Ghrelin, paraoxonase and arylesterase levels in depressive patients before and after citalopram treatment

Abstract

Objectives

The purpose of this study was to examine alterations in lipid profiles and in the serum concentrations of acylated and desacylated ghrelin, paraoxonase and arylesterase in psychiatric patients before and after treatment with 40 mg citalopram daily for 3 months.

Design and methods

Samples were collected from 22 healthy controls and 24 psychiatric patients before and after citalopram treatment. Blood levels of acylated and desacylated ghrelin were measured by radioimmunoassay. Paraoxonase and arylesterase activities were determined spectrophotometrically. Lipid parameters were measured on the OLYMPUS-AU400.

Results

It was found that the levels of acylated, desacylated ghrelin, paraoxonase arylesterase, total cholesterol and triglyceride were lower in depressive patients before citalopram treatment than in the control group. Those parameters were not restored after citalopram treatment except for the arylesterase level.

Conclusion

Decreased PON1 and ghrelin levels as well as fluctuations in lipid profiles may be involved in the etiology of depressive disorders.

Introduction

Depression, which is common in developed and developing countries, is among the major diseases of our era. This disease, which is characterized by despondency, apathy, indifference and anhedonia, behavioral sluggishness and increasing inactivity, cognitive feelings of guilt, pessimism, regret and low self-worth, psychophysiological disturbances of sleep and appetite and lack of sexual desire, influences all metabolic functions in the organism. ECA (Epidemiological Catchment Area) studies suggest that the disease, for which the mean age of onset is 27 years and the incidence varies between 9% and 20% [1], is twice as common in women as in men [2].

Drugs used in the treatment of depression influence either weight gain or weight loss through the endocrine system. Several hormones act on weight regulation. One of these is the most recently discovered such hormone, ghrelin [3], which is synthesized by many organs and tissues. Although the main site of ghrelin synthesis is considered to be the stomach [4], comparison of total ghrelin levels in different tissues on a mg basis showed that the kidneys synthesize more than the stomach. Besides its main function of regulating weight, ghrelin is also reported to increase growth hormone (GH) release, adrenocorticotropic hormone (ACTH) and prolactin secretion, nutrition, gastric acid secretion, gastric motility and cell proliferation [5], [6].

Recent studies have shown that ghrelin also inhibits serotonin secretion [7]. Citalopram, which is commonly used to treat major depression, is a selective serotonin [5-HT (5-hydroxytryptamine)] reuptake inhibitor (SSRI) [8], [9]. Preliminary findings about serotonin in depression indicate that the level of its major metabolite, 5-hydroxyacetic acid (5-HIAA), is low in cerebrospinal fluid (CSF) [10], [11]. Drugs in the selective serotonin reuptake inhibitor (SSRI) group, such as citalopram, inhibit this reuptake and thus induce an increase in serotonin in the synaptic gap [12]. These data imply that there may be a correlation between circulating levels of ghrelin and depression.

Ghrelin is found in two major forms in biological fluids. When caprylic acid is bound to the 3rd serine residue from the N-terminal end, the hormone is called acylated ghrelin; when there is no such binding it is called desacylated ghrelin. There is less of the acylated form than the desacylated form in biological fluids. Acylated ghrelin is the first known peptide hormone with a bound fatty acid, so it is also called the lipopeptide hormone [5]. This hormone, a peptide of 28 amino acids, is transported in the circulation bound to very high-density lipoprotein (VHDL) and high-density lipoprotein (HDL). Paraoxonase and ghrelin are reported to have an HDL-linked antioxidant capacity. Antioxidant capacity decreases in depression. These findings suggest that both ghrelin and paraoxonase may be closely correlated with lipid profiles [13].

Paraoxonase-1 (PON1) was first found in human serum by Uriel [14]. It is a glycoprotein with 354 amino acids and can hydrolyze paraoxon, a potent inhibitor of cholinesterase. Mackness et al. demonstrated that PON1 is transported with HDL in the blood [15]. For the first few years after its discovery it was studied mainly by toxicologists because it can hydrolyze organophosphate compounds, but it has recently come to the fore thanks to its antioxidant property [16]. The gene coding for paraoxonase is located in the q21–22 area of the long arm of chromosome 7 in humans and on chromosome 6 in mice. Humans and mice have three different PON genes (PON1, PON2, and PON3) closely juxtaposed on the same chromosome. PON1 and PON3 enzymes are associated with HDL and can prevent low-density lipoprotein (LDL) oxidation. PON2, which is not associated with HDL, also prevents LDL oxidation, thereby inhibiting monocyte chemotaxis induced by oxidized LDL [17]. PON2 and PON3 cannot hydrolyze paraoxon as they have no lysine residue at position 105 [18]. Although paraoxonase and arylesterase [(ARE) E.C.3.1.1.2] are considered two different enzymes, previous studies have shown that a single gene product in human serum has both ARE and PON activities [18]. Paraoxonase/arylesterase, which has an approximate molecular weight of 43–46 kDa, needs Ca⁺² for stability and activity. Human serum paraoxonase displays two genetic polymorphisms. It has been shown that replacement of glutamine-192 (Q allele) by arginine (R allele) resulted in the 1st polymorphism, and replacement of leucine-55 (L allele) with methionine (M allele) resulted in the 2nd polymorphism [19], [20].

As indicated above, acylated and desacylated ghrelin are linked with VHDL and HDL in the circulation [13]. Paraoxonase is an important liver enzyme that can hydrolyze paraoxon (PON1, EC3.1.8.1), which is also bound to HDL in the blood [16]. There is a significant relationship between lipid profiles and psychiatric disorders [21]. Furthermore, the most common side effect of citalopram in patients is weight gain, and numerous studies point to a correlation between ghrelin and weight gain [22]. Thus, the aim of this study was to examine changes in the levels of acylated and desacylated ghrelin and paraoxonase/arylesterase and in lipid parameters and BMI in psychiatric patients before and after treatment with citalopram.