NAAA inhibitor F96 attenuates BBB disruption and secondary injury after traumatic brain injury (TBI).

Abstract

Traumatic brain injury (TBI) is a leading cause of death worldwide, for which there is currently no comprehensive treatment available. Preventing blood-brain barrier (BBB) disruption is crucial for TBI treatment. N-acylethanolamine acid amidase (NAAA)-regulated palmitoylethanolamide (PEA) signaling play an important role in the control of inflammation. However, the role of NAAA in BBB dysfunction following TBI remains unclear. In the present study, we found that TBI induces the increase of PEA levels in the injured cortex, which prevent the disruption of BBB after TBI. TBI also induces the infiltration of NAAA-contained neutrophils, increasing the contribution of NAAA to the PEA degradation. Neutrophil-derived NAAA weakens PEA/PPARα-mediated BBB protective effects after TBI, facilitates the accumulation of immune cells, leading to secondary expansion of tissue injury. Inactivation of NAAA increased PEA levels in injured site, prevents early BBB damage and improves secondary injury, thereby eliciting long-term functional improvements after TBI. This study identified a new role of NAAA in TBI, suggesting that NAAA is a new important target for BBB dysfunction related CNS diseases.

• Authors: Yitian Li, Pan Zhou, Ting Hu, Jie Ren, Yaping Xu, Yan Qiu, Canzhong Lu, Yuhang Li
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 912 Pg. 174561 (Dec 05 2021) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 34655598 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• 3-(6-phenylhexanoyl)oxazolidin-2-one
• Amides
• Enzyme Inhibitors
• Ethanolamines
• Neuroprotective Agents
• Oxazolidinones
• PPAR alpha
• Palmitic Acids
• Ppara protein, mouse
• palmidrol
• Amidohydrolases
• NAAA protein, mouse

Topics

• Amides (metabolism)
• Amidohydrolases (antagonists & inhibitors, metabolism)
• Animals
• Blood-Brain Barrier (drug effects, metabolism)
• Brain Injuries, Traumatic (blood, metabolism, pathology)
• Cell Line
• Disease Models, Animal
• Endothelial Cells (drug effects)
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Ethanolamines (metabolism)
• Female
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Neurons (drug effects, metabolism)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Neutrophils (metabolism)
• Oxazolidinones (pharmacology, therapeutic use)
• PPAR alpha (deficiency, genetics)
• Palmitic Acids (metabolism)
• Mice