MED1/BDNF/TrkB pathway is involved in thalamic hemorrhage-induced pain and depression by regulating microglia.

Abstract

Central post-stroke pain (CPSP) and associated depression remain poorly understood and pharmacological treatments are unsatisfactory. Recently, microglia activation was suggested to be involved in CPSP pathophysiology. The goal of this study was to investigate the effectiveness of a co-ultramicronized combination of N-palmitoylethanolamide and luteolin (PEALut) in a mouse model of thalamic hemorrhage (TH)-induced CPSP. TH was established through the collagenase-IV injection in thalamic ventral-posterolateral-nucleus. PEALut effects in CPSP-associated behaviors were evaluated during a 28-days observation period. We found that repeated administrations of co-ultra PEALut significantly reduced mechanical hypersensitivity after TH, as compared to vehicle, by reducing the early microglial activation in the perilesional site. Moreover, PEALut prevented the development of depressive-like behavior (21 days post-TH). These effects were associated with the restoration of synaptic plasticity in LEC-DG pathway and monoamines levels found impaired in TH mice. Hippocampal MED1 and TrkB expressions were significantly increased in TH compared to sham mice 21 days post-TH, whereas BDNF levels were decreased. PEALut restored MED1/TrkB/BDNF expression in mice. Remarkably, we found significant overexpression of MED1 in the human autoptic brain specimens after stroke, indicating a translational potential of our findings. These results pave the way for better-investigating depression in TH- induced CPSP, together with the involvement of MED1/TrkB/BDNF pathway, proposing PEALut as an adjuvant treatment.

• Authors: Rosmara Infantino, Concetta Schiano, Livio Luongo, Salvatore Paino, Gelsomina Mansueto, Serena Boccella, Francesca Guida, Flavia Ricciardi, Monica Iannotta, Carmela Belardo, Ida Marabese, Gorizio Pieretti, Nicola Serra, Claudio Napoli, Sabatino Maione
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 164 Pg. 105611 (03 2022) ISSN: 1095-953X [Electronic] United States
• PMID: 34995755 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022. Published by Elsevier Inc.

Chemical References

• Brain-Derived Neurotrophic Factor
• Med1 protein, mouse
• Mediator Complex Subunit 1
• Ntrk2 protein, mouse
• Receptor, trkB

Topics

• Animals
• Brain-Derived Neurotrophic Factor (metabolism)
• Depression (etiology, metabolism)
• Intracranial Hemorrhages (complications, metabolism)
• Mediator Complex Subunit 1 (metabolism)
• Mice
• Microglia (metabolism)
• Motor Activity (physiology)
• Pain (etiology, metabolism)
• Rats, Sprague-Dawley
• Receptor, trkB (metabolism)
• Signal Transduction (physiology)
• Thalamus (metabolism)
• Rats