Tianeptine, but not other antidepressants, improves rat brain mitochondrial efficiency

R Bains1, A Markham1, M Spedding2, P Franklin1. 1School of Pharmacy, Health and Well-being, University of Sunderland, SR1 3SD, UK, Sunderland, UK, 2Spedding Research Solutions SARL, 6 Rue Ampere, Le Vesinet, 78110, Paris, France

Impairments in cellular resistance and neuroplasticity caused by stress and depression are thought to underlie the key changes seen in mood disorders (Manji et al., 2001). Neurotrophic factors such as BDNF enhance cell survival through signalling pathways. Chronic administration of antidepressants increases BDNF expression and function (Reus et al., 2012; Hodes et al., 2010). BDNF has been shown to improve mitochondrial respiratory efficiency (Markham et al., 2004). We wished to examine the effects of antidepressants on mitochondrial function to see if in addition to chronic effects they could modify mitochondrial respiration directly.

Forebrains from female Wistar rats (250-300g) were rapidly removed and placed in isolation buffer containing 220mM mannitol, 60mM sucrose, 5mM Tris-HCl, 0.5mM EGTA and 1mg ml-1 bovine serum albumin (BSA; fatty acid free) pH 7.4. Homogenates were centrifuged at 2,000 rpm for 6 min at 0-4°°C and the resulting supernatant decanted off and spun for 8 min at 10,000 rpm. The pellet produced was resuspended in 9 ml of buffer and aliquots layered onto 10 ml ice-cold Percoll solution containing 250mM sucrose, 5mM Tris-HCl, 0.1mM EGTA and 18% (w/v) Percoll, pH 7.4. The resulting density gradient was centrifuged at 10,000 rpm for 45 min. A loose mitochondrial pellet, free from most contamination, was formed at the bottom of the tube with a synaptosomal fraction forming a separate layer at the top of the tube. The two layers were then isolated and centrifuged at 10,000 rpm in isolation buffer minus EGTA (incubation buffer) to remove the Percoll.

Oxygen consumption was measured polarographically (Sweetman & Weetman, 1972) using a Clark-type oxygen electrode (Rank Bros, Bottisham, UK). Respiratory studies were performed after the method of Markham et al., (2004) and recorded on a Kipp and Zonen Flat bed recorder. Calculating the RCI (Respiratory Control Index; a measure of the efficiency of respiratory coupling) assessed mitochondrial integrity. Data were analysed using a one-way ANOVA followed by Dunnett’s post-test.

Tianeptine (10μM) significantly increased RCI for succinate supported respiration from control 5.67 ± 0.39 to 7.53 ± 0.25 (p<0.05, n=9). Sertraline, S-citalopram, imipramine, venlafaxine and fluoxetine, all 10μM, had no significant effect on mitochondrial respiration. None of the antidepressants (10μM) had a significant effect on glutamate plus malate respiration.

Tianeptine has been shown to have neuroprotective effects in animal models of stress (Della et al., 2012) via an antioxidant effect. It may also have beneficial actions by modifying mitochondrial respiration and improving respiratory efficiency.

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