Biology subjects

Westbrook, R. F.

Publications and source records attributed to Westbrook, R. F..

2 recordsLinked to original sources

bioRxiv2020

The selective estrogen receptor modulator tamoxifen protects against subtle cognitive decline and early markers of injury twenty-four hours after hippocampal silent infarct

Silent infarcts (SI) are subcortical cerebral infarcts that occur in the absence of typical symptoms associated with ischemia but are linked to cognitive decline and the development of dementia. There are no approved treatments for SI, but one potential treatment is tamoxifen, a selective estrogen receptor modulator. While SI can have long-term consequences, it is critical to establish whether treatments are able to selectively target its early consequences, to avoid progression to complete injury. We induced SI in the dorsal hippocampal CA1 of rats and assessed whether tamoxifen is protective 24 hours later against cognitive deficits and injury responses to SI including gliosis, apoptosis, inflammation and changes in estrogen receptors (ERs). Hippocampal SI led to subtle cognitive impairment on the object place recognition task, an effect ameliorated by tamoxifen administration. SI did not lead to detectable hippocampal cell loss but did increase apoptosis, astrogliosis, microgliosis and inflammation. Tamoxifen protected against the effects of SI on all measures except microgliosis. SI also increased ER and decreased ER{beta} in the hippocampus, which was again mitigated by tamoxifen. Exploratory data analyses using scatterplot matrices and principal component analysis indicated that the SI rats given tamoxifen were indistinguishable from sham controls. Further, SI rats were significantly different from all other groups, an effect produced by low levels of ER and increased apoptosis, gliosis, inflammation, ER{beta}, and time spent with the unmoved object. The results demonstrate that tamoxifen is protective against the early cellular and cognitive consequences of hippocampal SI as early as 24 hours after injury. This effect is driven by mitigation of apoptosis, gliosis, and inflammation and normalization of ER levels in the CA1, leading to improved cognitive outcomes after hippocampal SI.

neuroscience↗

bioRxiv2020

Hippocampal silent infarct leads to subtle cognitive decline that is associated with inflammation and gliosis at twenty-four hours after injury in a rat model

Silent infarcts (SI) are subcortical cerebral infarcts that occur in the absence of clinical symptoms commonly associated with ischemia and are linked to dementia development. Little is known about the pathophysiology underlying the cognitive dysfunction associated with SI, and few studies have examined the early cellular responses and neurobiological underpinnings. We induced SI in adult male Sprague-Dawley rats using an infusion of endothelin-1 in the CA1 dorsal hippocampus. Twenty-four hours later, we assessed cognition using the hippocampal-dependent object place recognition task. We also examined whether the resulting cognitive effects were associated with common markers of ischemia, specifically cell and synapse loss, gliosis, and inflammation, using histology and immunohistochemistry. Hippocampal SI led to subtle cognitive impairment on the object place recognition task 24-hours post-injury. This was characterized by a significant difference in exploration proportion relative to a pre-injury baseline and a positive association between time spent with both the moved and unmoved objects. SI did not result in any detectable cell or synaptophysin loss, but did increase apoptosis, gliosis and inflammation in the CA1. Principal component analysis indicated the main variables associated with hippocampal SI included increased time spent with the unmoved object, gliosis, apoptosis and inflammation as well as decreased exploration proportion and CA1 cells. Our data demonstrate that hippocampal SI can lead to cognitive dysfunction 24-hours after injury. Further, this appears to be driven by early degenerative processes including apoptosis, gliosis and inflammation, suggesting that these may be targets for early interventions treating hippocampal SI and its cognitive consequences.

neuroscience↗