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Fluoxetine Protection in Decompression Sickness in Mice is Enhanced by Blocking TREK-1 Potassium Channel with the
Nicolas Vallée1, Kate Lambrechts2, Sébastien De Maistre3
1Institut de Recherche Biomédicale des Armées, Equipe Résidante de Recherche Subaquatique Opérationnelle Toulon, France.
Abstract:
In mice, disseminated coagulation, inflammation, and ischemia induce neurological damage that can lead to death. These symptoms result from circulating bubbles generated by a pathogenic decompression. Acute fluoxetine treatment or the presence of the TREK-1 potassium channel increases the survival rate when mice are subjected to an experimental dive/decompression protocol. This is a paradox because fluoxetine is a blocker of TREK-1 channels. First, we studied the effects of an acute dose of fluoxetine (50 mg/kg) in wild-type (WT) and TREK-1 deficient mice (knockout homozygous KO and heterozygous HET). Then, we combined the same fluoxetine treatment with a 5-day treatment protocol with spadin, in order to specifically block TREK-1 activity (KO-like mice). KO and KO-like mice were regarded as antidepressed models. In total, 167 mice (45 WTcont 46 WTflux 30 HETflux and 46 KOflux) constituting the flux-pool and 113 supplementary mice (27 KO-like 24 WTflux2 24 KO-likeflux 21 WTcont2 17 WTno dive) constituting the spad-pool were included in this study. Only 7% of KO-TREK-1 treated with fluoxetine (KOflux) and 4% of mice treated with both spadin and fluoxetine (KO-likeflux) died from decompression sickness (DCS) symptoms. These values are much lower than those of WT control (62%) or KO-like mice (41%). After the decompression protocol, mice showed significant consumption of their circulating platelets and leukocytes. Spadin antidepressed mice were more likely to exhibit DCS. Nevertheless, mice which had both blocked TREK-1 channels and fluoxetine treatment were better protected against DCS. We conclude that the protective effect of such an acute dose of fluoxetine is enhanced when TREK-1 is inhibited. We confirmed that antidepressed models may have worse DCS outcomes, but concomitant fluoxetine treatment not only decreased DCS severity but increased the survival rate.
Insights
Acute fluoxetine treatment enhances survival from decompression sickness (DCS) in mice, especially when TREK-1 channels are inhibited. This study reveals a protective effect against DCS, even in models mimicking depression.
Area of Science:
- Neuroscience
- Pharmacology
- Physiology
Background:
- Decompression sickness (DCS) in mice involves neurological damage, coagulation, inflammation, and ischemia, often leading to death.
- Pathogenic decompression causes circulating bubbles, triggering DCS symptoms.
- Fluoxetine treatment and TREK-1 potassium channel presence increase survival rates during experimental dive/decompression protocols, presenting a paradox as fluoxetine blocks TREK-1.
Purpose of the Study:
- To investigate the paradoxical protective effects of acute fluoxetine treatment on DCS in wild-type (WT) and TREK-1 deficient mice.
- To examine the combined effects of fluoxetine and spadin (a TREK-1 inhibitor) on DCS outcomes, using TREK-1 deficient mice as antidepressed models.
- To determine if inhibiting TREK-1 activity enhances fluoxetine's protective effects against DCS.
Main Methods:
- Acute fluoxetine (50 mg/kg) treatment was administered to wild-type (WT), TREK-1 deficient (KO), and heterozygous (HET) mice.
- A 5-day spadin treatment protocol was used to block TREK-1 activity, creating 'KO-like' (antidepressed) models, which were then treated with fluoxetine.
- Survival rates and DCS symptom severity were assessed in 167 mice (flux-pool) and 113 supplementary mice (spad-pool) after a decompression protocol.
Main Results:
- Survival rates were significantly higher in mice with inhibited TREK-1 channels: only 7% of KO mice treated with fluoxetine (KOflux) and 4% of mice treated with both spadin and fluoxetine (KO-likeflux) died from DCS.
- WT control mice (62% mortality) and KO-like mice (41% mortality) exhibited much higher DCS-related death rates.
- Mice showed significant consumption of platelets and leukocytes post-decompression; however, concomitant fluoxetine treatment decreased DCS severity and increased survival, particularly when TREK-1 was inhibited.
Conclusions:
- The protective effect of acute fluoxetine against DCS is significantly enhanced by the concurrent inhibition of TREK-1 channels.
- Antidepressed models (KO and KO-like mice) may exhibit worse DCS outcomes, but fluoxetine treatment mitigates this, improving survival and reducing severity.
- These findings suggest a novel therapeutic strategy for DCS by combining fluoxetine with TREK-1 inhibition.
