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Increased Circulating ADMA in Young Male Rats Caused Cognitive Deficits and Increased Intestinal and Hippocampal
Mei-Hsin Hsu1, Yi-Chuan Huang1, Yu-Chieh Chen1
1Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City 833, Taiwan.
Abstract:
Endothelial dysfunction is characterized by disturbances in nitric oxide (NO) bioavailability and increased circulating asymmetric dimethylarginine (ADMA) due to the enormous release of free radicals. Increased circulating ADMA may cause endothelial dysfunction and a variety of clinical disorders, such as liver and kidney disease. Young male Sprague-Dawley rats at postnatal day 17 ± 1 received continuous ADMA infusion via an intraperitoneal pump to induce endothelial dysfunction. Four groups of rats (n = 10 per group) were allocated: control, control and resveratrol, ADMA infusion, and ADMA infusion and resveratrol groups. Spatial memory, NLR family pyrin-domain-containing 3 (NLRP3) inflammasome, cytokine expression, tight junction proteins in the ileum and dorsal hippocampus, and microbiota composition were examined. We found cognitive deficits; increased NLRP3 inflammasome in the plasma, ileum, and dorsal hippocampus; decreased ileum and dorsal hippocampal cytokine activation and tight junction proteins; and microbiota composition alterations in the ADMA-infusion young male rats. Resveratrol had beneficial effects in this context. In conclusion, we observed NLRP3 inflammasome activation in peripheral and central dysbiosis in young male rats with increased circulating ADMA, and found that resveratrol had beneficial effects. Our work adds to the mounting evidence that inhibiting systemic inflammation is a promising therapeutic avenue for cognition impairment, probably via the gut-brain axis.
Insights
Elevated asymmetric dimethylarginine (ADMA) causes endothelial dysfunction and cognitive deficits in rats. Resveratrol treatment mitigated these effects, suggesting a therapeutic role for inhibiting systemic inflammation via the gut-brain axis.
Area of Science:
- Neuroscience
- Gastroenterology
- Cardiovascular Biology
Background:
- Endothelial dysfunction, marked by reduced nitric oxide (NO) bioavailability and elevated asymmetric dimethylarginine (ADMA), is linked to free radical damage.
- Increased ADMA is implicated in endothelial dysfunction and various clinical conditions, including liver and kidney diseases.
- Cognitive impairment may be associated with systemic inflammation and gut dysbiosis.
Purpose of the Study:
- To investigate the effects of sustained asymmetric dimethylarginine (ADMA) infusion on cognitive function, inflammation, and gut microbiota in young male rats.
- To evaluate the potential therapeutic benefits of resveratrol in mitigating ADMA-induced endothelial dysfunction and associated pathologies.
Main Methods:
- Young male Sprague-Dawley rats received continuous ADMA infusion to induce endothelial dysfunction.
- Animals were divided into control and ADMA-infused groups, with and without resveratrol treatment (n=10 per group).
- Evaluated parameters included spatial memory, NLRP3 inflammasome activation, cytokine expression, tight junction proteins (ileum and dorsal hippocampus), and gut microbiota composition.
Main Results:
- ADMA infusion led to cognitive deficits, increased NLRP3 inflammasome in plasma, ileum, and hippocampus, and reduced cytokine activation and tight junction proteins in the ileum and hippocampus.
- Significant alterations in gut microbiota composition were observed in ADMA-infused rats.
- Resveratrol administration demonstrated beneficial effects, ameliorating cognitive impairment and associated inflammatory markers.
Conclusions:
- Increased circulating ADMA induces endothelial dysfunction, peripheral and central inflammation (NLRP3 inflammasome activation), gut dysbiosis, and cognitive impairment in young male rats.
- Resveratrol exhibits protective effects, suggesting its potential as a therapeutic agent for ADMA-related cognitive dysfunction.
- Inhibiting systemic inflammation, potentially through the gut-brain axis, represents a promising strategy for managing cognitive impairment.
