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Published on: February 9, 2014
Vasopressin Impairment During Sepsis Is Associated with Hypothalamic Intrinsic Apoptotic Pathway and Microglial
Luis Henrique Angenendt da Costa1, Nilton Nascimento Dos Santos Júnior1, Carlos Henrique Rocha Catalão1
1Department of Neurosciences and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
Abstract:
Previous studies have shown that in the early phase of sepsis, the plasma concentration of arginine vasopressin (AVP) is increased, but in the late phase, its levels remain inadequately low, despite of persistent hypotension. One hypothesis suggested for this relative deficiency is apoptosis of vasopressinergic neurons. Here, we investigated apoptosis pathways in the hypothalamus during sepsis, as well as mechanisms underlying this process. Male Wistar rats were submitted to sepsis by cecal ligation and puncture (CLP) or nonmanipulated (naive) as control. After 6 and 24 h, the animals were decapitated and brain and blood were collected to assess hypothalamic apoptotic markers, IFN-γ plasma levels, and evidence for breakdown of the blood-brain barrier (BBB). Sepsis caused a decrease in mitochondrial antiapoptotic proteins (Bcl-2, Bcl-xL) in the hypothalamus, but had no effect on markers of cell death mediated by death receptors or immune cells. In the supraoptic nuclei of these animals, microglia morphology was consistent with activation, associated with an increase in plasma IFN-γ. A transitory breakdown of BBB in the hypothalamus was seen at 6 h following CLP. The results indicate that the intrinsic but not extrinsic apoptosis pathway is involved in the cell death observed in vasopressinergic neurons, and that this condition is temporally associated with microglial activation and BBB leaking.
Insights
Sepsis triggers apoptosis in vasopressinergic neurons via the intrinsic pathway, leading to low arginine vasopressin (AVP) levels. This neuronal cell death is linked to microglial activation and blood-brain barrier (BBB) disruption.
Area of Science:
- Neuroscience
- Immunology
- Endocrinology
Background:
- Sepsis is associated with altered arginine vasopressin (AVP) levels, particularly a late-phase deficiency.
- Apoptosis of vasopressinergic neurons is hypothesized to contribute to this AVP deficiency.
- Understanding the mechanisms of neuronal apoptosis in sepsis is crucial for therapeutic development.
Purpose of the Study:
- To investigate apoptosis pathways in the hypothalamus during sepsis.
- To identify mechanisms underlying sepsis-induced neuronal cell death.
- To correlate hypothalamic apoptosis with blood-brain barrier (BBB) integrity and immune responses.
Main Methods:
- Sepsis was induced in male Wistar rats using cecal ligation and puncture (CLP).
- Hypothalamic tissues and plasma were collected at 6 and 24 hours post-CLP for analysis.
- Assessed apoptotic markers (mitochondrial and death receptor pathways), plasma IFN-γ, and BBB integrity.
Main Results:
- Sepsis significantly decreased mitochondrial antiapoptotic proteins (Bcl-2, Bcl-xL) in the hypothalamus.
- No significant changes were observed in death receptor-mediated cell death markers.
- Microglial activation and increased plasma IFN-γ were observed, along with transient BBB breakdown at 6 hours post-CLP.
Conclusions:
- The intrinsic apoptosis pathway, not the extrinsic pathway, is implicated in vasopressinergic neuron cell death during sepsis.
- Sepsis-induced neuronal apoptosis is temporally associated with microglial activation and BBB disruption.
- These findings elucidate mechanisms contributing to AVP deficiency in late-phase sepsis.
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