Stress-induced premature senescence can contribute to the accelerated metabolic aging process in diabetes. Progressive accumulation of senescent cells in the brain, especially those displaying the harmful inflammatory senescence-associated secretory phenotype (SASP), may lead to cognitive impairment linked with metabolic disturbances. In this context, the senescence within the neurovascular unit (NVU) should be studied as much as in the neurons as emerging evidence shows that neurogliovascular communication is critical for brain health. It is also known that cerebrovascular dysfunction and decreased cerebral blood flow (CBF) precede the occurrence of neuronal pathologies and overt cognitive impairment. Various studies have shown that endothelial cells, the major component of the NVU, acquire a senescent phenotype via various molecular mediators and pathways upon exposure to high glucose and other conditions mimicking metabolic disturbances. In addition, senescence in the other cells that are part of the NVU, like pericytes and vascular smooth cells, was also triggered upon exposure to diabetic conditions. The senescence within the NVU may compromise functional and trophic coupling among glial, vascular, and neuronal cells and the resulting SASP may contribute to the chronic neurovascular inflammation observed in Alzheimer’s Disease and Related Dementias (ADRD). The link between diabetes-mediated cerebral microvascular dysfunction, NVU senescence, inflammation, and cognitive impairment must be widely studied to design therapeutic strategies.
Since 1959, the Russian Farm-Fox study has bred foxes to be either tame or, more recently, aggressive, and scientists have used them to gain insight into the brain structures associated with these behavioral features. In mice, hippocampal area CA2 has emerged as one of the essential regulators of social aggression, and so to eventually determine whether we could identify differences in CA2 between tame and aggressive foxes, we first sought to identify CA2 in foxes (Vulpes vulpes). As no clearly defined area of CA2 has been described in species such as cats, dogs, or pigs, it was not at all clear whether CA2 could be identified in foxes. In this study, we cut sections of temporal lobes from male and female red foxes, perpendicular to the long axis of the hippocampus, and stained them with markers of CA2 pyramidal cells commonly used in tissue from rats and mice. We observed that antibodies against Purkinje cell protein 4 best stained the pyramidal cells in the area spanning the end of the mossy fibers and the beginning of the pyramidal cells lacking mossy fibers, resembling the pattern seen in rats and mice. Our findings indicate that foxes do have a "molecularly defined" CA2, and further, they suggest that other carnivores like dogs and cats might as well. With this being the case, these foxes could be useful in future studies looking at CA2 as it relates to aggression.
Introduction Post‐stroke cognitive impairment (PSCI) contributes to significant long‐term disability in stroke victims. 30% of ischemic stroke victims in the United States also have diabetes, which increases the risk of hemorrhagic transformation as well as PSCI. Ferroptosis, an iron‐induced cell death can instigate increased oxidative stress and contribute to impaired neurovascular repair leading to PSCI in diabetes. In our previous studies, we were able to identify that treating diabetic animals with an iron chelator, deferoxamine (DFX), prevents post‐stroke vasoregression and improves functional outcomes. Furthermore, DFX prevented the activation of ferroptosis in brain microvascular endothelial cells in vitro. Untreated diabetic animals experienced progressive cognitive decline while being monitored for 8 weeks. These findings led us to speculate that endothelial ferroptosis also plays a role in vasoregression and impacts cognitive outcomes post‐stroke. Therefore, this study was designed to test the hypothesis that inhibiting ferroptosis in the post‐stroke period will improve cognitive recovery in diabetic animals. Methods Animals were housed in reverse light cycle. 8 weeks after diabetes onset, male rats underwent 60 min middle cerebral artery occlusion (MCAO). On Day 3, after stroke injury was confirmed by MRI, animals were randomized to UAMC‐3 (2mg/kg) or vehicle treatment for 2 weeks. Sensorimotor and cognitive behavioral tests were performed during the animals’ active hours up to 8 weeks post MCAO. Results (Table 1): 60 min occlusion caused significant acute neurological deficits. There were no differences between the groups in indices measured by novel object recognition (NOR), Y‐maze and sucrose preference tests. Interestingly, step through latency in passive avoidance test (PAT) was lower in the UAMC‐3203 group. Conclusion Treatment with a ferroptosis inhibitor for 2 weeks after stroke did not impact recognition and working memory but worsened aversive learning in diabetic male rats. Unlike our previous study in which behavior tests were performed during rats’ passive hours, there was no progressive cognitive decline in untreated animals. Further evaluation of behavior testing times as well as tissue markers of neurovascular degeneration, inflammation and ferroptosis are required to determine whether molecular and cellular markers are affected by the treatment before overt changes in behavioral outcomes.
Diabetes increases the risk of hemorrhagic transformation as well as post-stroke cognitive impairment (PCSI). We have shown that iron chelation in the subacute phase improves stroke cognitive outcomes in experimental models of diabetes. We hypothesized that inhibition of ferroptosis, iron-induced cell death, in the post-stroke period will prevent PSCI in diabetic animals. Methods: Male rats, housed in reverse light cycle, underwent sham or 60-min middle cerebral artery occlusion surgery 8 weeks after diabetes onset. After MRI, rats that met the preset inclusion criteria (adhesive removal time > 35 sec. and either a modified Bederson score <= 6 or weight loss > 10% on Day 3) were randomized to ferroptosis inhibitor UAMC-3 (2mg/kg) or vehicle treatment for 2 weeks (n=8-12). Sensorimotor and cognitive outcomes were monitored for 8 weeks in the dark (active) cycle. Results: As confirmed by MRI, inclusion criteria predicted successful stroke surgery in 95% of the animals. There were significant acute neurological deficits. Long-term weight gain and survival were better in this cohort as compared to our historical data collected in regular light cycle experiments. Blood glucose levels were comparable. In contrast to our previous data, there were no significant differences in indices measured by novel object recognition (NOR), Y-maze, and sucrose preference tests after stroke but there was a trend for a greater number of animals showing a cognitive decline in treated cohorts. Step-through latency in the passive avoidance test (PAT) was lower in the treated stroke group. Open field (OF) suggested anxiety-like behavior in RX group. Conclusions: Preset inclusion criteria were effective in controlling for stroke severity. Ferroptosis inhibition impaired aversive learning and appeared to worsen cognitive outcomes in some of the animals. Better post-stroke weight gain/maintenance and greater engagement of animals in behavioral tests conducted in the “dark” cycle may explain the lack of a progressive memory decline after stroke. While further studies are required to better understand whether ferroptosis and housing lighting impacts stroke recovery in diabetes, based on current findings, inhibition of ferroptosis with UAMC-3 is not desirable. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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