Enhanced Activation of the S1PR2-IL-1β-Src-BDNF-TrkB Pathway Mediates Neuroinflammation in the Hippocampus and Cognitive Impairment in Hyperammonemic Rats
Abstract
:1. Introduction
2. Results
2.1. Blocking S1PR2 in Vivo with JTE-013 Reverses Cognitive Impairment in Hyperammonemic Rats
2.2. Blocking S1PR2 Ex Vivo with JTE-013 Reverses Altered Membrane Expression of AMPA and NMDA Receptors in Hippocampal Slices from Hyperammonemic Rats
2.3. Blocking S1PR2 Ex Vivo with JTE-013 Reverses Microglia and Astrocytes Activation and the Increase in IL-1β in Hippocampal Slices from Hyperammonemic Rats
2.4. Increaseing IL-1β Enhances Activation of IL-1 Receptor, Which Activates Src, Increasing CCL2 Levels in Hippocampus of Hyperammonemic Rats, Which Is Reversed by Blocking S1PR2 or the IL-1 Receptor and by Inhibiting Src
2.5. Increased CCL2 Enhances Activation of CCR2, Leading to Microglia Activation, Increased p38 Phosphorylation and BDNF Levels, Which Activate Astrocytes
- (a)
- S1PR2 → IL-1β → IL-1R → Src → CCL2 → CCR2 → microglia activation.
- (b)
- S1PR2 → IL-1β → IL-1R → Src → astrocytes activation.
2.6. BDNF Levels Increased in CA1 Neurons, Leading to Increased Activation of TrkB, Which Contributes to a Sustained Increased in BDNF and Activation of Microglia and Astrocytes
2.7. Enhanced Activation of TrkB-PI3K-Akt-CREB Pathway Contributes to Enhanced Levels of BDNF but Not CCL2 in Hippocampus of Hyperammonemic Rats
3. Discussion
- (a)
- S1PR2 → IL-1β → IL-1R → Src → GLUN2B → p38 → altered membrane expression of AMPA receptors → impaired cognitive function;
- (b)
- S1PR2 → IL-1β → IL-1R → Src → CCL2 → CCR2 → microglia activation;
- (c)
- S1PR2 → IL-1β → IL-1R → Src → GLUN2B → p38 → BDNF → TrkB → astrocytes activation;
- (d)
- S1PR2 → IL-1β → IL-1R → Src → GLUN2B →p38 → BDNF → TrkB → PI3K → Akt → CREB → BDNF.
Limitations of the Study and Future Research Directions
4. Materials and Methods
4.1. In Vivo Experiments
4.1.1. Continuous Intracerebral Administration of JTE-013 to Rats Using Osmotic Pumps
- (1)
- CV: Control rats implanted with mini-osmotic pumps containing vehicle (sterile saline + 1% DMSO).
- (2)
- CJ: Control rats implanted with mini-osmotic pumps containing 1.22 mM JTE-013 (383150-41-2, Axon Medchem BV, Groningen, The Netherlands) diluted in sterile saline + DMSO 1%, as in Kimura et al. [62].
- (3)
- HV: hyperammonemic rats implanted with mini-osmotic pumps containing vehicle.
- (4)
- HJ: Hyperammonemic rats implanted with mini-osmotic pumps containing JTE-013.
4.1.2. Evaluation of Spatial Learning in the 8-Arms Radial Maze
4.1.3. Evaluation of Novel Object Recognition (NOR) Memory
4.2. Ex Vivo Experiments
4.2.1. Analysis of Protein Content and Phosphorylation in Hippocampal Slices Using Western Blotting
4.2.2. Analysis of Membrane Expression of AMPA and NMDA Receptor Subunits and S1PR2
4.2.3. Immunohistochemistry
4.3. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Sancho-Alonso, M.; Arenas, Y.M.; Izquierdo-Altarejos, P.; Martinez-Garcia, M.; Llansola, M.; Felipo, V. Enhanced Activation of the S1PR2-IL-1β-Src-BDNF-TrkB Pathway Mediates Neuroinflammation in the Hippocampus and Cognitive Impairment in Hyperammonemic Rats. Int. J. Mol. Sci. 2023, 24, 17251. https://doi.org/10.3390/ijms242417251
Sancho-Alonso M, Arenas YM, Izquierdo-Altarejos P, Martinez-Garcia M, Llansola M, Felipo V. Enhanced Activation of the S1PR2-IL-1β-Src-BDNF-TrkB Pathway Mediates Neuroinflammation in the Hippocampus and Cognitive Impairment in Hyperammonemic Rats. International Journal of Molecular Sciences. 2023; 24(24):17251. https://doi.org/10.3390/ijms242417251
Chicago/Turabian StyleSancho-Alonso, María, Yaiza M. Arenas, Paula Izquierdo-Altarejos, Mar Martinez-Garcia, Marta Llansola, and Vicente Felipo. 2023. "Enhanced Activation of the S1PR2-IL-1β-Src-BDNF-TrkB Pathway Mediates Neuroinflammation in the Hippocampus and Cognitive Impairment in Hyperammonemic Rats" International Journal of Molecular Sciences 24, no. 24: 17251. https://doi.org/10.3390/ijms242417251