Brain creatine kinase activity is increased by chronic administration of paroxetine

Abstract

Major depression is a serious and recurrent disorder often manifested with symptoms at the psychological, behavioral, and physiological levels. In addition, several works also suggest brain metabolism impairment as a mechanism underlying depression. Creatine kinase (CK) plays a central role in the metabolism of high-energy consuming tissues such as brain, where it functions as an effective buffering system of cellular ATP levels. Considering that CK plays an important role in brain energy homeostasis and that some antidepressants may modulate energy metabolism, we decided to investigate CK activity from rat brain after chronic administration of paroxetine (selective serotonin reuptake inhibitor), nortriptiline (tricyclic antidepressant) and venlafaxine (selective serotonin-norepinephrine reuptake inhibitor). Adult male Wistar rats received daily injections of paroxetine (10 mg/kg), nortriptiline (15 mg/kg), venlafaxine (10 mg/kg) or saline in 1.0 mL/kg volume for 15 days. Twelve hours after the last administration, the rats were killed by decapitation, the hippocampus, striatum and prefrontal cortex were immediately removed, and activity of CK was measured. Our results demonstrated that chronic administration of paroxetine increased CK activity in the prefrontal cortex, hippocampus and striatum of adult rats. On the other hand, nortriptiline and venlafaxine chronic administration did not affect CK activity in these brain areas. In order to verify whether the effect of paroxetine on CK is direct or indirect, we also measured the in vitro effect of this drug on the activity of the enzyme. We verified that paroxetine did not affect CK activity in vitro. Considering that metabolism impairment is probably involved in the pathophysiology of depressive disorders, an increase in CK activity by antidepressants may be an important mechanism of action of these drugs.

Proteomic investigation of the prefrontal cortex in the rat clomipramine model of depression

“…The increase in the level of CKB in the serum of non-psychotic major depression patients had been revealed previously in comparison with other types of depression syndromes [42], and in the serum of bipolar disorder patients in manic phase [43]. The activity of this protein was also increased in the PFC of rats after chronic treatment with the antidepressant paroxetine [44]. On the other hand, both isoforms of creatine kinase have been found to be downregulated in the dorsolateral prefrontal cortices of bipolar disorder patients [45].…”

A pilot dose-finding clinical trial of creatine monohydrate augmentation to SSRIs/SNRIs/NASA antidepressant treatment in major depression

“…Such a common mechanism to both creatine and SSRIs/SNRIs/ NASA may be related, on the one hand, to its effects on serotononergic systems [see Allen et al (2010) for Creatine in depression Nemets and Levine 131 possible creatine interaction with the serotononinergic system]. On the other hand, such a common mechanism of action may relate to the Cr/PCr brain system, as previous studies showed that antidepressant treatment is associated with increased brain creatine and/or phosphocreatine levels (Pettegrew et al, 2002;Sartorius et al, 2003;Silveri et al, 2003;Lugenbiel et al, 2010) and Santos et al (2009) reported that paroxetine (but not venlafaxine) increases brain creatine kinase activity (suggested to induce increased synthesis of creatine phosphate from creatine). Yet, such a common mechanism may involve glutamatergic systems, as these were suggested to be involved in the action of certain antidepressants [i.e.…”

Metabonomic Evaluation of Chronic Unpredictable Mild Stress-Induced Changes in Rats by Intervention of Fluoxetine by HILIC-UHPLC/MS

“…Creatine is widely distributed in the muscles, brain, heart and other tissues, and can be catalyzed by creatine kinase into phosphocreatine and adensine diphosphate (ADP), making the creatine-creatine phosphate system under dynamic equilibrium. The creatine-creatine phosphate system can regulate the energy homeostasis by the action of energy buffer, energy transport and metabolic regulation [28, 29] . Creatine can benefit the supplement of energy in brain, in order to maintain the ATP levels of nerve cell activity.…”