Proteomic analysis of rat hippocampus exposed to the antidepressant paroxetine

Abstract

Antidepressant drugs can exert significant effects on the mood of a patient suffering major depression and other disorders. These drugs generally have pharmacological actions on the uptake or metabolism of the neurotransmitters serotonin, noradrenaline and, to a lesser extent, dopamine. However, there are many aspects of antidepressant action we do not understand. We have applied proteomic analysis in a rat hippocampal model in an attempt to identify relevant molecules that operate in pathways functionally relevant to antidepressant action. Rats were administered either 5 mg/kg daily of the antidepressant paroxetine or vehicle for 12 days, then hippocampal protein was recovered and resolved by 2-D gel electrophoresis. After antidepressant exposure, we observed increased expression or modification of cytochrome c oxidase, subunit Va, cyclin-dependent kinase inhibitor 2A interacting protein, dynein, axonemal, heavy polypeptide 3 and RHO GDP-dissociation inhibitor alpha. Decreased expression or modification was observed for complexin 1 (CPLX1), alpha-synuclein, parvalbumin, ribosomal protein large P2, prohibitin, nerve growth factor, beta subunit (NGFB), peroxiredoxin 6 (PRDX6), 1-acylglycerol-3-phosphate O-acyltransferase 2_predicted, cystatin B (CYTB) and lysosomal membrane glycoprotein 1. CPLX1, the most strongly regulated protein observed, mediates the fusion of cellular transport vesicles with their target membranes and has been implicated in the pathophysiology of mood disorders, as well as antidepressant action. CPLX1 and the other proteins identified may represent links into molecular processes of importance to mood dysregulation and control, and their respective genes may represent novel candidates for studies of antidepressant pharmacogenetics.

NACP-Rep1 relates to Beck Depression Inventory Scores in Healthy Humans

“…Accordingly, antidepressant therapies, such as selective inhibitors of serotonin reuptake and non-selective inhibitors of monoamines, focus on shifting the norepinephrine and serotonin balance. Furthermore, the recent findings are also in line with a proteomic analysis of the hippocampal rat brain according to which rats that had been given paroxetin showed a pattern of dysregulated proteins crucial for synaptic function and neurotransmission, including a decreased expression of SNCA (McHugh et al 2010). Moreover, recent investigations suggest the involvement of SNCA in catelochamine synthesis (Lee et al 2001;Perez et al 2002).…”

Effects of periadolescent fluoxetine and paroxetine on elevated plus-maze, acoustic startle, and swimming immobility in rats while on and off-drug

“…Others have administered SSRIs by osmotic pump in order to maintain plasma concentrations in animals within the same range as human therapeutic concentrations [27,28]. The intent of these studies was different than ours.…”

Peroxiredoxin 6: A Bifunctional Enzyme with Glutathione Peroxidase and Phospholipase A2Activities

“…On the other side of the coin, abnormally low levels of Prdx6 have been described in cataracts of the lens (27), whereas overexpression of Prdx6 in mice protects against the development of lens opacity (44). Altered Prdx6 expression also has been reported in animal and cellular models of alcoholic liver disease (67,83), cellular premature senescence (11), and various drug treatments (melatonin, luteolin, paroxetine, ochratoxin A, and capsaicin) (3,58,92,104,105). Whether any of these associations will provide definitive insights into pathogenesis or will provide targets for therapy remains to be determined.…”