Mechanisms for Interferon-α-Induced Depression and Neural Stem Cell Dysfunction

Abstract

SummaryNew neurons generated by the neural stem cells (NSCs) in the adult hippocampus play an important role in emotional regulation and respond to the action of antidepressants. Depression is a common and serious side effect of interferon-α (IFN-α), which limits its use as an antiviral and antitumor drug. However, the mechanism(s) underlying IFN-induced depression are largely unknown. Using a comprehensive battery of behavioral tests, we found that mice subjected to IFN-α treatment exhibited a depression-like phenotype. IFN-α directly suppressed NSC proliferation, resulting in the reduced generation of new neurons. Brain-specific mouse knockout of the IFN-α receptor prevented IFN-α-induced depressive behavioral phenotypes and the inhibition of neurogenesis, suggesting that IFN-α suppresses hippocampal neurogenesis and induces depression via its receptor in the brain. These findings provide insight for understanding the neuropathology underlying IFN-α-induced depression and for developing new strategies for the prevention and treatment of IFN-α-induced depressive effects.

Interferon-alpha treatment induces depression-like behaviour accompanied by elevated hippocampal quinolinic acid levels in rats

“…IFN-␣ has previously been shown to induce depression-like behaviour in both clinical [2,22,23,] and pre-clinical studies [20,25,36,37], although some studies have not found the same [6,33]. The inconsistency may arise from the IFN-␣ type, as some human IFN-␣ does not have biological activity in rodents, as discussed by [6,17,33].…”

“…Indeed, we found a positive correlation between immobility and hippocampal quinolinic acid levels. Interestingly, recent findings have revealed that IFN-␣ suppresses hippocampal neural stem cell proliferation and reduces neurogenesis in hippocampus of mice with IFN-␣-induced depression-like behaviour [37]. Thus, it is possible that the increased quinolinic acid level arise form activated hippocampal microglia producing the neurotoxic compound that can affect neurogenesis.…”

HSV targeting of the host phosphatase PP1α is required for disseminated disease in the neonate and contributes to pathogenesis in the brain

“…A dampened type I IFN response in the brain may be important for proper development of the newborn brain because multiple lines of evidence suggest that altering the cytokine balance in the brain can have profound developmental consequences (36,37). Specifically, intracranial inoculation of type I IFNs alone in mice has been shown to result in neurologic deficits later in life (38). Taken together, these results may suggest specific dampening of the IFN response in the newborn brain to avoid a cytokine response that could be detrimental to proper development.…”

Influence of Recombinant Interferon Alfa on Electric Activity and Isolated Heart Metabolism

“…Ці властивості обумовлюють застосування інтер-феронів під час розвитку інфекції, канцерогенезі [14]. Відомо, що ІФН діє на клітини ендотелію, спричиняючи антиангіогенний ефект [6; 9].…”

“…Інтерферони (ІФН) являють собою ро-дину цитокінів з плейотропною дією, що включає в себе інгібування вірусної реплікації, клітинної про-ліферації і активацію імунної системи. Рецептори до ІФНів експресуються на всіх клітинах організму.Ці властивості обумовлюють застосування інтер-феронів під час розвитку інфекції, канцерогенезі [14]. Відомо, що ІФН діє на клітини ендотелію, спричиняючи антиангіогенний ефект [6; 9].…”