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TNF-α-induced depressive-like phenotype and p38(MAPK) activation are abolished by ascorbic acid treatment
Morgana Moretti1, Josiane Budni2, Andiara Espíndola Freitas2
1Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis 88040-900, SC, Brazil; Department of Natural Sciences, Universidade Regional de Blumenau, Blumenau 89012-900, SC, Brazil.
Abstract:
We investigated the effects of ascorbic acid on depressive-like behavior induced by tumor necrosis factor (TNF-α) in mice. Additionally, we examined the effects of combined administration of ascorbic acid and antidepressants, MK-801 and 7-nitroindazole in mice exposed or not to TNF-α and the capacity of TNF-α and ascorbic acid to modulate hippocampal and cerebrocortical phosphorylation of extracellular signal-regulated kinase (ERK), p38(MAPK) and c-Jun N-terminal kinase (JNK). In control animals, ascorbic acid reduced the immobility time in the tail suspension test (TST). Unilateral intracerebroventricular administration of TNF-α produced a depressive-like behavior in the TST, and the treatment with ascorbic acid prevented this effect. Sub-effective dose of ascorbic acid combined with sub-effective doses of fluoxetine, imipramine, bupropion, MK-801 or 7-nitroindazole produced a synergistic antidepressant-like effect in mice exposed or not to TNF-α. No treatment caused significant alterations in the locomotor activity of mice. Administration of TNF-α increased the phosphorylation of p38(MAPK) in hippocampus and cerebral cortex, and the treatment with ascorbic acid prevented this effect. Ascorbic acid increased phosphorylation of ERK1 in the hippocampus of saline- and TNF-α-treated animals, however it did not produce alterations in the cerebral cortex. No effects on phosphorylation of ERK2 or JNK were found. The observed effect of ascorbic acid seems to be associated, at least partially, with a reduced p38(MAPK) phosphorylation, activation of the monoaminergic systems as well as inhibition of N-methyl-D-aspartate (NMDA) receptors and nitric oxide (NO) synthesis.
Insights
Ascorbic acid (vitamin C) reduced depressive-like behavior in mice, counteracting tumor necrosis factor-alpha (TNF-α) effects. It also enhanced antidepressant efficacy, potentially via p38 MAPK signaling.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Tumor necrosis factor-alpha (TNF-α) is implicated in depressive disorders.
- Ascorbic acid (vitamin C) possesses potential neuroprotective and anti-inflammatory properties.
- Understanding the interplay between inflammation and depression is crucial for developing novel therapeutics.
Purpose of the Study:
- To investigate the antidepressant-like effects of ascorbic acid in a mouse model of TNF-α-induced depression.
- To evaluate the synergistic effects of ascorbic acid combined with conventional antidepressants and other agents.
- To explore the molecular mechanisms underlying ascorbic acid's actions, focusing on MAPK signaling pathways.
Main Methods:
- Depressive-like behavior was assessed using the tail suspension test (TST) in mice.
- Tumor necrosis factor-alpha (TNF-α) was administered intracerebroventricularly to induce depressive-like behavior.
- Western blotting was used to measure the phosphorylation of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK).
Main Results:
- Ascorbic acid reduced immobility in the TST and prevented TNF-α-induced depressive-like behavior.
- Combined administration of ascorbic acid with sub-effective doses of fluoxetine, imipramine, bupropion, MK-801, or 7-nitroindazole produced synergistic antidepressant effects.
- TNF-α increased p38 MAPK phosphorylation, which was prevented by ascorbic acid treatment. Ascorbic acid also increased ERK1 phosphorylation in the hippocampus.
Conclusions:
- Ascorbic acid exhibits significant antidepressant-like effects, both independently and synergistically with other antidepressants.
- These effects are associated with the modulation of p38 MAPK and potentially ERK1 phosphorylation.
- Ascorbic acid may represent a novel therapeutic strategy for depression, possibly through its anti-inflammatory and neurochemical modulatory actions.
