Effects of acute pro-inflammatory stimulation and 25-hydroxycholesterol on hippocampal plasticity and learning involve NLRP3 inflammasome and cellular stress responses

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 20, 2025

Neuroinflammation is an increasingly important target for therapeutics in neuropsychiatry and contributes to cognitive dysfunction, disability death across a range of illnesses. We previously found that acute effects pro-inflammatory stimulation with lipopolysaccharide (LPS) on hippocampal long-term potentiation (LTP), form synaptic plasticity involved learning memory, requires synthesis the oxysterol, 25-hydroxycholesterol (25HC) exogenous 25HC mimics LPS. However, downstream mechanisms engaged by LPS remain uncertain. Here we use rat slices vivo behavioral studies provide evidence modulation both activation NLRP3 inflammasome, caspase-1 interleukin-1 receptor. Furthermore, engage cellular stress responses including 5α-reduced neurosteroids are prevented modulators these responses. In using one-trial inhibitory avoidance task, inhibition pre-treatment inhibitor NLRP3. The present strong support role as mediator importance inflammasome deleterious inflammation.

Language: Английский

Oxysterol Alterations in SOD1G93A ALS Rats: 25-Hydroxycholesterol and LPS-Binding Protein in Disease Progression

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: May 7, 2025

Abstract Background Disruptions in cholesterol and oxysterol metabolism, along with neuroinflammation, are linked to amyotrophic lateral sclerosis (ALS), though the underlying mechanisms remain unclear. Given evidence of increased intestinal permeability ALS, we investigated its link neuroinflammation alterations SOD1G93A rats. Methods Oxysterols were quantified plasma spinal cord from presymptomatic symptomatic rats age-matched controls via ultra-high performance liquid chromatography coupled high-resolution mass spectrometry. Circulating LBP, a marker permeability, was ELISA. Results involved bile acid biosynthesis - 7α-hydroxycholesterol, 27-hydroxycholesterol (27-OH), 3β-hydroxycholestenoic The neuronal 24(S)-hydroxycholesterol (24(S)-OH) decreased but plasma. In contrast, 27-OH 25-hydroxycholesterol (25-OH) levels elevated both cord, 25-OH rising during stage. Presymptomatic animals also exhibited LBP levels, which strongly correlated suggesting between systemic inflammation ALS. Conclusion Oxysterol suggest compromised blood‒spinal barrier integrity early neuroinflammation. Elevated indicate circulating LPS as contributors neurodegeneration. These findings highlight markers mediators gut‒brain axis interactions ALS pathogenesis, particularly phase.

Language: Английский

Effects of acute pro-inflammatory stimulation and 25-hydroxycholesterol on hippocampal plasticity & learning involve NLRP3 inflammasome and cellular stress responses

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 18, 2024

Neuroinflammation is an increasingly important target for therapeutics in neuropsychiatry and contributes to cognitive dysfunction, disability death across a range of illnesses. We previously found that acute effects pro-inflammatory stimulation with lipopolysaccharide (LPS) on hippocampal long-term potentiation (LTP), form synaptic plasticity involved learning memory, requires synthesis the oxysterol, 25-hydroxycholesterol (25HC) exogenous 25HC mimics LPS. However, downstream mechanisms engaged by LPS remain uncertain. Here we use rat slices vivo behavioral studies provide evidence modulation both activation NLRP3 inflammasome, caspase-1 interleukin-1 receptor. Furthermore, engage cellular stress responses including 5a-reduced neurosteroids are prevented modulators these responses. In using one-trial inhibitory avoidance task, inhibition pre-treatment inhibitor NLRP3. The present strong support role as mediator importance inflammasome deleterious inflammation.

Language: Английский