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Neuronal intracellular pH directly mediates nitric oxide-induced programmed cell death
A M Vincent1, M TenBroeke, K Maiese
1Laboratory of Cellular and Molecular Cerebral Ischemia, Department of Neurology, 6E-19 UHC, Wayne State University, Detroit, MI 48201, USA.
Journal of Neurobiology
|July 21, 1999
Summary
Nitric oxide (NO) causes neuronal injury by acidifying intracellular pH (pH(i)), activating endonucleases. Preventing this acidification protects neurons, suggesting a target for preventing neurodegeneration.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Neuronal injury is linked to endonuclease activation.
- Endonuclease activity is highly dependent on pH levels.
- Nitric oxide (NO) is implicated in neuronal toxicity.
Purpose of the Study:
- To investigate the role of intracellular pH (pH(i)) regulation in nitric oxide (NO)-induced neuronal toxicity.
- To determine the relationship between pH(i) changes, endonuclease activity, and neuronal cell death.
Main Methods:
- Primary rat hippocampal neurons were treated with NO generators.
- Intracellular pH (pH(i)) was measured using BCECF.
- Neuronal injury was assessed via Trypan blue exclusion and TUNEL assays.
Main Results:
- NO exposure caused rapid intracellular acidification followed by an alkaline shift.
- Artificial induction of intracellular acidification mimicked NO toxicity, decreasing neuronal survival and increasing DNA fragmentation.
- Preventing the initial acidification protected neurons from NO-induced injury.
- Neuronal injury and programmed cell death during acidification were dependent on endonuclease activity, not caspases.
Conclusions:
- Rapid, transient intracellular acidification is a critical event in NO-induced neuronal injury.
- Endonuclease activation during acidification contributes significantly to neuronal damage.
- Modulating pH(i) or endonuclease activity may offer therapeutic strategies for neuroprotection.