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| 2. |
- Levison, S. W., et al.
(författare)
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Mechanisms of tertiary neurodegeneration after neonatal hypoxic-ischemic brain damage
- 2022
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Ingår i: Pediatric Medicine. - : AME Publishing Company. - 2617-5428. ; 5
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Forskningsöversikt (refereegranskat)abstract
- Neonatal encephalopathy linked to hypoxia-ischemia (H-I) which is regarded as the most important neurological problem of the newborn, can lead to a spectrum of adverse neurodevelopmental outcomes such as cerebral palsy, epilepsy, hyperactivity, cognitive impairment and learning difficulties. There have been numerous reviews that have focused on the epidemiology, diagnosis and treatment of neonatal H-I; however, a topic that is less often considered is the extent to which the injury might worsen over time, which is the focus of this review. Similarly, there have been numerous reviews that have focused on mechanisms that contribute to the acute or subacute injury; however, there is a tertiary phase of recovery that can be defined by cellular and molecular changes that occur many weeks and months after brain injury and this topic has not been the focus of any review for over a decade. Therefore, in this article we review both the clinical and pre-clinical data that show that tertiary neurodegeneration is a significant contributor to the final outcome, especially after mild to moderate injuries. We discuss the contributing roles of apoptosis, necroptosis, autophagy, protein homeostasis, inflammation, microgliosis and astrogliosis. We also review the limited number of studies that have shown that significant neuroprotection and preservation of neurological function can be achieved administering drugs during the period of tertiary neurodegeneration. As the tertiary phase of neurodegeneration is a stage when interventions are eminently feasible, it is our hope that this review will stimulate a new focus on this stage of recovery towards the goal of producing new treatment options for neonatal hypoxic-ischemic encephalopathy.
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| 3. |
- Martinello, K. A., et al.
(författare)
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Acute LPS sensitization and continuous infusion exacerbates hypoxic brain injury in a piglet model of neonatal encephalopathy
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Co-existing infection/inflammation and birth asphyxia potentiate the risk of developing neonatal encephalopathy (NE) and adverse outcome. In a newborn piglet model we assessed the effect of E. coli lipopolysaccharide (LPS) infusion started 4 h prior to and continued for 48 h after hypoxia on brain cell death and systemic haematological changes compared to LPS and hypoxia alone. LPS sensitized hypoxia resulted in an increase in mortality and in brain cell death (TUNEL positive cells) throughout the whole brain, and in the internal capsule, periventricular white matter and sensorimotor cortex. LPS alone did not increase brain cell death at 48 h, despite evidence of neuroinflammation, including the greatest increases in microglial proliferation, reactive astrocytosis and cleavage of caspase-3. LPS exposure caused splenic hypertrophy and platelet count suppression. The combination of LPS and hypoxia resulted in the highest and most sustained systemic white cell count increase. These findings highlight the significant contribution of acute inflammation sensitization prior to an asphyxial insult on NE illness severity.
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| 4. |
- Martinello, K. A., et al.
(författare)
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Hypothermia is not therapeutic in a neonatal piglet model of inflammation-sensitized hypoxia-ischemia
- 2022
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Ingår i: Pediatric Research. - : Springer Science and Business Media LLC. - 0031-3998 .- 1530-0447. ; 91:6, s. 1416-1427
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Perinatal inflammation combined with hypoxia-ischemia (HO exacerbates injury in the developing brain. Therapeutic hypothermia (HT) is standard care for neonatal encephalopathy; however, its benefit in inflammation-sensitized HI (IS-HI) is unknown. METHODS: Twelve newborn piglets received a 2 mu g/kg bolus and 1 mu g/kg/h infusion over 52 h of Escherichia coli lipopolysaccharide (LPS). HI was induced 4 h after LPS bolus. After HI, piglets were randomized to HT (33.5 degrees C 1-25 h after HI, n = 6) or normothermia (NT, n = 6). Amplitude-integrated electroencephalogram (aEEG) was recorded and magnetic resonance spectroscopy (MRS) was acquired at 24 and 48 h. At 48 h, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive brain cell death, microglial activation/proliferation, astrogliosis, and cleaved caspase-3 (CC3) were quantified. Hematology and plasma cytokines were serially measured. RESULTS: Two HT piglets died. aEEG recovery, thalamic and white matter MRS lactate/N-acetylaspartate, and TUNEL-positive cell death were similar between groups. HT increased microglial activation in the caudate, but had no other effect on glial activation/ proliferation. HT reduced CC3 overall. HT suppressed platelet count and attenuated leukocytosis. Cytokine profile was unchanged by HT. CONCLUSIONS: We did not observe protection with HT in this piglet IS-HI model based on aEEG, MRS, and immunohistochemistry. immunosuppressive effects of HT and countering neuroinflammation by LPS may contribute to the observed lack of HT efficacy. Other immunomodulatory strategies may be more effective in IS-HI.
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| 5. |
- Dean, J. M., et al.
(författare)
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A Critical Review of Models of Perinatal Infection
- 2015
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Ingår i: Developmental Neuroscience. - : S. Karger AG. - 0378-5866 .- 1421-9859. ; 37:4-5, s. 289-304
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Forskningsöversikt (refereegranskat)abstract
- One of the central, unanswered questions in perinatology is why preterm infants continue to have such poor long-term neurodevelopmental, cognitive and learning outcomes, even though severe brain injury is now rare. There is now strong clinical evidence that one factor underlying disability may be infection, as well as nonspecific inflammation, during fetal and early postnatal life. In this review, we examine the experimental evidence linking both acute and chronic infection/inflammation with perinatal brain injury and consider key experimental determinants, including the microglia response, relative brain and immune maturity and the pattern of exposure to infection. We highlight the importance of the origin and derivation of the bacterial cell wall component lipopolysaccharide. Such experimental paradigms are essential to determine the precise time course of the inflammatory reaction and to design targeted neuroprotective strategies to protect the perinatal brain from infection and inflammation. (C) 2015 S. Karger AG, Basel
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| 6. |
- Nair, Syam, et al.
(författare)
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Lipopolysaccharide-induced alteration of mitochondrial morphology induces a metabolic shift in microglia modulating the inflammatory response in vitro and in vivo
- 2019
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Ingår i: Glia. - : Wiley. - 0894-1491 .- 1098-1136. ; 67:6, s. 1047-1061
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Tidskriftsartikel (refereegranskat)abstract
- Accumulating evidence suggests that changes in the metabolic signature of microglia underlie their response to inflammation. We sought to increase our knowledge of how pro-inflammatory stimuli induce metabolic changes. Primary microglia exposed to lipopolysaccharide (LPS)-expressed excessive fission leading to more fragmented mitochondria than tubular mitochondria. LPS-mediated Toll-like receptor 4 (TLR4) activation also resulted in metabolic reprogramming from oxidative phosphorylation to glycolysis. Blockade of mitochondrial fission by Mdivi-1, a putative mitochondrial division inhibitor led to the reversal of the metabolic shift. Mdivi-1 treatment also normalized the changes caused by LPS exposure, namely an increase in mitochondrial reactive oxygen species production and mitochondrial membrane potential as well as accumulation of key metabolic intermediate of TCA cycle succinate. Moreover, Mdivi-1 treatment substantially reduced LPS induced cytokine and chemokine production. Finally, we showed that Mdivi-1 treatment attenuated expression of genes related to cytotoxic, repair, and immunomodulatory microglia phenotypes in an in vivo neuroinflammation paradigm. Collectively, our data show that the activation of microglia to a classically pro-inflammatory state is associated with a switch to glycolysis that is mediated by mitochondrial fission, a process which may be a pharmacological target for immunomodulation.
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