacial de la mandíbula e implícitamente en las relaciones interoclusales. La visión actual de la oclusión sigue basándose en observaciones empíricas de un siglo de antigüedad que carecen de soporte apropiado en el marco del nivel de evidencia. En la dimensión funcional los modelos de oclusión conservan los mismos vacíos que existían desde su estructuración en el siglo pasado, particularmente en sus representaciones espaciales estáticas, uniáxicas y anti-dinámicas que desestiman la individualidad de cada sujeto. Cada especialidad puede tener tantas razones como puntos de vista diferentes de "maloclusión" así como formas de tratarla.

Occlusion schools have created a mechanistic construct that seeks to explain, under a reductionist and deterministic model, a craneal-cervical and stomatognathic complex dynamic. These occlusion models dedicate more importance to dental morphology and its interpretative geometries than a stomatognathic morphophysiology. Craneocervical musculoskeletal configuration has the gained power to concomitantly influence the jaw location in the space and implicitly in the interocclusal relations. The current vision of the occlusion is based on empirical observations of almost a century that lack support in the level of evidence framework. In the functional dimension occlusion models maintain the same gaps that existed from its origins since the last century, particularly in its static, uniaxic and anti-dynamic spatial representations that dismiss the individuality of each subject. Each specialty can have as many reasons as different points of view about "malocclusion" as well as techniques to treat it.