Adriamycin-induced, TNF-alpha-mediated central nervous system toxicity
Jitbanjong Tangpong1, Marsha P Cole, Rukhsana Sultana
1Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536, USA.
Neurobiology of Disease
|May 16, 2006
Summary
Adriamycin (ADR) chemotherapy causes brain injury by increasing tumor necrosis factor-alpha (TNF), leading to mitochondrial dysfunction and apoptosis. Neutralizing TNF may prevent ADR-induced central nervous system (CNS) toxicity.
Area of Science:
- Neuroscience
- Toxicology
- Biochemistry
Background:
- Adriamycin (ADR) is a potent chemotherapeutic agent with known cardiotoxicity.
- The central nervous system (CNS) effects of ADR are not well understood, with the blood-brain barrier often considered protective.
- This study investigates ADR's impact on brain tissue and its underlying mechanisms.
Purpose of the Study:
- To determine if systemic adriamycin (ADR) administration induces toxicity in brain tissue.
- To elucidate the mechanisms of ADR-induced CNS injury.
- To explore the role of tumor necrosis factor-alpha (TNF) in ADR neurotoxicity.
Main Methods:
- Systemic ADR injection in mice.
- Detection of ADR autofluorescence and TNF alpha immunoreactivity in brain tissue.
- Assessment of brain mitochondrial respiration, apoptosis markers (cytochrome c, caspase 3, TUNEL), and apoptotic protein levels (p53, Bax, Bcl-xL).
- Evaluation of the effect of anti-TNF antibodies on ADR-induced brain injury.
Main Results:
- ADR detected outside the blood-brain barrier; increased TNF alpha in cortex and hippocampus.
- ADR treatment reduced mitochondrial respiration and induced apoptosis in brain tissue.
- Upregulation of pro-apoptotic proteins (p53, Bax) and altered anti-apoptotic protein (Bcl-xL) levels observed.
- p53 migrated to mitochondria, interacting with Bcl-xL.
- Neutralizing TNF antibodies prevented ADR-induced mitochondrial injury and TNF elevation in the brain.
Conclusions:
- Systemic adriamycin (ADR) causes CNS injury, contrary to the belief that the blood-brain barrier prevents neurotoxicity.
- Tumor necrosis factor-alpha (TNF) plays a critical role in mediating ADR-induced brain mitochondrial dysfunction and apoptosis.
- Targeting circulating TNF represents a potential therapeutic strategy to mitigate ADR-induced CNS side effects.
Related Concept Videos
01:29Drugs Affecting Neurotransmitter Synthesis
Drugs affecting neurotransmitter synthesis can impact the adrenergic neuron and the synthesis of neurotransmitters. For example, α-methyltyrosine and carbidopa target specific enzymes involved in catecholamine synthesis. α-methyltyrosine inhibits the enzyme tyrosine hydroxylase, which converts tyrosine into dopamine. By blocking this enzyme, α-methyltyrosine reduces dopamine production and other catecholamines. Carbidopa, on the other hand, inhibits the enzyme dopa decarboxylase, which converts...
01:12Local Anesthetics: Adverse Effects
While local anesthetics are generally safe and well-tolerated, they can occasionally cause adverse effects that vary in severity. Local anesthetics can induce toxicity at two distinct levels. They can either produce local effects through direct contact with the neural elements or be absorbed into the bloodstream from the injection site, leading to systemic effects.
Once absorbed into the systemic circulation, local anesthetics can affect the organs that depend on the functioning of sodium...
Once absorbed into the systemic circulation, local anesthetics can affect the organs that depend on the functioning of sodium...
01:27Cryptococcal Meningitis
Cryptococcal meningitis is a life-threatening opportunistic infection predominantly associated with HIV/AIDS, accounting for over 100,000 deaths annually worldwide. However, it also affects individuals with other forms of immunosuppression, including those undergoing immunosuppressive therapy, organ transplant recipients, patients with innate immunodeficiencies, and individuals with hematological disorders. The infection is caused mainly by Cryptococcus neoformans and Cryptococcus gattii,...
01:24Drug Toxicity: Dose-Dependent Reactions
Drug toxicities can be stratified into pharmacological, pathological, or genotoxic based on their mechanisms. The incidence and severity of these toxicities generally increase with the drug's concentration in the body and exposure time.Pharmacological toxicity is evident when the therapeutic effects of drugs overshoot into adverse reactions in a predictable, dose-dependent manner. Central nervous system (CNS) depression from barbiturates is a classic example, with effects escalating from...
01:24Drugs for Treatment of Crohn's Disease in IBD Using Biologic Agents: Anti-TNF
Tumor Necrosis Factor (TNF), a proinflammatory cytokine, contributes significantly to the inflammation seen in Crohn's disease. It exists as soluble TNF and membrane-bound TNF, with actions mediated through TNF receptors (TNFR). TNFR activation leads to the release of proinflammatory cytokines, T-cell activation, collagen production, and leukocyte migration, all contributing to inflammation in Crohn's disease. Anti-TNF monoclonal antibodies, namely infliximab (Remicade), adalimumab (Humira),...
01:20Desensitization and Tachyphylaxis
Tachyphylaxis is described as a rapid decrease in response to a drug after repeated or continuous administration of the same drug dose. It is a phenomenon where the body becomes less responsive to a particular substance or intervention over time, requiring higher doses or stronger interventions to achieve the same effect. It results from adaptive changes in the body's receptors, signaling pathways, or physiological processes that occur in response to prolonged exposure to a stimulus.
Several...
Several...