Molecular Alterations in the Hippocampus after Experimental Subarachnoid Hemorrhage

Abstract

Patients with aneurysmal subarachnoid hemorrhage (SAH) frequently have deficits in learning and memory that may or may not be associated with detectable brain lesions. We examined mediators of long-term potentiation after SAH in rats to determine what processes might be involved. There was a reduction in synapses in the dendritic layer of the CA1 region on transmission electron microscopy as well as reduced colocalization of microtubule-associated protein 2 (MAP2) and synaptophysin. Immunohistochemistry showed reduced staining for GluR1 and calmodulin kinase 2 and increased staining for GluR2. Myelin basic protein staining was decreased as well. There was no detectable neuronal injury by Fluoro-Jade B, TUNEL, or activated caspase-3 staining. Vasospasm of the large arteries of the circle of Willis was mild to moderate in severity. Nitric oxide was increased and superoxide anion radical was decreased in hippocampal tissue. Cerebral blood flow, measured by magnetic resonance imaging, and cerebral glucose metabolism, measured by positron emission tomography, were no different in SAH compared with control groups. The results suggest that the etiology of loss of LTP after SAH is not cerebral ischemia but may be mediated by effects of subarachnoid blood such as oxidative stress and inflammation.

Endovascular Perforation Subarachnoid Hemorrhage Fails to Cause Morris Water Maze Deficits in the Mouse

“…Nonetheless, it is possible that despite not affecting the number of surviving hippocampal neurons, SAH could have had more subtle molecular effects. 31,32 This possibility is distinctly unlikely given the absence of MWM deficits (an assessment critically dependent on hippocampal function) documented herein. Finally, SAHrelated morality remained at 18% despite significant post-SAH support.…”

“…Following cisterna magna injection of oxyhemoglobin, Huang et al 37 documented TUNEL-positive neuronal cell death in the cortex at 24 and 72 hours, but did not specify what area of the cortex was assessed and provided no quantification. Given the paucity of data regarding the extent and especially the location of neuronal cell injury-particularly in CA1, the brain region most implicated in MWM deficits in rat SAH 15,31,32 and rodent TBI 38 -it is difficult to predict whether either of these alternative mouse models might better recapitulate the long-term cognitive deficits seen in SAH patients.…”

“…30 Second, multiple molecular alterations in the hippocampi occur after rat SAH, including loss of synaptic function and long-term potentiation. 31,32 Third, cognitive deficits have been strongly correlated to hippocampal CA1 neuronal cell number after experimental SAH. 15 To be sure, other structural areas may also play a role, including left hemispheric lesions, 33 reductions in total gray and white matter volume 34 (in patients), and cortical neuronal cell loss (in rats).…”

Long-Term Cognitive Deficits After Subarachnoid Hemorrhage in Rats

“…Only recently has this work been extended to examine cognitive deficits [9][10][11][12][13]. Because post-SAH cognitive and memory deficits may persist for months to years in humans [3,14,15], there is need to optimize preclinical modeling to facilitate investigation of putative injury mechanisms and therapeutic interventions.…”

Cerebral Artery Remodeling in Rodent Models of Subarachnoid Hemorrhage

“…This suggests that an injection of blood in vivo does not create persistent vasospasm, which we consider essential to induce remodeling. Although the majority of the literature using the single prechiasmatic blood injection model determined vasospasm by histology [22,46], there is no consistency in the results and some even do not show any vasospasm [47,48]. Second, in animal models, the particular strain that is used may be relevant.…”