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Differential patterns of cocaine-induced organ toxicity in murine heart versus liver
1The Charles A. Dana Research Institute and Harvard-Thorndike Laboratory, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Abstract:
To determine cocaine's toxicity in different organs, BALB/c mice were intraperitoneally injected daily for 15 days with either saline or cocaine: 10 mg/kg, 30 mg/kg, or 60 mg/kg. Cardiac function, hepatic pathophysiology, heart and liver apoptosis, and tumor necrosis factor (TNF-alpha) levels were analyzed. After administration of cocaine, cardiac function decreased. Inflammatory cell infiltration and eosinophilic contraction bands were visible in the hearts of mice treated with 60mg/kg cocaine. Moreover, histopathology demonstrated that cocaine caused hepatic necrosis. TdT-mediated dUTP nick end-labeling (TUNEL) staining and DNA ladder analysis indicated that cocaine caused apoptosis in both the heart and liver. Moreover, immunoassay showed that TNF-alpha levels significantly increased in the heart and liver with cocaine administration. However, our RT-PCR study showed that there was no significant difference in either the heart or liver in the levels of mRNA for TNF-alpha between cocaine-treated and saline control mice. The present study demonstrated that cocaine is toxic to multiple organs, and at low dose can induce hepatic damage without gross pathological injury to the heart. The results suggest that the liver is more sensitive than the heart to cocaine toxicity, and induction of apoptosis or TNF-alpha elevation may be a common mechanism responsible for cocaines toxicity.
Insights
Cocaine is toxic to multiple organs, inducing liver damage and apoptosis even at low doses. The liver appears more sensitive to cocaine
Area of Science:
- Toxicology
- Cardiovascular Science
- Hepatology
Background:
- Cocaine use is associated with significant cardiovascular and hepatic complications.
- Understanding the organ-specific toxicity of cocaine is crucial for clinical management.
Purpose of the Study:
- To investigate the effects of varying cocaine doses on cardiac and hepatic function in a murine model.
- To elucidate the mechanisms underlying cocaine-induced organ damage, including apoptosis and TNF-alpha.
- To compare the sensitivity of the heart and liver to cocaine toxicity.
Main Methods:
- BALB/c mice received daily intraperitoneal injections of saline or cocaine (10, 30, or 60 mg/kg) for 15 days.
- Cardiac function was assessed, and heart and liver tissues were analyzed for histopathology, apoptosis (TUNEL staining, DNA laddering), and TNF-alpha levels (immunoassay and RT-PCR).
Main Results:
- Cocaine administration decreased cardiac function and induced cardiac inflammatory changes at higher doses.
- Hepatic necrosis was observed, indicating significant liver damage.
- Cocaine induced apoptosis in both the heart and liver.
- TNF-alpha levels increased in the heart and liver, but mRNA levels did not differ significantly, suggesting post-transcriptional regulation.
Conclusions:
- Cocaine exhibits toxicity in multiple organs, with the liver being more sensitive than the heart.
- Cocaine can cause hepatic damage at low doses without apparent gross cardiac injury.
- Apoptosis and TNF-alpha elevation are potential mechanisms contributing to cocaine's organ toxicity.
