Disruption of the blood-brain barrier (BBB) and the subsequent formation of brain edema is the most severe consequence of intracerebral hemorrhage (ICH), leading to drastic neuroinflammatory responses and neuronal cell death. A better understanding of ICH pathophysiology to develop effective therapy relies on selecting appropriate animal models. The collagenase injection ICH model and the autologous arterial whole blood infusion ICH model have been developed to investigate the pathophysiology of ICH. However, it remains unclear whether the temporal progression and the underlying mechanism of BBB breakdown are similar between these two ICH models. In this study, we aimed to determine the progression and the mechanism of BBB disruption via the two commonly used murine ICH models: the collagenase-induced ICH model (c-ICH) and the double autologous whole blood ICH model (b-ICH). Intrastriatal injection of 0.05 U collagenase or 20 μL autologous blood was used for a comparable hematoma volume in these two ICH models. Then we analyzed BBB permeability using Evan’s blue and IgG extravasation, evaluated tight junction (TJ) damage by transmission electron microscope (TEM) and Western blotting, and assessed matrix metalloproteinase-9 (MMP-9) activity and aquaporin 4 (AQP4) mRNA expression by Gelatin gel zymography and RT-PCR, respectively. The results showed that the BBB leakage was associated with a decrease in TJ protein expression and an increase in MMP-9 activity and AQP4 expression on day 3 in the c-ICH model compared with that on day 5 in the b-ICH model. Additionally, using TEM, we found that the TJ was markedly damaged on day 3 in the c-ICH model compared with that on day 5 in the b-ICH model. In conclusion, the BBB was disrupted in the two ICH models; compared to the b-ICH model, the c-ICH model presented with a more pronounced disruption of BBB at earlier time points, suggesting that the c-ICH model might be a more suitable model for studying early BBB damage and protection after ICH.

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Post-stroke depression exacerbates neurologic deficits and quality of life. Depression after ischemic stroke is known to some extent. However, depression after intracerebral hemorrhage (ICH) is relatively unknown. Increasing evidence shows that exposure to an enriched environment (EE) after cerebral ischemia/reperfusion injury has neuroprotective effects in animal models, but its impact after ICH is unknown. In this study, we investigated the effect of EE on long-term functional outcomes in mice subjected to collagenase-induced striatal ICH. Mice were subjected to ICH with the standard environment (SE) or ICH with EE for 6 h/day (8:00 am–2:00 pm). Depressive, anxiety-like behaviors and cognitive tests were evaluated on day 28 with the sucrose preference test, tail suspension test, forced swim test, light-dark transition experiment, morris water maze, and novel object recognition test. Exposure to EE improved neurologic function, attenuated depressive and anxiety-like behaviors, and promoted spatial learning and memory. These changes were associated with increased expression of transcription factor Nrf2 and brain-derived neurotrophic factor (BDNF) and inhibited glutaminase activity in the perihematomal tissue. However, EE did not change the above behavioral outcomes in Nrf2−/− mice on day 28. Furthermore, exposure to EE did not increase BDNF expression compared to exposure to SE in Nrf2−/− mice on day 28 after ICH. These findings indicate that EE improves long-term outcomes in sensorimotor, emotional, and cognitive behavior after ICH and that the underlying mechanism involves the Nrf2/BDNF/glutaminase pathway.

Background: Post-stroke depression (PSD) has a negative impact on neurologic outcomes and quality of life. Although depression after ischemic stroke has been studied clinically and preclinically, very little is known about the frequency and severity of depression after intracerebral hemorrhage (ICH). Increasing evidence shows that exposure to an enriched environment (EE) after cerebral ischemia/reperfusion injury has neuroprotective effects in animal models, but its effects after ICH are unknown. Methods: In this study, we investigated the effects of an EE on long-term functional outcome in mice subjected to a collagenase-induced striatal ICH model. Mice were subjected to ICH only or ICH with EE for 6 h/day (8:00 am-2:00 pm). Depressive- and anxiety-like behaviors were evaluated on day 28 with the sucrose preference test, tail suspension test, forced swim test, and light-dark transition experiment. Results: EE exposure reduced brain edema, improved neurologic function, attenuated depressive- and anxiety-like behaviors, promoted spatial learning and memory, increased the expression of transcription factor Nrf2 and brain-derived neurotrophic factor (BDNF), and inhibited glutaminase activity in the ICH brain. However, in Nrf2-/- mice with ICH, EE did not mitigate depression-like behaviors on day 28. Conclusions: These findings indicate that EE improves long-term sensorimotor, emotional, and cognitive-behavior outcomes after ICH and that the underlying mechanism involves the Nrf2/BDNF/glutaminase pathway.