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Chronic exposure to Dextromethorphan disrupts intestinal integrity and brain metabolism in male mice
Jihong Cai1, Siming Ding1, Renjuan Cao1
1School of Environment and Energy, South China University of Technology, Guangzhou 510006, PR China.
Abstract:
Dextromethorphan (DXM), a centrally acting non-narcotic antitussive, is subject to abuse worldwide, yet the risks associated with its long-term intake remain unclear. In this study, we examined the behavioral effects of repeated once-daily intraperitoneal administration of DXM at doses of 30 mg/kg and 50 mg/kg for 14 consecutive days in male mice and evaluated the toxic effects and underlying mechanisms in the intestine and brain using exploratory magnetic resonance imaging and physiological and biochemical indicators. The results suggested that DXM administration may attenuate neuronal activity in the prefrontal cortex and hippocampus and was associated with intestinal and brain tissue damage as well as apoptosis. At the high dose, the pro-inflammatory cytokine IL-1β was increased by 30% in both intestinal and brain tissues, whereas the anti-inflammatory cytokine IL-10 was decreased by 15% in the intestine and by 35.7% in the brain. DXM exposure also altered the gut microbiota composition. In parallel, serum lipopolysaccharide (LPS) levels were increased by 1.3-fold, suggesting potential disruption of the intestinal barrier and possible systemic effects via circulation. DXM was associated with alterations in gut microbiota composition, and gut-derived metabolites were correlated with dysregulation of lysophosphatidylcholine (LPC) metabolism in the brain. The abnormal accumulation of LPC was associated with lipid metabolic disturbances, which were in turn correlated with alterations in the brain microenvironment and neuroinflammation. Collectively, these results suggest that long-term DXM exposure may be associated with intestinal injury and alterations in brain metabolism, providing insights into the potential health risks associated with chronic DXM abuse.
Insights
Long-term dextromethorphan (DXM) abuse in mice caused intestinal and brain damage, altered gut bacteria, and disrupted brain metabolism, indicating potential health risks.
Area of Science:
- Neuroscience
- Toxicology
- Gastroenterology
Background:
- Dextromethorphan (DXM) is a widely abused antitussive.
- The long-term health risks of DXM abuse are not well understood.
Purpose of the Study:
- To investigate the toxic effects and underlying mechanisms of repeated DXM administration in the intestine and brain.
- To evaluate behavioral changes and potential systemic effects.
Main Methods:
- Repeated daily intraperitoneal administration of DXM (30 and 50 mg/kg) to male mice for 14 days.
- Assessment of behavioral effects, tissue damage, apoptosis, cytokine levels (IL-1β, IL-10), gut microbiota, serum lipopolysaccharide (LPS), and brain lysophosphatidylcholine (LPC) metabolism.
- Exploratory magnetic resonance imaging (MRI) was utilized.
Main Results:
- DXM administration attenuated neuronal activity in the prefrontal cortex and hippocampus.
- Intestinal and brain tissue damage, along with apoptosis, were observed.
- Increased pro-inflammatory IL-1β and decreased anti-inflammatory IL-10 levels were noted in both tissues at high doses.
- DXM altered gut microbiota, increased serum LPS, and dysregulated brain LPC metabolism, correlating with neuroinflammation.
Conclusions:
- Long-term DXM exposure is associated with intestinal injury and brain metabolic alterations.
- DXM abuse may disrupt the intestinal barrier, leading to systemic effects.
- Findings suggest potential neuroinflammatory and metabolic risks linked to chronic DXM use.
