2023-09-14 21:03:34
It was known that the neurons around the brain area damaged by the stroke play a major role in functional recovery via the development of new nerve endings, reorganization of synapses and remyelination. However, the molecular mechanisms triggering this cascade of events allowing neuronal repair remained very poorly understood.
These lipids which stimulate brain self-repair following an ischemic stroke
The study deciphers the role of a specific protein, PLA2G2E, secreted by peri-lesional neurons subjected to ischemic stress. The PLA2G2E protein generates 2 other proteins, DGLA and 15-HETrE, which trigger these recovery processes through Padi4-dependent neuronal induction of “cluster” formation associated with neural repair.
After ischemic stroke (stoppage of blood flow to the brain), patients often experience functional decline, particularly due to the brain’s difficulty regenerating following the injury. However, the brain is well equipped with a recovery mechanism: surviving neurons can activate these mechanisms to limit and even reverse the damage caused by the stroke. However, until this study, it was unclear what triggers these repair processes.
This work reveals that neurons surrounding the cell death zone secrete lipids that can trigger this autonomous neuronal repair of the brain following ischemic stroke.
“There was already evidence that more lipids are produced following such tissue damage and help regulate inflammation,” specifies here the main author, Dr Takashi Shichita. The researchers here follow these changes in the production of lipid metabolites in the mouse model of ischemic stroke and observe that:
levels of a specific fatty acid, dihomo-γ-linolenic acid (DGLA) and its derivatives increase following stroke; the PLA2GE2 protein (Phospholipase A2 Group IIE) mediates this increase in DGLA; manipulating PLA2GE2 expression demonstrates the key role of the enzyme on functional recovery: PLA2GE2 deficiency leads to more inflammation, lower expression and the production of factors stimulating neuronal repair; in mice lacking PLA2GE2, levels of another protein (PADI4) are reduced; in fact, PADI4 regulates transcription and inflammation. Remarkably, increased PADI4 expression in mice limits tissue damage and inflammation following ischemic stroke; finally, PADI4 promotes the transcription of genes involved in brain repair; the researchers finally identify the entire signaling pathway involved in this repair process.
These data obtained on the mouse model of ischemic stroke lead to a recovery pathway that probably exists in humans, while human neurons surrounding the stroke site also express the PLA2G2E and PADI4 proteins. Then, recent research also reported that a lower serum level of DGLA was correlated with the severity of ischemic stroke and cognitive decline in humans.
The discovery of this new mechanism which triggers brain repair following an ischemic stroke will most likely lead to the development of compounds promoting the effects of PADI4, to stimulate and accelerate the recovery of patients.
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