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Cerebrolysin Prevents Brain Injury in a Mouse Model of Liver Damage.

ABSTRACT: Liver damage can lead to secondary organ damage by toxic substances and catabolic products accumulation which can increase the permeability of blood-brain barrier, leading to cognitive impairment. The only real treatment for end stage liver failure is grafting. With some, but not all, neurological symptoms subsiding after transplantation, the presence of brain damage can impair both the short and long-term outcome. We tested if Cerebrolysin can prevent brain injury in an experimental model of non-viral liver damage in mice. Behavior, abdominal ultrasound evaluation and immunohistochemistry were used to evaluate the animals. No ultrasound or behavior differences were found between the control and treated animals, with both groups displaying more anxiety and no short-term memory benefit compared to sham mice. Cerebrolysin treatment was able to maintain a normal level of cortical NeuN+ cells and induced an increase in the area occupied by BrdU+ cells. Surprisingly, no difference was observed when investigating Iba1+ cells. With neurological complications of end-stage liver disease impacting the rehabilitation of patients receiving liver grafts, a neuroprotective treatment of patients on the waiting lists might improve their rehabilitation outcome by ensuring a minimal cerebral damage.

SUBMITTER: Morega S

PROVIDER: S-EPMC8699728 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Cerebrolysin Prevents Brain Injury in a Mouse Model of Liver Damage.

Morega Shandiz S Cătălin Bogdan B Simionescu Cristiana Eugenia CE Sapalidis Konstantinos K Rogoveanu Ion I

Brain sciences 20211209 12

Liver damage can lead to secondary organ damage by toxic substances and catabolic products accumulation which can increase the permeability of blood-brain barrier, leading to cognitive impairment. The only real treatment for end stage liver failure is grafting. With some, but not all, neurological symptoms subsiding after transplantation, the presence of brain damage can impair both the short and long-term outcome. We tested if Cerebrolysin can prevent brain injury in an experimental model of no ...[more]

PMID: 34942925

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Project description:Fas ligand (FasL)-mediated hepatocyte apoptosis occurs in the context of acute liver injury that can be accompanied by intravascular coagulation (IC). We tested the hypothesis that analysis of selected protein fractions from livers undergoing apoptosis will shed light on mechanisms that are involved in liver injury that might be amenable to intervention. Proteomic analysis of the major insoluble liver proteins after FasL exposure for 4-5 hours identified fibrinogen-? (FIB-?) dimers and FIB-?-containing high molecular mass complexes among the major insoluble proteins visible via Coomassie blue staining. Presence of the FIB-?-containing products was confirmed using FIB-?-specific antibodies. The FIB-?-containing products partition selectively and quantitatively into the liver parenchyma after inducing apoptosis. Similar formation of FIB-? products occurs after acetaminophen administration. The observed intrahepatic IC raised the possibility that heparin therapy may ameliorate FasL-mediated liver injury. Notably, heparin administration in mice 4 hours before or up to 2 hours after FasL injection resulted in a dramatic reduction of liver injury-including liver hemorrhage, serum alanine aminotransferase, caspase activation, and liver apoptosis-compared with heparin-untreated mice. Heparin did not directly interfere with FasL-induced apoptosis in isolated hepatocytes, and heparin-treated mice survived the FasL-induced liver injury longer compared with heparin-untreated animals. There was a sharp, near-simultaneous rise in FasL-induced intrahepatic apoptosis and coagulation, with IC remaining stable while apoptosis continued to increase.Formation of FIB-? dimers and their high molecular mass products are readily detectable within the liver during mouse apoptotic liver injury. Heparin provides a potential therapeutic modality, because it not only prevents extensive FasL-related liver injury but also limits the extent of injury if given at early stages of injury exposure.

Project description:Neonatal hypoxic-ischemic (HI) brain injury is a leading cause of mortality and morbidity in infants and children for which there is no promising therapy at present. Previously, we reported induction of neuronal pentraxin 1 (NP1), a novel neuronal protein of the long-pentraxin family, following HI injury in neonatal brain. Here, we report that genetic deletion of NP1 expression prevents HI injury in neonatal brain. Elevated expression of NP1 was observed in neurons, not in astrocytes, of the ipsilateral cortical layers (I-IV) and in the hippocampal CA1 and CA3 areas of WT brains following hypoxia-ischemia; brain areas that developed infarcts (at 24-48 h), showed significantly increased numbers of TUNEL-(+) cells and tissue loss (at 7 days). In contrast, NP1-KO mice showed no evidence of brain infarction and tissue loss after HI. The immunofluorescence staining of brain sections with mitochondrial protein COX IV and subcellular fractionation analysis showed increased accumulation of NP1 in mitochondria, pro-death protein Bax activation and NP1 co-localization with activated caspase-3 in WT, but not in the NP1-KO brains; corroborating NP1 interactions with the mitochondria-derived pro-death pathways. Disruption of NP1 translocation to mitochondria by NP1-siRNA in primary cortical cultures significantly reduced ischemic neuronal death. NP1 was immunoprecipitated with activated Bax [6A7] proteins; HI caused increased interactions of NP1 with Bax, thereby, facilitating Bax translocation to mitochondrial and neuronal death. To further delineate the specificity of NPs, we found that NP1 but not the NP2 induction is specifically involved in brain injury mechanisms and that knockdown of NP1 only results in neuroprotection. Furthermore, live in vivo T2-weighted magnetic resonance imaging (MRI) including fractional anisotropy (FA) mapping showed no sign of delayed brain injury or tissue loss in the NP1-KO mice as compared to the WT at different post-HI periods (4-24 weeks) examined; indicating a long-term neuroprotective efficacy of NP1 gene deletion. Collectively, our results demonstrate a novel mechanism of neuronal death and predict that inhibition of NP1 expression is a promising strategy to prevent hypoxic-ischemic injury in immature brain.

Dataset Information

Cerebrolysin Prevents Brain Injury in a Mouse Model of Liver Damage.

Publications

Cerebrolysin Prevents Brain Injury in a Mouse Model of Liver Damage.

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