Fluoxetine Protection in Decompression Sickness in Mice is Enhanced by Blocking TREK-1 Potassium Channel with the “spadin” Antidepressant

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.

Thirty-five Day Fluoxetine Treatment Limits Sensory-Motor Deficit and Biochemical Disorders in a Rat Model of Decompression Sickness

“…This is generally attributed to prothrombotic phenomena and an inflammation causing diapedesis. However, the reduction in the number of leukocytes was significantly lower in the Flux rats, which implies that fluoxetine would reduce diapedesis, as has been observed in previous studies (Blatteau et al, 2012 , 2015 ; Vallee et al, 2016 ). These effects are generally attributed either to the direct interaction of bubbles circulating with the platelets, or to the abrasion of the endothelial cells by these circulating bubbles (Nossum et al, 1999 , 2002 ).…”

“…In animals, we have been able to demonstrate (Blatteau et al, 2012 , 2015 ; Vallee et al, 2016 ) that fluoxetine administered at a high dose before hyperbaric exposure presents a curative interest in the event of the occurrence of decompression sickness. Several hypotheses could explain the beneficial effect of fluoxetine on DCS.…”

“…The acute dose of fluoxetine (50 mg/kg), as opposed to the lower chronic dose of 20 mg/kg, delivers better neuroprotection against decompression sickness when the TREK 1 channels have previously been blocked by spadin (Vallee et al, 2016 ): they inhibit NMDA-R receptors, regulate the inflammatory effects, and have analgesic properties. This same acute dose of 50 mg/kg administered alone seems to have less effect (Blatteau et al, 2012 , 2015 ).…”

“…The Severe DCS status was attributed when the rat presented severe locomotor signs in the form of paresia or paralysis of at least 1 limb and/or a beam walk test score reduced by at least two points. The DCS status includes rats without serious motor symptoms, with high transaminase values (±10% of extreme values for the controls) suggesting the presence of bubbles in the liver (L'abbate et al, 2010 ; Vallee et al, 2016 ). The other rats were considered as No DCS.…”

“…This counters the reduction in the neuroprotective cell excitability exercised by TREK 1. Our previous studies, which blocked the TREK 1 channel, either by using native KO mice (Vallee et al, 2012 ), or by internalizing the channel pharmacologically with spadin (Vallee et al, 2016 ), to have “anti-depressed” mice models, have highlighted increased susceptibility to decompression sickness with an unfavorable prognosis for survival (Vallee et al, 2012 , 2016 ). Then, Baek et al ( 2015 ) observed that in mice treated for more than 14 days, fluoxetine increased inflammatory intestinal problems, contrary to the anti-inflammatory action observed during a single acute dose.…”