Dynamics of Cerebral Tissue Injury and Perfusion After Temporary Hypoxia-Ischemia in the Rat

Transient occlusion of the middle cerebral artery (MCAO) in rats leads to abnormal accumulation of b-amyloid (Ab) peptides in the thalamus. This study investigated the chemical composition of these deposits. Adult male human b-amyloid precursor protein (APP) overexpressing (hAPP695) rats and their wild-type littermates were subjected to transient MCAO for 2 h or sham operation. After 26-week survival time, histological examination revealed an overlapping distribution pattern for rodent and human Ab in the thalamus of hAPP695 rats subjected to MCAO. X-ray microanalysis showed that the deposits did not contain significant amount of iron, zinc, or copper typical to senile plaques. In contrast, the deposit both in hAPP695 and non-transgenic rats contained calcium and phosphorus in a ratio (1.2860.15) characteristic to hydroxyapatites. Alizarin red staining confirmed that calcium coaccumulated in these Ab deposits. It is suggested that APP expression is induced by ischemic insult in cortical neurons adjacent to infarct, which in turn is reflected as increased release of Ab peptides by their corticothalamic axon endings. This together with insufficient clearance or atypical degradation of Ab peptides lead to dysregulation of calcium homeostatis and coaccumulation in the thalamus.

Section: Discussionmentioning

confidence: 99%

Coaccumulation of Calcium and β-Amyloid in the Thalamus after Transient Middle Cerebral Artery Occlusion in Rats

Mäkinen¹,

Groen

Clarke

et al. 2007

“…10,37,40,41 Twenty-minute occlusion resulted in isolated SNL in two studies, 11,42 whereas a third reported infarction but histological assessment used silver impregnation only. 43 Finally, all studies assessing p15-minute occlusions reported isolated SNL, 10,11,35,37,40 except in Zhan et al 38 where microinfarcts with as short as 5-minute tMCAo were reported; however, their definition for 'microinfarct' in fact probably refers to patchy SNL. 15 Importantly, the severity of striatal SNL clearly increases with longer occlusion times, from B5% up to B20% between 10-and 20-minute MCAo.…”

Section: Animal Modelsmentioning

confidence: 99%

Selective Neuronal Loss in Ischemic Stroke and Cerebrovascular Disease

Baron

Yamauchi

Fujioka

et al. 2013

207

208

As a sequel of brain ischemia, selective neuronal loss (SNL)-as opposed to pannecrosis (i.e. infarction)-is attracting growing interest, particularly because it is now detectable in vivo. In acute stroke, SNL may affect the salvaged penumbra and hamper functional recovery following reperfusion. Rodent occlusion models can generate SNL predominantly in the striatum or cortex, showing that it can affect behavior for weeks despite normal magnetic resonance imaging. In humans, SNL in the salvaged penumbra has been documented in vivo mainly using positron emission tomography and 11 C-flumazenil, a neuronal tracer validated against immunohistochemistry in rodent stroke models. Cortical SNL has also been documented using this approach in chronic carotid disease in association with misery perfusion and behavioral deficits, suggesting that it can result from chronic or unstable hemodynamic compromise. Given these consequences, SNL may constitute a novel therapeutic target. Selective neuronal loss may also develop at sites remote from infarcts, representing secondary 'exofocal' phenomena akin to degeneration, potentially related to poststroke behavioral or mood impairments again amenable to therapy. Further work should aim to better characterize the time course, behavioral consequences-including the impact on neurological recovery and contribution to vascular cognitive impairment-association with possible causal processes such as microglial activation, and preventability of SNL.

“…Even though T 1 -w and T 2 -w MRI have been shown to closely reflect the extent of irreversibly damaged tissue in the past, there is evidence that this correlation will not always hold in certain brain regions and at later time points (Knight et al, 1994;Neumann-Haefelin et al, 2000). Paramagnetic properties of inflammatory cells or blood degradation products, as well as regionspecific changes in water content and breakdown of macromolecular structures with influence on relaxation times, have been discussed as possible reasons for this phenomenon (Dijkhuizen et al, 1998;Lin et al, 2002a). Our own analysis showed a time-dependent accumulation of iron-containing macrophages in the region around leaky blood vessels, which led to selective T 2 * sensitivity without any influence on either T 1 or T 2 detectable at 10 weeks after MCAO (Hoehn et al, 2004;Weber et al, 2005).…”

Section: Lesion Developmentmentioning

confidence: 99%

Temporal profile of T₂-Weighted MRI Distinguishes between Pannecrosis and Selective Neuronal Death after Transient Focal Cerebral Ischemia in the Rat

Wegener

Weber

Ramos‐Cabrer

et al. 2005

Transient middle cerebral artery occlusion (MCAO) by an intraluminal thread leads to primarily subcortical infarctions with little sensorimotor impairment in the Wistar rat strain. We investigated the course of infarct development in this lesion type for 10 weeks using magnetic resonance imaging (MRI) along with histological characterization. MCAO was induced in male Wistar rats (260 to 300 g) for 60 mins. Animals received follow-up T 1 -and T 2 -weighted MRI from day 1 until week 10. Separate groups of animals were analyzed histologically after 2, 6, and 10 weeks. Histology included immunohistochemistry for neuronal and astrocytic markers as well as hematoxylin eosin and luxol fast blue-cresyl violet staining. In contrast to lesions involving the cortex, exclusively subcortical infarctions were characterized by a complete resolution of initially increased T 1 and T 2 relaxation times by 10 weeks. Between 2 and 10 weeks, neuronal death and gliosis as well as a dense inflammatory infiltrate were evident in these lesions, without damage to fiber tracts or development of cystic cavities. Exclusively subcortical lesions in Wistar rats are characterized by normalization of T 1 and T 2 relaxation times, which might, however, not be mistaken for tissue recovery. Despite this MRI normalization, selective neuronal death and gliosis develop. Although MRI at individual time points might therefore be ambiguous, the temporal profile of relaxation time changes over the chronic time period allows discrimination of the lesion development into selective neuronal death or pannecrosis.