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Hypothermia Does Not Reverse Cellular Responses Caused by Lipopolysaccharide in Neonatal Hypoxic-Ischaemic Brain
Damjan Osredkar1, Hemmen Sabir, Mari Falck
1Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
Insights
Bacterial lipopolysaccharide (LPS) sensitisation worsens brain injury in newborn rats after hypoxia-ischaemia. Therapeutic hypothermia (HT) failed to protect against this infection-sensitised injury, indicating a need for new treatment strategies.
Area of Science:
- Neuroscience
- Neonatal Research
- Inflammation Biology
Background:
- Bacterial lipopolysaccharide (LPS) exacerbates hypoxia-ischaemia (HI) brain injury in newborn rats.
- Therapeutic hypothermia (HT) is ineffective in this infection-sensitised HI model.
- Mechanisms underlying therapeutic failure require elucidation.
Purpose of the Study:
- Investigate cellular mechanisms of LPS-sensitised HI brain injury.
- Determine the efficacy of therapeutic hypothermia (HT) in this model.
- Understand the role of apoptosis, astrogliosis, and microglial activation.
Main Methods:
- Newborn rats received LPS or vehicle, followed by hypoxia-ischaemia.
- Animals were treated with normothermia (NT) or HT.
- Neuronal death, apoptosis, astrogliosis, and microglial activation were assessed via Western blot and immunohistochemistry.
Main Results:
- LPS sensitisation significantly increased apoptotic neuronal loss and caspase-3 activation.
- Significant astrogliosis and a trend towards increased microglial activation were observed in LPS-sensitised rats.
- Therapeutic hypothermia (HT) did not mitigate these LPS-induced changes.
Conclusions:
- LPS-sensitised HI brain injury involves neuronal apoptosis, astrogliosis, and microglial activation.
- Therapeutic hypothermia (HT) is not neuroprotective in this infection-sensitised neonatal brain injury model.
- This study highlights the limitations of current therapeutic strategies.
Introduction:
Bacterial lipopolysaccharide (LPS) injection prior to hypoxia-ischaemia significantly increases hypoxia-ischaemic brain injury in 7-day-old (P7) rats. In addition, therapeutic hypothermia (HT) is not neuroprotective in this setting. However, the mechanistic aspects of this therapeutic failure have yet to be elucidated. This study was designed to investigate the underlying cellular mechanisms in this double-hit model of infection-sensitised hypoxia-ischaemic brain injury.
Material And Methods:
P7 rat pups were injected with either vehicle or LPS, and after a 4-hour delay were exposed to left carotid ligation followed by global hypoxia inducing a unilateral stroke-like hypoxia-ischaemic injury. Pups were randomised to the following treatments: (1) vehicle-treated pups receiving normothermia treatment (NT) (Veh-NT; n = 40), (2) LPS-treated pups receiving NT treatment (LPS-NT; n = 40), (3) vehicle-treated pups receiving HT treatment (Veh-HT; n = 38) and (4) LPS-treated pups receiving HT treatment (LPS-HT; n = 35). On postnatal day 8 or 14, Western blot analysis or immunohistochemistry was performed to examine neuronal death, apoptosis, astrogliosis and microglial activation.
Results:
LPS sensitisation prior to hypoxia-ischaemia significantly exacerbated apoptotic neuronal loss. NeuN, a neuronal biomarker, was significantly reduced in the LPS-NT and LPS-HT groups (p = 0.008). Caspase-3 activation was significantly increased in the LPS-sensitised groups (p < 0.001). Additionally, a significant increase in astrogliosis (glial fibrillary acidic expression, p < 0.001) was seen, as well as a trend towards increased microglial activation (Iba 1 expression, p = 0.051) in LPS-sensitised animals. Treatment with HT did not counteract these changes.
Conclusion:
LPS-sensitised hypoxia-ischaemic brain injury in newborn rats is mediated through neuronal death, apoptosis, astrogliosis and microglial activation. In this double-hit model, treatment with HT does not ameliorate these changes.
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