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An Ex vivo Model of an Oligodendrocyte-directed T-Cell Attack in Acute Brain Slices
Published on: February 5, 2015
Apoptosis of oligodendrocytes in secondary cultures from neonatal rat brains
1Department of Neurology, F-140, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA. wcammer@aecom.yu.edu
Abstract:
The plaques in multiple sclerosis (MS) autopsy tissue contain tumor necrosis factor-alpha (TNF-alpha) at high concentrations. Moreover, microglia are able to convert L-tryptophan to quinolinic acid. Thus, TNF-alpha and quinolinic acid are endogenous compounds which may compromise oligodendrocytes during inflammatory demyelination. It is also known that cellular functions depend on adequate concentrations of glutathione (GSH). As some apoptotic oligodendrocytes have been observed in MS plaques, it was therefore logical to determine whether oligodendrocyte apoptosis would occur in response to TNF-alpha, quinolinic acid or GSH depletion. Oligodendrocytes were treated in vitro with TNF-alpha, quinolinic acid and the GSH-depleting agent, buthionine sulfoximine (BSO), respectively, and the numbers of intact and apoptotic cells were counted. TNF-alpha reduced the numbers of mature oligodendrocytes, but not immature oligodendrocytes, without producing apoptosis. Quinolinic acid and BSO each caused oligodendrocyte loss via apoptosis, and GSH ethyl ester partly protected the cells against BSO. The data suggest that oligodendrocytes undergo apoptosis under adverse conditions that result from an endogenous toxicant or depletion of GSH.
Insights
In multiple sclerosis (MS) plaques, the compounds tumor necrosis factor-alpha (TNF-alpha) and quinolinic acid, along with glutathione (GSH) depletion, can trigger oligodendrocyte apoptosis, leading to cell loss during demyelination.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Multiple sclerosis (MS) plaques contain high concentrations of tumor necrosis factor-alpha (TNF-alpha).
- Microglia convert L-tryptophan to quinolinic acid, another compound found in MS lesions.
- Oligodendrocytes, crucial for myelin maintenance, are vulnerable to inflammatory damage and exhibit apoptosis in MS plaques.
Purpose of the Study:
- To investigate the role of TNF-alpha, quinolinic acid, and glutathione (GSH) depletion in inducing oligodendrocyte apoptosis in vitro.
- To determine if GSH ethyl ester can protect oligodendrocytes from apoptosis induced by GSH depletion.
Main Methods:
- Oligodendrocytes were cultured in vitro and exposed to TNF-alpha, quinolinic acid, or buthionine sulfoximine (BSO), a GSH-depleting agent.
- Cell counts were performed to quantify intact and apoptotic oligodendrocytes.
- GSH ethyl ester was used to assess its protective effects against BSO-induced apoptosis.
Main Results:
- TNF-alpha reduced mature oligodendrocyte numbers but did not induce apoptosis.
- Both quinolinic acid and BSO treatment led to significant oligodendrocyte apoptosis.
- GSH ethyl ester provided partial protection to oligodendrocytes against BSO-induced apoptosis.
Conclusions:
- Oligodendrocyte apoptosis is a key mechanism of cell loss in MS, triggered by endogenous neurotoxicants like quinolinic acid.
- GSH depletion contributes to oligodendrocyte vulnerability and apoptosis.
- These findings highlight potential therapeutic targets for mitigating oligodendrocyte damage in MS.
