Prolyl oligopeptidase (POP) has been connected to memory and mood through regulation of the brain levels of its biologically active peptide substrates and phosphatidylinositol system. This is the first study in a radial-arm maze of the effects of a single dose of a novel potent prolyl oligopeptidase inhibitor, KYP-2047 (5 mg ⁄ kg, dissolved in 5% Tween 80), on memory and learning of scopolamine-treated (0.4 mg ⁄ kg, dissolved in saline) rats. Habituated (days 1 and 2) and trained (days 3-11) young (3 months) and old (8-9 months) male Wistar rats were given (i) saline + Tween, (ii) saline + KYP-2047, (iii) scopolamine + Tween or (iv) scopolamine + KYP-2047 30 min. prior to testing their memory. Food rewards located in four randomly chosen arms of the maze. The rat had 10 min. to find and eat the rewards. Time spent in the maze, visits to each arm and number of eaten rewards were measured. Old rats made generally more errors, spent more time and visited fewer arms per minute in the maze than young rats. The memory-and function-impairing effects of scopolamine were also seen more clearly in old than young rats. KYP-2047 had no or only a marginal effect on memory of either age group, but when given without scopolamine, it slightly increased the maze motility of young rats and decreased the motility of old rats. In a separate locomotor activity test, KYP-2047 enhanced the motility of young rats supporting a suggested role of POP in motor functions.
Prolyl oligopeptidase (PREP) is an intracellular enzyme digesting small proline-containing peptides. Since PREP resides the same brain areas as neurotensin in the nigrostriatal and mesolimbic dopaminergic pathways, we were interested to study if there is an intracellular interaction between them. A colocalization of PREP with neurotensin and neurotensin receptor 1 (NTS1) in the rat striatum, nucleus accumbens (NAcc), substantia nigra (SN) and ventral tegmental area (VTA) was studied with immunofluorescence. From the same brain areas, the levels of dopamine and its metabolites were measured 1 h after the injection of saline, NTS1 ligands (JMV-449; 5 μg) or antagonist (SR142948; 5 μg) to the rat striatum or NAcc. We also studied whether an intraperitoneal injection of a PREP inhibitor (KYP-2047; 5 mg/kg) affects the levels of dopamine and its metabolites alone or modifies the effects of the NTS1 ligands. PREP was highly colocalized with neurotensin and NTS1 in the VTA, and with NTS1 in the SN. Colocalization was moderate or low in other brain areas. When injected to the striatum, JMV-449 had a tendency to increase dopamine (p = 0.052) and metabolite levels in the striatum and SN, whereas SR142948 did not. After the injection to the NAcc, JMV-449 but not SR142948, increased dopamine levels in the VTA and dopamine metabolite levels in the NAcc and VTA. KYP-2047 decreased the dopamine levels in the striatum, but increased dopamine metabolite levels in the NAcc and VTA. Our results suggest a novel role for PREP in the modulation of dopaminergic transmission, which may be different in nigrostriatal and mesolimbic pathways.
Prolyl oligopeptidase (POP), is an 80-kDa serine protease that hydrolyzes peptides smaller than 30-mer at the carboxyl side of an internal proline-residue. POP is commonly believed to cleave a number of neuropeptides claimed to be involved in learning, memory and mood. While the support to the neuropeptide cleavage theory has been declining, new data suggest novel functions for POP, e.g. as a regulator of protein secretion, α-synuclein aggregation and cell proliferation/differentiation. Intriguingly, many of these novel functions may not depend on the hydrolytic activity of POP. One of the new roles is an involvement of POP in neurotransmission. Indeed, POP has been associated with a variety of different neurotransmitters. According to our previous results, POP is located in GABAergic and cholinergic neurotransmitter systems and in short glutamatergic projection neurons between cortex and thalamus. Based on these findings, POP may be involved in inhibitory and excitatory signal transmission and in the thalamocortical and corticothalamic signalling in the brain. It has also been shown that POP inhibition can affect the functions of neurotransmitters and that the ligands of neurotransmitter receptors can alter the activity of POP. Thus, there is a connection between the neurotransmitters and POP, although the mechanisms and the functional significance of this linkage are still unknown. Here, we will review the data about the connections of POP with conventional neurotransmitter systems and provide an overview of the role of POP in neurotransmission.
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