White Matter Injury After Intracerebral Hemorrhage

Spontaneous intracerebral hemorrhage (ICH) accounts for 15% of all stroke cases. ICH is a devastating form of stroke associated with high morbidity, mortality, and disability. Preclinical studies have explored the mechanisms of neuronal death and gray matter damage after ICH. However, few studies have examined the development of white matter injury (WMI) following ICH. Research on WMI indicates that its pathophysiological presentation involves axonal damage, demyelination, and mature oligodendrocyte loss. However, the detailed relationship and mechanism between WMI and ICH remain unclear. Studies of other acute brain insults have indicated that WMI is strongly correlated with cognitive deficits, neurological deficits, and depression. The degree of WMI determines the short- and long-term prognosis of patients with ICH. This review demonstrates the structure and functions of the white matter in the healthy brain and discusses the pathophysiological mechanism of WMI following ICH. Our review reveals that the development of WMI after ICH is complex; therefore, comprehensive treatment is essential. Understanding the relationship between WMI and other brain cells may reveal therapeutic targets for the treatment of ICH

Choroid plexus immune cell response in murine hydrocephalus induced by intraventricular hemorrhage

Abstract Background Intraventricular hemorrhage (IVH) and associated hydrocephalus are significant complications of intracerebral and subarachnoid hemorrhage. Despite proximity to IVH, the immune cell response at the choroid plexus (ChP) has been relatively understudied. This study employs CX3CR-1GFP mice, which marks multiple immune cell populations, and immunohistochemistry to outline that response. Methods This study had four parts all examining male adult CX3CR-1GFP mice. Part 1 examined naïve mice. In part 2, mice received an injection 30 µl of autologous blood into right ventricle and were euthanized at 24 h. In part 3, mice underwent intraventricular injection of saline, iron or peroxiredoxin 2 (Prx-2) and were euthanized at 24 h. In part 4, mice received intraventricular iron injection and were treated with either control or clodronate liposomes and were euthanized at 24 h. All mice underwent magnetic resonance imaging to quantify ventricular volume. The ChP immune cell response was examined by combining analysis of GFP(+) immune cells and immunofluorescence staining. Results IVH and intraventricular iron or Prx-2 injection in CX3CR-1GFP mice all induced ventriculomegaly and activation of ChP immune cells. There were very marked increases in the numbers of ChP epiplexus macrophages, T lymphocytes and neutrophils. Co-injection of clodronate liposomes with iron reduced the ventriculomegaly which was associated with fewer epiplexus and stromal macrophages but not reduced T lymphocytes and neutrophils. Conclusion There is a marked immune cell response at the ChP in IVH involving epiplexus cells, T lymphocytes and neutrophils. The blood components iron and Prx-2 may play a role in eliciting that response. Reduction of ChP macrophages with clodronate liposomes reduced iron-induced ventriculomegaly suggesting that ChP macrophages may be a promising therapeutic target for managing IVH-induced hydrocephalus

Formation of Multinucleated Giant Cells after Experimental Intracerebral Hemorrhage: Characteristics and Role of Complement C3

Hematoma clearance is critical for mitigating intracerebral hemorrhage (ICH)-induced brain injury. Multinucleated giant cells (MGCs), a type of phagocyte, and the complement system may play a pivotal role in hematoma resolution, but whether the complement system regulates MGC formation after ICH remains unclear. The current study investigated the following: (1) the characteristics of MGC formation after ICH, (2) whether it was impacted by complement C3 deficiency in mice and (3) whether it also influenced hematoma degradation (hemosiderin formation). Young and aged male mice, young female mice and C3-deficient and -sufficient mice received a 30 μL injection of autologous whole blood into the right basal ganglia. Brain histology and immunohistochemistry were used to examine MGC formation on days 3 and 7. Hemosiderin deposition was examined by autofluorescence on day 28. Following ICH, MGCs were predominantly located in the peri-hematoma region exhibiting multiple nuclei and containing red blood cells or their metabolites. Aging was associated with a decrease in MGC formation after ICH, while sex showed no discernible effect. C3 deficiency reduced MGC formation and reduced hemosiderin formation. Peri-hematomal MGCs may play an important role in hematoma resolution. Understanding how aging and complement C3 impact MGCs may provide important insights into how to regulate hematoma resolution

Additional file 1 of Choroid plexus immune cell response in murine hydrocephalus induced by intraventricular hemorrhage

Supplementary Material

Activation of Nurr1 with Amodiaquine Protected Neuron and Alleviated Neuroinflammation after Subarachnoid Hemorrhage in Rats

Background. Nurr1, a member of the nuclear receptor 4A family (NR4A), played a role in neuron protection, anti-inflammation, and antioxidative stress in multidiseases. We explored the role of Nurr1 on subarachnoid hemorrhage (SAH) progression and investigated the feasibility of its agonist (amodiaquine, AQ) as a treatment for SAH. Methods. SAH rat models were constructed by the endovascular perforation technique. AQ was administered intraperitoneally at 2 hours after SAH induction. SAH grade, mortality, weight loss, neurological performance tests, brain water content, western blot, immunofluorescence, Nissl staining, and qPCR were assessed post-SAH. In vitro, hemin was introduced into HT22 cells to develop a model of SAH. Results. Stimulation of Nurr1 with AQ improved the outcomes and attenuated brain edema. Nurr1 was mainly expressed in neuron, and administration of AQ alleviated neuron injury in vivo and enhanced the neuron viability and inhibited neuron apoptosis and necrosis in vitro. Besides, AQ reduced the amount of IL-1β+Iba-1+ cells and inhibited the mRNA level of proinflammatory cytokines (IL-1β and TNF-α) and the M1-like phenotype markers (CD68 and CD86). AQ inhibited the expression of MMP9 in HT22 cells. Furthermore, AQ reduced the expression of nuclear NF-κB and Nurr1 while increased cytoplasmic Nurr1 in vivo and in vitro. Conclusion. Pharmacological activation of Nurr1 with AQ alleviated the neuron injury and neuroinflammation. The mechanism of antineuroinflammation may be associated with the Nurr1/NF-κB/MMP9 pathway in the neuron. The data supported that AQ might be a promising treatment strategy for SAH

Bis(2-ethylhexyl)-tetrabromophthalate Poses a Higher Exposure Risk and Induces Gender-Specific Metabolic Disruptions in Zebrafish Liver

Bis(2-ethylhexyl)-tetrabromophthalate (TBPH), a typical novel brominated flame retardant, has been ubiquitously identified in various environmental and biotic media. Consequently, there is an urgent need for precise risk assessment based on a comprehensive understanding of internal exposure and the corresponding toxic effects on specific tissues. In this study, we first investigated the toxicokinetic characteristics of TBPH in different tissues using the classical pseudo-first-order toxicokinetic model. We found that TBPH was prone to accumulate in the liver rather than in the gonad, brain, and muscle of both female and male zebrafish, highlighting a higher internal exposure risk for the liver. Furthermore, long-term exposure to TBPH at environmentally relevant concentrations led to increased visceral fat accumulation, signaling potential abnormal liver function. Hepatic transcriptome analysis predominantly implicated glycolipid metabolism pathways. However, alterations in the profile of associated genes and biochemical indicators revealed gender-specific responses following TBPH exposure. Besides, histopathological observations as well as the inflammatory response in the liver confirmed the development of nonalcoholic fatty liver disease, particularly in male zebrafish. Altogether, our findings highlight a higher internal exposure risk for the liver, enhancing our understanding of the gender-specific metabolic-disrupting potential associated with TBPH exposure

Image_1_Role of complement C1q/C3-CR3 signaling in brain injury after experimental intracerebral hemorrhage and the effect of minocycline treatment.tif

AimThe complement cascade is activated and may play an important pathophysiologic role in brain injury after experimental intracerebral hemorrhage (ICH). However, the exact mechanism of specific complement components has not been well studied. This study determined the role of complement C1q/C3-CR3 signaling in brain injury after ICH in mice. The effect of minocycline on C1q/C3-CR3 signaling-induced brain damage was also examined.MethodsThere were three parts to the study. First, the natural time course of C1q and CR3 expression was determined within 7 days after ICH. Second, mice had an ICH with CR3 agonists, LA-1 or vehicle. Behavioral score, neuronal cell death, hematoma volume, and oxidative stress response were assessed at 7 days after ICH. Third, the effect of minocycline on C1q/C3-CR3 signaling and brain damage was examined.ResultsThere were increased numbers of C1q-positive and CR3-positive cells after ICH. Almost all perihematomal C1q-positive and CR3-positive cells were microglia/macrophages. CR3 agonist LA-1 aggravated neurological dysfunction, neuronal cell death, and oxidative stress response on day 7 after ICH, as well as enhancing the expression of the CD163/HO-1 pathway and accelerating hematoma resolution. Minocycline treatment exerted neuroprotective effects on brain injury following ICH, partly due to the inhibition of C1q/C3-CR3 signaling, and that could be reversed by LA-1.ConclusionsThe complement C1q/C3-CR3 signaling is upregulated after ICH. The activation of C1q/C3-CR3 signaling by LA-1 aggravates brain injury following ICH. The neuroprotection of minocycline, at least partly, is involved with the repression of the C1q/C3-CR3 signaling pathway.</p

Image_3_Role of complement C1q/C3-CR3 signaling in brain injury after experimental intracerebral hemorrhage and the effect of minocycline treatment.tif

AimThe complement cascade is activated and may play an important pathophysiologic role in brain injury after experimental intracerebral hemorrhage (ICH). However, the exact mechanism of specific complement components has not been well studied. This study determined the role of complement C1q/C3-CR3 signaling in brain injury after ICH in mice. The effect of minocycline on C1q/C3-CR3 signaling-induced brain damage was also examined.MethodsThere were three parts to the study. First, the natural time course of C1q and CR3 expression was determined within 7 days after ICH. Second, mice had an ICH with CR3 agonists, LA-1 or vehicle. Behavioral score, neuronal cell death, hematoma volume, and oxidative stress response were assessed at 7 days after ICH. Third, the effect of minocycline on C1q/C3-CR3 signaling and brain damage was examined.ResultsThere were increased numbers of C1q-positive and CR3-positive cells after ICH. Almost all perihematomal C1q-positive and CR3-positive cells were microglia/macrophages. CR3 agonist LA-1 aggravated neurological dysfunction, neuronal cell death, and oxidative stress response on day 7 after ICH, as well as enhancing the expression of the CD163/HO-1 pathway and accelerating hematoma resolution. Minocycline treatment exerted neuroprotective effects on brain injury following ICH, partly due to the inhibition of C1q/C3-CR3 signaling, and that could be reversed by LA-1.ConclusionsThe complement C1q/C3-CR3 signaling is upregulated after ICH. The activation of C1q/C3-CR3 signaling by LA-1 aggravates brain injury following ICH. The neuroprotection of minocycline, at least partly, is involved with the repression of the C1q/C3-CR3 signaling pathway.</p

Image_2_Role of complement C1q/C3-CR3 signaling in brain injury after experimental intracerebral hemorrhage and the effect of minocycline treatment.tif

AimThe complement cascade is activated and may play an important pathophysiologic role in brain injury after experimental intracerebral hemorrhage (ICH). However, the exact mechanism of specific complement components has not been well studied. This study determined the role of complement C1q/C3-CR3 signaling in brain injury after ICH in mice. The effect of minocycline on C1q/C3-CR3 signaling-induced brain damage was also examined.MethodsThere were three parts to the study. First, the natural time course of C1q and CR3 expression was determined within 7 days after ICH. Second, mice had an ICH with CR3 agonists, LA-1 or vehicle. Behavioral score, neuronal cell death, hematoma volume, and oxidative stress response were assessed at 7 days after ICH. Third, the effect of minocycline on C1q/C3-CR3 signaling and brain damage was examined.ResultsThere were increased numbers of C1q-positive and CR3-positive cells after ICH. Almost all perihematomal C1q-positive and CR3-positive cells were microglia/macrophages. CR3 agonist LA-1 aggravated neurological dysfunction, neuronal cell death, and oxidative stress response on day 7 after ICH, as well as enhancing the expression of the CD163/HO-1 pathway and accelerating hematoma resolution. Minocycline treatment exerted neuroprotective effects on brain injury following ICH, partly due to the inhibition of C1q/C3-CR3 signaling, and that could be reversed by LA-1.ConclusionsThe complement C1q/C3-CR3 signaling is upregulated after ICH. The activation of C1q/C3-CR3 signaling by LA-1 aggravates brain injury following ICH. The neuroprotection of minocycline, at least partly, is involved with the repression of the C1q/C3-CR3 signaling pathway.</p