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Reactive mononuclear phagocytes release neurotoxins after ischemic and traumatic injury to the central nervous system
D Giulian1, M Corpuz, S Chapman
1Department of Neurology, Baylor College of Medicine, Houston, TX 77030.
Abstract:
Reactive microglia and invading macrophages, which appear in brain damaged by stroke or trauma, secrete neuron-killing factors. This release of cytotoxic substances is a delayed process and is not detected until inflammatory cells reach a peak of reactivity by the second day after injury. Proximity to the site of injury and density of mononuclear phagocytes determine in part the amount of neurotoxic activity released by injured tissues. Moreover, drugs that suppress the accumulation of reactive microglia and macrophages also reduce tissue production of neuron poisons. Neurotoxins released by brain inflammatory cells or extracted directly from inflamed tissues are heat-stable, protease-resistant molecules < 500 daltons with actions blocked by N-methyl-D-aspartate (NMDA) receptor antagonists. These molecules are distinguished from free radical intermediates, bind to cation exchange resins, lack carboxyl moieties, and are separated from excitatory amino acids including glutamate or aspartate and from the NMDA receptor-mediated toxin quinolinic acid by ion exchange and reverse phase chromatography. Our data suggest that an unrecognized class of neuron-killing molecules produced by inflammatory cells mediate the delayed neuronal loss associated with stroke and trauma.
Insights
Inflammatory cells in brain injuries release delayed neurotoxins that cause neuronal death. These potent, heat-stable molecules are distinct from known toxins and may be targeted by new therapies for stroke and trauma.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Brain injury, such as stroke or trauma, triggers an inflammatory response involving reactive microglia and macrophages.
- These immune cells release factors that are toxic to neurons, contributing to delayed neuronal loss.
- The neurotoxic activity is linked to the density and reactivity of these inflammatory cells at the injury site.
Purpose of the Study:
- To identify and characterize the specific neuron-killing factors secreted by inflammatory cells in the injured brain.
- To understand the nature and properties of these neurotoxins.
- To explore their role in mediating delayed neuronal death after stroke and trauma.
Main Methods:
- Analysis of neurotoxic activity in brain tissues affected by stroke or trauma.
- Biochemical characterization of neurotoxins, including heat stability, protease resistance, and molecular weight determination (< 500 daltons).
- Chromatographic separation (ion exchange, reverse-phase) to distinguish toxins from known neuroactive substances like glutamate, aspartate, and quinolinic acid.
- Testing the effect of N-methyl-D-aspartate (NMDA) receptor antagonists on neurotoxin activity.
Main Results:
- A class of heat-stable, protease-resistant neurotoxins (< 500 daltons) was identified in inflamed brain tissues.
- These toxins are produced by reactive microglia and macrophages.
- Their activity is blocked by NMDA receptor antagonists and they are chemically distinct from free radicals, excitatory amino acids, and quinolinic acid.
- Drugs suppressing inflammatory cell accumulation also reduced neurotoxin production.
Conclusions:
- An unrecognized class of neurotoxins produced by inflammatory cells mediates delayed neuronal loss following stroke and trauma.
- These findings suggest novel therapeutic targets for mitigating brain damage in these conditions.
- Further research is needed to fully elucidate the structure and precise mechanism of action of these newly identified neurotoxins.