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- Chakkarapani, A. A., et al.
(author)
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Therapies for neonatal encephalopathy: Targeting the latent, secondary and tertiary phases of evolving brain injury
- 2021
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In: Seminars in Fetal and Neonatal Medicine. - : Elsevier BV. - 1744-165X. ; 26:5
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Journal article (peer-reviewed)abstract
- In term and near-term neonates with neonatal encephalopathy, therapeutic hypothermia protocols are well established. The current focus is on how to improve outcomes further and the challenge is to find safe and complementary therapies that confer additional protection, regeneration or repair in addition to cooling. Following hypoxia-ischemia, brain injury evolves over three main phases (latent, secondary and tertiary), each with a different brain energy, perfusion, neurochemical and inflammatory milieu. While therapeutic hypothermia has targeted the latent and secondary phase, we now need therapies that cover the continuum of brain injury that spans hours, days, weeks and months after the initial event. Most agents have several therapeutic actions but can be broadly classified under a predominant action (e.g., free radical scavenging, anti-apoptotic, anti-inflammatory, neuroregeneration, and vascular effects). Promising early/secondary phase therapies include Allopurinol, Azithromycin, Exendin-4, Magnesium, Melatonin, Noble gases and Sildenafil. Tertiary phase agents include Erythropoietin, Stem cells and others. We review a selection of promising therapeutic agents on the translational pipeline and suggest a framework for neuroprotection and neurorestoration that targets the evolving injury. © 2021 Elsevier Ltd
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| 3. |
- Levison, S. W., et al.
(author)
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Mechanisms of tertiary neurodegeneration after neonatal hypoxic-ischemic brain damage
- 2022
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In: Pediatric Medicine. - : AME Publishing Company. - 2617-5428. ; 5
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Research review (peer-reviewed)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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| 4. |
- Martinello, K. A., et al.
(author)
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Hypothermia is not therapeutic in a neonatal piglet model of inflammation-sensitized hypoxia-ischemia
- 2022
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In: Pediatric Research. - : Springer Science and Business Media LLC. - 0031-3998 .- 1530-0447. ; 91:6, s. 1416-1427
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Journal article (peer-reviewed)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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